The Journal of Urology

Volume 178, Issue 1, Pages 1-364 (July 2007)

1. This Month in Clinical Urology Pages 1-3 Martin I. Resnick

2. This Month in Pediatric Urology Pages 5-6 Jack S. Elder

3. This Month in Investigative Urology Pages 7-8 Anthony Atala Editorials

4. Getting Through it All Page 9 Martin I. Resnick

5. β2 Microglobulin: A Surprising Therapeutic Target for Prostate Cancer and Renal Cell Carcinoma Pages 10-11 Michael R. Freeman

6. Upper Urinary Tract Cancer—Challenges for the Urologist Pages 12-13 Peter J. Bostrom and Mark S. Soloway

7. Evaluation of Nitrous Oxide Anesthesia for Endoscopic and Laparoscopic Urological Applications Page 14 Jaime Landman

Review Articles

8. Techniques for Fluoroscopic Percutaneous Renal Access Pages 15-23 Nicole L. Miller, Brian R. Matlaga and James E. Lingeman

9. The Comparative Safety of Oral Versus Intranasal Desmopressin for the Treatment of Children With Nocturnal Enuresis Pages 24-30 W.L.M. Robson, A.K.C. Leung and J.P. Norgaard Historical Article

10. The Circumcision of Jesus Christ Pages 31-34 Johan J. Mattelaer, Robert A. Schipper and Sakti Das Adult Urology

Oncology: Adrenal/Renal/Upper Tract/Bladder

11. Prognostic Impact of Tumor Size on pT2 Renal Cell Carcinoma: An International Multicenter Experience Pages 35-40 Tobias Klatte, Jean-Jacques Patard, Rakhee H. Goel, Mark D. Kleid, Francois Guille, Bernard Lobel, Clement-Claude Abbou, Alexandre De La Taille, Jacques Tostain, Luca Cindolo, et al.

12. Editorial Comment Page 40 Peter E. Clark

13. Reply by Authors Page 40

14. Comparison of 1,800 Laparoscopic and Open Partial Nephrectomies for Single Renal Tumors Pages 41-46 Inderbir S. Gill, Louis R. Kavoussi, Brian R. Lane, Michael L. Blute, Denise Babineau, J. Roberto Colombo Jr., Igor Frank, Sompol Permpongkosol, Christopher J. Weight, Jihad H. Kaouk, et al.

15. Positive Margins in Laparoscopic Partial Nephrectomy in 855 Cases: A Multi- Institutional Survey From the United States and Europe Pages 47-50 A. Breda, S.V. Stepanian, J. Liao, J.S. Lam, G. Guazzoni, M. Stifelman, K. Perry, A. Celia, G. Breda, P. Fornara, et al. 16. Editorial Comment Page 50 Surena F. Matin

17. Squamous Cell Carcinoma of the Renal Pelvis and Ureter: Incidence, Symptoms, Treatment and Outcome Pages 51-56 Sten Holmäng, Subodh M. Lele and Sonny L. Johansson

18. Urine Telomerase Activity for the Detection of Bladder Cancer in Females Pages 57-61 Sara Bravaccini, Maria Aurora Sanchini, Anna Maria Granato, Roberta Gunelli, Oriana Nanni, Dino Amadori, Daniele Calistri and Rosella Silvestrini

19. A Phase III, Multicenter Comparison of Hexaminolevulinate Fluorescence Cystoscopy and White Light Cystoscopy for the Detection of Superficial Papillary Lesions in Patients With Bladder Cancer Pages 62-67 H. Barton Grossman, Leonard Gomella, Yves Fradet, Alvaro Morales, Joseph Presti, Chad Ritenour, Unyime Nseyo and Michael J. Droller

20. A Comparison of Hexaminolevulinate Fluorescence Cystoscopy and White Light Cystoscopy for the Detection of Carcinoma In Situ in Patients With Bladder Cancer: A Phase III, Multicenter Study Pages 68-73 Yves Fradet, H. Barton Grossman, Leonard Gomella, Seth Lerner, Michael Cookson, David Albala and Michael J. Droller

21. Editorial Comment Page 73 Harry W. Herr

22. Urachal Carcinoma: Contemporary Surgical Outcomes Pages 74-78 Harry W. Herr, Bernard H. Bochner, David Sharp, Guido Dalbagni and Victor E. Reuter

23. Editorial Comment Page 78 Neil Fleshner

Urological Survey

24. Urological Oncology: Renal, Ureteral and Retroperitoneal Tumors Pages 79-80 Fray F. Marshall

25. Urolithiasis, Endourology and Laparoscopy Pages 80-81 Ralph Clayma Oncology: Prostate/Testis/Penis/Urethra

26. Decrease in Racial Disparities in the Staging Evaluation for Prostate Cancer After Publication of Staging Guidelines Pages 82-87 Nitya Abraham, Fei Wan, Chantal Montagnet, Yu-Ning Wong and Katrina Armstrong

27. Editorial Comment Page 87 Tracy M. Downs

28. Under Diagnosis and Over Diagnosis of Prostate Cancer Pages 88-92 Theresa Graif, Stacy Loeb, Kimberly A. Roehl, Sara N. Gashti, Christopher Griffin, Xiaoying Yu and William J. Catalona

29. Under Diagnosis and Over Diagnosis of Prostate Cancer in a Screening Population With Serum PSA 2 to 10 ng/ml Pages 93-97 Alexandre E. Pelzer, Jasmin Bektic, Thomas Akkad, Stefano Ongarello, Georg Schaefer, Christian Schwentner, Ferdinand Frauscher, Georg Bartsch and Wolfgang Horninger

30. Editorial Comment Page 97 H. Ballentine Carter

31. Reply by Authors Page 97

32. Clinical Judgment Analysis of the Parameters Used by Consultant Urologists in the Management of Prostate Cancer Pages 98-102 Michael G. Clarke, James R.M. Wilson, Katherine P. Kennedy and Ruaraidh P. MacDonagh 33. Does the Intrarectal Instillation of Lidocaine Gel Before Periprostatic Neurovascular Bundle Block During Transrectal Ultrasound Guided Prostate Biopsies Improve Analgesic Efficacy? A Prospective, Randomized Trial Pages 103-106 Tae Jin Yun, Hak Jong Lee, Seung Hyup Kim, Sang Eun Lee, Jeong Yeon Cho and Chang Kyu Seong

34. Finasteride Decreases the Risk of Prostatic Intraepithelial Neoplasia Pages 107-110 Ian M. Thompson, M. Scott Lucia, Mary W. Redman, Amy Darke, Francisco G. La Rosa, Howard L. Parnes, Scott M. Lippman and Charles A. Coltman

35. Editorial Comment Page 110 Yair Lotan

36. Effect of Prostate Volume on Tumor Grade in Patients Undergoing Radical Prostatectomy in the Era of Extended Prostatic Biopsies Pages 111-114 Wassim Kassouf, Hiroyuki Nakanishi, Atsushi Ochiai, Kara N. Babaian, Patricia Troncoso and R. Joseph Babaian

37. Is Routine Digital Rectal Examination Required for the Followup of Prostate Cancer? Pages 115-119 Katherine S. Warren and Jonathan P. McFarlane

38. Standard Versus Limited Pelvic Lymph Node Dissection for Prostate Cancer in Patients With a Predicted Probability of Nodal Metastasis Greater Than 1% Pages 120-124 Karim Touijer, Farhang Rabbani, Javier Romero Otero, Fernando P. Secin, James A. Eastham, Peter T. Scardino and Bertrand Guillonneau

39. Population Based Incidence and Age Distribution of Spermatocytic Seminoma Pages 125-128 Philippe Carrière, Peter Baade and Lin Fritschi

40. Bilateral Testicular Germ Cell Tumors in Turkey: Increase in Incidence in Last Decade and Evaluation of Risk Factors in 30 Patients Pages 129-133 Akdogan Bulent, Divrik Rauf Taner, Tombul Tolga, Yazici Sertac, Tasar Celik, Zorlu Ferruh and Ozen Haluk

41. Editorial Comment Page 133 W. Bedford Waters Urological Survey

42. Urological Oncology: Prostate Cancer Pages 134-137 Patrick C. Walsh

43. Urological Oncology: Testis Cancer and Advances in Oncological Therapy Pages 137-138 Jerome P. Richie

44. Urological Oncology: Bladder, Penis and Urethral Cancer, and Basic Principles of Oncology Pages 138-139 James E. Montie Infection/Inflammation

45. Combined Prednisone and Mycophenolate Mofetil Treatment for Retroperitoneal Fibrosis Pages 140-144 Paul J. Scheel Jr., Jonathan Piccini, M. Hafizur Rahman, Leo Lawler and Thomas Jarrett

46. Editorial Comment Pages 143-144 Sebastian Martini and Harm Peters

47. Effect of Comestibles on Symptoms of Interstitial Cystitis Pages 145-152 Barbara Shorter, Martin Lesser, Robert M. Moldwin and Leslie Kushner

48. Results of Cystocele Repair: A Comparison of Traditional Anterior Colporrhaphy, Polypropylene Mesh and Porcine Dermis Pages 153-156 LiAnn N. Handel, Tara L. Frenkl and Young H. Kim

49. Editorial Comment Page 156 Philippe E. Zimmern

Urological Survey

50. Infection and Inflammation of the Genitourinary Tract Pages 157-158 Richard E. Berger

51. Imaging Pages 158-159 Cary Siegel Urolithiasis/Endourology

52. Auricular Acupressure as a Treatment for Anxiety Before Extracorporeal Shock Wave Lithotripsy in the Elderly Pages 160-164 Bruno Mora, Michele Iannuzzi, Thomas Lang, Barbara Steinlechner, Renate Barker, Michael Dobrovits, Christian Wimmer and Alexander Kober

53. Editorial Comment Page 164 Robert B. Nadler

54. Percutaneous Nephrolithotripsy With the Patient in a Modified Supine Position Pages 165-168 Elias Assad Chedid Neto, Anuar Ibrahim Mitre, Cristiano Mendes Gomes, Marco Antonio Arap and Miguel Srougi

55. Editorial Comment Page 168 Manoj Monga Trauma/Reconstruction/Diversion

56. Application of Self-Expandable Metal Stents for Ureteroileal Anastomotic Strictures: Long-Term Results Pages 169-173 Evangelos N. Liatsikos, George C. Kagadis, Dimitrios Karnabatidis, Konstantinos Katsanos, Zafiria Papathanassiou, Constantinos Constantinides, Petros Perimenis, George C. Nikiforidis, Jens-Uwe Stolzenburg and Dimitrios Siablis Urological Survey

57. Trauma, and Genital and Urethral Reconstruction Pages 174-176 Allen F. Morey

58. Diagnostic Urology, Urinary Diversion and Perioperative Care Pages 176-177 Richard K. Babayan Voiding Dysfunction

59. Malignant Ureteral Obstruction: Outcomes After Intervention. Have Things Changed? Pages 178-183 Lih-Ming Wong, Laurence K. Cleeve, Alvin D. Milner and Alexander G. Pitman

60. Editorial Comment Page 183 Steven C. Campbell

61. Nitrous Oxide Inhalation to Improve Patient Acceptance and Reduce Procedure Related Pain of Flexible Cystoscopy for Men Younger Than 55 Years Pages 184-188 J.G. Calleary, J. Masood, R. Van-Mallaerts and J.M. Barua

62. Editorial Comment Page 188 Stanley Zaslau

63. Urethral and Bladder Current Perception Thresholds: Normative Data in Women Pages 189-192 Kimberly Kenton, Jennifer Simmons, Mary Pat FitzGerald, Lior Lowenstein and Linda Brubaker

64. Editorial Comment Page 192 Jean-Jacques Wyndaele

65. The Volume at Which Women Leak First on Urodynamic Testing is Not Associated With Quality of Life, Measures of Urethral Integrity or Surgical Failure Pages 193-196 Lior Lowenstein, Yashika Dooley, Kimberly Kenton, Leslie Rickey, Mary Pat FitzGerald, Elizabeth Mueller and Linda Brubaker

66. Sacral Neuromodulation for Nonobstructive Urinary Retention—Is Success Predictable? Pages 197-199 Meidee Goh and Ananias C. Diokno

67. Editorial Comment Page 199 Toby C. Chai

68. Reply by Authors Page 199

69. The Effects of Long-Term Administration of Oral Desmopressin on the Baseline Secretion of Antidiuretic Hormone and Serum Sodium Concentration for the Treatment of Nocturia: A Circadian Study Pages 200-203 J.H. Bae, M.M. Oh, K.S. Shim, J. Cheon, J.G. Lee, J.J. Kim and D.G. Moon

70. The Surgical Management of Obstructive Stents Used for Urethral Strictures Pages 204-207 Abdelwahab A. Elkassaby, Ahmed M. Al-Kandari and Ahmed A. Shokeir

71. Relationship Between the Integrity of the Pelvic Floor Muscles and Early Recovery of Continence After Radical Prostatectomy Pages 208-211 Cheryn Song, Chin Kyung Doo, Jun-Hyuk Hong, Myung-Soo Choo, Choung-Soo Kim and Hanjong Ahn

72. Impact of Unilateral Sural Nerve Graft on Recovery of Potency and Continence Following Radical Prostatectomy: 3-Year Longitudinal Study Pages 212-216 Shunichi Namiki, Seiichi Saito, Haruo Nakagawa, Takehiko Sanada, Atsushi Yamada and Yoichi Arai

73. Editorial Comment Page 216 Arthur L. Burnett Urological Survey

74. Voiding Function and Dysfunction, Bladder Physiology and Pharmacology, and Female Urology Pages 217-222 Alan J. Wein

75. Benign Prostatic Hyperplasia Pages 222-224 Steven A. Kaplan

Transplantation/Vascular Surgery

76. Anesthesia for Laparoscopic Donor Nephrectomy: Is Nitrous Oxide Contraindicated? Pages 225-227 Rizk El-Galley, Lee Hammontree, Donald Urban, Albert Pierce and Yasser Sakawi

77. Editorial Comment Page 227 Jay B. Brodsky and Harry J.M. Lemmens Urological Survey

78. Renal Transplantation and Renovascular Hypertension Page 228 David A. Goldfarb Sexual Function/Infertility

79. Indwelling Ureteral Stents and Sexual Health: A Prospective, Multivariate Analysis Pages 229-231 M.C. Sighinolfi, S. Micali, S. De Stefani, A. Mofferdin, A. Grande, M. Giacometti, N. Ferrari, M. Rivalta and G. Bianchi

80. Ejaculatory Disorders May Affect Screening for Prostate Cancer Pages 232-238 Jochen Walz, Paul Perrotte, Andrea Gallina, Francois Bénard, Luc Valiquette, Michael McCormack, Francesco Montorsi and Pierre I. Karakiewicz

81. Editorial Comment Pages 237-238 Andrea Salonia Urological Survey

82. Male and Female Sexual Function and Dysfunction; Andrology Pages 239-241 Allen Seftel

83. Male Infertility Pages 242-244 Craig Niederberger

Pediatric Urology

84. Management of High Grade Renal Trauma: 20-Year Experience at a Pediatric Level I Trauma Center Pages 246-250 C.G. Henderson, S. Sedberry-Ross, R. Pickard, D.I. Bulas, B.J. Duffy, D. Tsung, M.R. Eichelberger, A.B. Belman and H.G. Rushton

85. Editorial Comment Page 250 Richard A. Santucci

86. Ectopic Ureterocele: Long-Term Results of Open Surgical Therapy in 54 Patients Pages 251-254 Aida Beganović, Aart J. Klijn, Pieter Dik and Tom P.V.M. De Jong

87. Kidney Folding: The Y-Plasty—A Means of Creating a Dependent Ureteropelvic Junction in the Child With Giant Hydronephrosis Pages 255-258 A. Barry Belman and H. Gil Rushton

88. Myocyte Apoptosis in Primary Obstructive Megaureters: The Role of Decreased Vascular and Neural Supply Pages 259-264 Seyedmehdi Payabvash, Abdol-Mohammad Kajbafzadeh, Seyed Mohammad Tavangar, Maryam Monajemzadeh and Zhina Sadeghi

89. Editorial Comment Page 264 Christian Schwentner

90. Reply by Authors Page 264

91. Durability of a Single Successful Endoscopic Polytetrafluoroethylene Injection for Primary Vesicoureteral Reflux: 14-Year Followup Results Pages 265-268 Selçuk Yücel, Tufan Tarcan and Ferruh S ims ek

92. Editorial Comment Page 268 Andrew J. Kirsch

93. Reply by Authors Page 268 94. Vesicoscopic Cross-Trigonal Ureteral Reimplantation: A Minimally Invasive Option for Repair of Vesicoureteral Reflux Pages 269-273 Stephen J. Canon, Venkata R. Jayanthi and Ashay S. Patel

95. Editorial Comment Page 273 Ricardo González

96. Reply by Authors Page 273

97. Kidney Transplantation in Children With Augmentation Cystoplasty Pages 274-277 Abbas Basiri, Hassan Otoukesh, Nasser Simforoosh, Rozita Hosseini and Farhat Farrokhi

98. Editorial Comment Page 277 Bedeir Ali-El-Dein

99. Outcomes of Delayed Hypospadias Repair: Implications for Decision Making Pages 278-281 Jennifer L. Dodson, Andrew D. Baird, Linda A. Baker, Steven G. Docimo and Ranjiv I. Mathews Urological Survey

100. Pediatric Urology Pages 282-283 Douglas A. Canning

101. Adrenal Hemorrhage Page 284 Anastasia M. Canacci and Gregory T. MacLennan Radiology Page

102. Syringocele of Cowper’s Gland Duct: An Increasingly Common Rarity Page 285 Richard A. Watson, Mark A. Lassoff, Ihor S. Sawczuk and Craig Thame

Investigative Urology

103. Single Trocar Laparoscopic Nephrectomy Using Magnetic Anchoring and Guidance System in the Porcine Model Pages 288-291 Ilia S. Zeltser, Richard Bergs, Raul Fernandez, Linda Baker, Robert Eberhart and Jeffrey A. Cadeddu

104. Targeting β2-Microglobulin Mediated Signaling as a Novel Therapeutic Approach for Human Renal Cell Carcinoma Pages 292-300 Takeo Nomura, Wen-Chin Huang, Seongil Seo, Haiyen E. Zhau, Hiromitsu Mimata and Leland W.K. Chung

105. Increased SKP2 and CKS1 Gene Expression Contributes to the Progression of Human Urothelial Carcinoma Pages 301-307 Kazumori Kawakami, Hideki Enokida, Tokushi Tachiwada, Kenryu Nishiyama, Naohiko Seki and Masayuki Nakagawa

106. Interstitial Photodynamic Therapy of the Canine Prostate Using Intra-Arterial Administration of Photosensitizer and Computerized Pulsed Light Delivery Pages 308-313 Zhengwen Xiao, Dwayne Dickey, Richard J. Owen, John Tulip and Ronald Moore

107. Enhanced Kidney Stone Fragmentation by Short Delay Tandem Conventional and Modified Lithotriptor Shock Waves: A Numerical Analysis Pages 314-319 Leung-Mun Tham, Heow Pueh Lee and Chun Lu

108. Biomechanical Properties of Vaginal Tissue. Part 1: New Experimental Protocol Pages 320-325 Chrystèle Rubod, Malik Boukerrou, Mathias Brieu, Patrick Dubois and Michel Cosson

109. Editorial Comment Page 325 Christian O. Twiss, Veronica Triaca and Shlomo Raz

110. Effects of Tolterodine on Afferent Neurotransmission in Normal and Resiniferatoxin Treated Conscious Rats Pages 326-331 Petter Hedlund, Tomi Streng, Tack Lee and Karl-Erik Andersson

111. Intraurethral Transfer of Satellite Cells by Myofiber Implants Results in the Formation of Innervated Myotubes Exerting Tonic Contractions Pages 332-337 Constant Lecoeur, Salem Swieb, Laurent Zini, Charlotte Rivière, Hélène Combrisson, Romain Ghérardi, Claude Abbou and René Yiou

112. hSMR3A as a Marker for Patients With Erectile Dysfunction Pages 338-343 Yuehong Tong, Moses Tar, Val Monrose, Michael DiSanto, Arnold Melman and Kelvin P. Davies

113. Infertility and Hypergonadotropic Hypogonadism as First Evidence of Hereditary Apolipoprotein A-I Amyloidosis Pages 344-348 Tiziano Scalvini, Paola Rossana Martini, Laura Obici, Regina Tardanico, Luciano Biasi, Gina Gregorini, Francesco Scolari and Giampaolo Merlini Urological Survey

114. Uro-Science Pages 349-350 Timothy L. Ratliff

115. Adrenal and Renal Physiology, and Medical Renal Disease Pages 350-351 W. Scott McDougal

116. Benign Prostatic Hyperplasia Page 351 Steven A. Kaplan Letters to the Editor/Errata

117. Re: Can Restaging Transurethral Resection of T1 Bladder Cancer Select Patients for Immediate Cystectomy?: H. W. Herr, S. M. Donat and G. Dalbagni J Urol 2007; 177: 75–79 Page 352 Alan M. Nieder, Mark S. Soloway and Michael A.S. Jewett

118. Re: Expression of Major Heat Shock Proteins in Prostate Cancer: Correlation With Clinicopathological Outcomes in Patients Undergoing Radical Prostatectomy: T. Kurahashi, H. Miyake, I. Hara and M. Fujisawa J Urol 2007; 177: 757–761 Pages 352-353 Salvador Vale 119. Voiding Function and Dysfunction, Bladder Physiology and Pharmacology, and Female Urology: A. J. Wein J Urol 2007; 177: 230–233 Page 353 Gerald Frankel

120. Reply by Author Page 353

121. Re: Choices: M. I. Resnick J Urol 2006; 176: 2342 Pages 353-354 Paul F. Schellhammer

122. Re: Circumcision—Are You With Us or Against Us?: J. S. Elder J Urol 2006; 176: 1911 Pages 354-355 Edgar J. Schoen Book Review

123. A.C. Novick, J.S. Jones, I.S. Gill, E.A. Klein, R. Rackley and J.H. Ross, Operative Urology at the Cleveland Clinic, Humana Press, Totowa, New Jersey (2006) 576 pages. Page 356 Mark Soloway CME Enrollment Form/Questionnaire

124. Home Study CME Enrollment Form Pages 358-359 News and Announcements

125. News and Announcements Pages 360-364

This Month in Clinical Urology

EJACULATORY DISORDERS AND significantly better urinary function after 1 month post- ϩ SCREENING FOR PROSTATE CANCER operatively than the UNS SNG group. After 3 months all groups were almost continent. The nerve graft proce- Sexual dysfunction is common in aging men and affects dure may contribute to the recovery of urinary function as quality of life. Because no studies have addressed the well as sexual function after radical prostatectomy. How- prevalence of reduced ejaculatory volume (REV) and ejac- ever, these findings need to be validated in a randomized ulatory pain (EjP) in a prostate cancer screening popula- trial. tion or in a corresponding cohort, Walz et al (page 232) from Montreal, Canada assessed a cohort of 1,273 men POPULATION BASED INCIDENCE (mean age 57.6 years) without clinical evidence of pros- AND AGE DISTRIBUTION OF tate cancer who completed a self-administered Danish Prostate Symptom Score for sexual dysfunction (DAN- SPERMATOCYTIC SEMINOMA PSS-sex). REV was reported in 46% of the men and 66% Spermatocytic seminoma is a rare testicular neoplasm were bothered by the condition. EjP was reported in 11% that presents as a slow growing mass with or without of the subjects and 89% found this symptom bothersome. This Month in Clinical Urology pain. It typically arises in the elderly and more commonly Finally 45% of the men reported erectile dysfunction, in the right testis, serum markers are always negative which was described as bothersome by 73%. REV was and there is no association with cryptorchidism or intra- associated with erectile dysfunction and advanced age. epithelial neoplasia. Unlike other germ cell tumors, me- However, EjP was not associated with either of these tastasis is rare, and so orchiectomy and surveillance are variables. It is important to recognize that all men will be usually sufficient unless the tumor is associated with sar- affected by ejaculatory disorders after definitive treat- coma. Carrière et al (page 125) from Brisbane, Australia ment for localized prostate cancer. Half of these patients report on the first population based estimate of incidence, have underlying REV before treatment and 1 in 10 men temporal trends and age distribution of this tumor. Of will be affected by EjP. (CME credit article) 9,658 cases of primary malignant testicular neoplasms identified by the cancer registries in Australia 58 were IMPACT OF UNILATERAL SURAL spermatocytic seminoma. This tumor comprised 1.1% of NERVE GRAFT ON RECOVERY OF all seminoma and the age standardized incidence rate was 0.4 per million. A temporal increase in incidence was POTENCY AND CONTINENCE AFTER found but did not reach statistical significance. Age at RADICAL PROSTATECTOMY diagnosis ranged from 19 to 92 years with a mean of 53.5 and a median of 54. Spermatocytic seminoma should be The indications for nerve sparing radical prostatectomy considered in the differential diagnosis of testicular germ depend on clinical stage, transrectal ultrasound findings, cell tumors presenting in young adults because this tu- the number and Gleason score of positive biopsies, pros- mor occurs as often in men younger than 55 years as it tate specific antigen, patient preference and intraopera- does in older men. (CME credit article) tive factors prioritizing cancer control. Namiki et al (page 212) from Tohoku, Japan conducted a 3-year longi- POSITIVE MARGINS WITH tudinal study assessing the impact of unilateral sural nerve graft on the recovery of potency and continence LAPAROSCOPIC PARTIAL after radical prostatectomy. A total of 113 patients un- NEPHRECTOMY dergoing radical prostatectomy were classified into three groups according to the degree of nerve sparing: 1) uni- Advances in laparoscopic techniques have prompted lateral nerve preservation with contralateral sural nerve studies examining the viability of laparoscopic partial graft interposition (UNSϩSNG), 2) bilateral nerve spar- nephrectomy (LPN) as an acceptable alternative to open ing (BNS) and 3) unilateral nerve sparing (UNS). Urinary partial nephrectomy (OPN). Laparoscopic partial ne- continence and potency were estimated by the UCLA phrectomy has been shown to be a technically feasible Prostate Cancer Index questionnaire. Patients in the alternative to OPN with similar surgical efficacy as mea- UNSϩSNG group were younger than those in the other sured by positive surgical margin rates. In this multi- groups, and at baseline this group and the BNS group institutional study Breda et al (page 47) evaluated the reported better sexual function than the UNS group. The surgical and oncologic efficacy of LPN at 17 centers in the BNS group showed more rapid recovery than the United States and Europe. In addition, the indications for UNSϩSNG group following surgery. After 24 months intraoperative frozen sections following LPN were evalu- there were no significant differences between the BNS ated. A total of 855 LPN procedures were performed and and the UNSϩSNG group. The BNS group reported bet- mean tumor size was 2.7 cm (range 2 to 4). Positive ter sexual function scores than the UNS group through- margins were identified in 21 cases on final pathological out the postoperative period. The BNS group maintained examination for an overall positive margin rate of 2.4%.

0022-5347/07/1781-0001/0 1 Vol. 178, 1-3, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1016/j.juro.2007.04.015 2 THIS MONTH IN CLINICAL UROLOGY hsMnhi lnclUrology Clinical in Month This Of the 21 patients with positive margins 14 underwent 1, 2006. Their charts were reviewed with respect to age, immediate radical nephrectomy based on frozen sections sex, duration of retention, underlying diagnosis for reten- and 7 were followed expectantly. The authors conclude tion and voiding ability. Of the patients 15 were men that early experience with LPNs in this multicenter (mean age 55.5 years) and 14 were women (mean age 62.2 study demonstrates oncologic efficacy comparable to that years). Although all patients performed intermittent self- of OPN with respect to the incidence of positive margins. catheterization, 18 were able to void (less than 50 cc per The practice of intraoperative frozen sections varied void). The remaining 11 patients had minimal or no ca- among the centers and is not definitive in guiding optimal pability to void. Of the 18 patients who were able to void surgical treatment. 12 underwent successful permanent implantation. How- ever, voiding improved in only 2 of the 11 patients (18%) PROGNOSTIC IMPACT OF after test stimulation. This difference was statistically significant and suggests that pre-implantation ability to TUMOR SIZE IN pT2 RENAL void can predict success of test stimulation. CELL CARCINOMA STANDARD VERSUS LIMITED PELVIC To determine the worldwide prognostic impact of tumor LYMPH NODE DISSECTION FOR size and, consequently, whether a tumor size cutoff exists for pT2 renal cell carcinoma that improves the prognostic PROSTATE CANCER accuracy of the current TNM staging system, Klatte et al Touijer et al (page 120) from New York, New York deter- (page 35) collected data on more than 706 patients from 9 mined the yield of standard vs limited pelvic lymphade- international institutions. Data included age at diagno- nectomy (PLND) for prostate cancer with a predicted risk sis, gender, 2002 TNM stage, tumor size, nuclear grade, of lymph node metastases greater than 1% according to performance status, histological subtype and disease spe- the Partin tables. They also evaluated the feasibility of cific survival (DSS). Median followup was 52 months. performing standard PLND laparoscopically. Of 648 pa- Univariate Cox regression analysis showed a significant tients with a greater than 1% predicted probability of association of tumor size with DSS. An ideal tumor size lymph node invasion 177 underwent limited laparoscopic cutoff of 11 cm was identified which led to the stratifica- PLND (group 1) and 471 underwent standard PLND tion of 2 groups with respect to DSS, with 5 and 10-year (group 2, open 367 and laparoscopic 104). On multivari- survival rates of 73% and 65% for pT2 11 cm or less, and ate logistic regression analysis controlling for biopsy 57% and 49% for pT2 greater than 11 cm, respectively. Gleason score, clinical stage and surgical approach, the The incidence of metastases was significantly greater in odds of node positivity were 7.15-fold higher for standard the larger than 11 cm group, while the Eastern Cooper- vs limited PLND. The median number of nodes retrieved ative Oncology Group performance status, Fuhrman was 9 and 14 after limited and standard PLND, respec- grade and histological subtype were similar. The data tively. A similar impact was noted in patients treated suggest that the current pT2 classification can be im- laparoscopically with standard vs limited PLND. The au- proved by subclassification into pT2a and pT2b based on thors conclude that standard lymph node dissection a tumor size cutoff of 11 cm. Patients in the proposed yields positive nodes more frequently and retrieves a pT2bN0M0 group are at higher risk for death from renal higher total nodal count than the often performed PLND cell carcinoma and should be considered for adjuvant limited to the external iliac nodes. (CME credit article) therapies. CONTEMPORARY SURGICAL SACRAL NEUROMODULATION OUTCOMES OF URACHAL FOR NONOBSTRUCTIVE CARCINOMA URINARY RETENTION Urachal carcinoma is rare, accounting for less than 1% of Sacral neuromodulation was approved in 1997 by the bladder neoplasms. Herr et al (page 74) from New York, Food and Drug Administration for the treatment of uri- New York focused on surgical outcomes in 50 patients nary urge incontinence, urinary urgency-frequency and with urachal carcinoma who were treated in a consistent nonobstructive urinary retention. Other studies suggest fashion with extended partial cystectomy and pelvic that sacral neuromodulation in young women with lymphadenectomy. All patients were diagnosed with lo- Fowler’s syndrome (urinary retention secondary to abnor- calized urachal carcinoma and were followed for 5ϩ mal striated sphincter activity) may have a more success- years. Of the 50 patients 93% with tumor confined to the ful outcome. None of these studies explains why some urachus and bladder survived versus 69% with extravesi- patients are treated successfully and others are not. Goh cal or peri-urachal tumor invasion, and none survived in and Diokno (page 197) from Royal Oak, Michigan, iden- whom tumor invaded the peritoneal cavity. Local recur- tified factors that may influence success during first stage rence was noted in 9 patients and 2 underwent salvage sacral neuromodulation testing, and investigated whether therapy. The most significant predictors of survival were there are factors that can predict successful stage II (per- pathological tumor stage and negative surgical margins. manent) sacral nerve stimulator implantation for pa- The authors conclude that wide resection of the tumor tients with nonobstructive urinary retention. A total of 29 and entire urachus, achieving negative soft tissues and patients were referred for evaluation of nonobstructive bladder margins, cures the majority of patients with non- urinary retention from January 1, 1999 through January metastatic urachal malignancy. (CME credit article) THIS MONTH IN CLINICAL UROLOGY 3

URINE TELOMERASE ACTIVITY FOR ated with worse incontinence and surgical outcome. THE DETECTION OF BLADDER Lowenstein et al (page 193) from Chicago, Illinois determined whether bladder volume is related to validated CANCER IN WOMEN quality of life measures, urethral sphincter assessments and standardized surgical outcome measures in women The search for an accurate, common, noninvasive and with USI, and whether bladder volume during urody- easily manageable examination for bladder cancer diag- namic testing could predict failure following rectus fas- nosis has been intensively pursued in recent years. cial sling. A total of 168 women were recruited for the Among the markers proposed to improve diagnostic sen- study, and preoperative and postoperative assessment sitivity in urine, attention has been increasingly focused included the Incontinence Impact Questionnaire (IIQ) on the role of telomerase activity (TA) for bladder cancer and Urogenital Distress Inventory (UDI). USI volume is detection. Previous studies have shown that TA in blad- the bladder volume at which USI was first detected. der washings and voided urine represents an important Women were divided into 4 groups according to USI vol- noninvasive tool for bladder cancer diagnosis. Bravaccini ume, and compared with respect to maximum urethral et al (page 57) from Forli, Italy present a case controlled closure pressure, Valsalva leak point pressure, IIQ and study of 144 healthy women and 68 with a first diagnosis UDI. USI persistence was evaluated only in patients who of bladder cancer. This study was performed to confirm had undergone sling surgery. USI volume was 100 ml in previously obtained diagnostic results and improve the 31% of women, 200 ml in 17%, 300 ml in 17% and more This Month in Clinical Urology accuracy of this diagnostic assay. At the best overall than 400 ml in 35%. Baseline and postoperative UDI, IIQ, cutoff of 50 arbitrary enzymatic units, sensitivity was maximum urethral closure pressure and Valsalva leak 87% and specificity was 66%. Interestingly, higher accu- point pressure did not differ by USI volume. Among the racy rates were noted in females younger than 75 years 116 patients treated with the sling procedure USI persis- than in older women. Other reasons in addition to age tence did not differ by USI volume. Women who demon- may account for the lower specificity in women with re- strated USI at lower bladder volumes did not report spect to men. In particular, a high number of telomerase greater bother from incontinence than those who leaked positive nonurothelial cells in urine from females could be at higher volumes, suggesting that leakage severity on responsible for false-positive results. The authors con- urodynamics is not an adequate reflection of incontinence clude that TA detected by telomeric repeat amplification related quality of life. (CME credit article) protocol appears to be a good diagnostic test in females although it is more accurate in younger than in older women. BOOK REVIEW

SIGNIFICANCE OF VOLUME AT On page 356 Soloway reviews Operative Urology at the WHICH WOMEN LEAK FIRST ON Cleveland Clinic. URODYNAMIC TESTING

A low bladder volume at which urodynamic stress incon- Martin I. Resnick tinence (USI) is detected is often assumed to be associ- Editor This Month in Pediatric Urology

OUTCOMES OF DELAYED VESICOSCOPIC CROSS-TRIGONAL HYPOSPADIAS REPAIR URETERAL REIMPLANTATION

Hypospadias repair is generally recommended at age 6 to Transtrigonal ureteral reimplantation is a common form 9 months, unless there are medical circumstances that of open surgical correction of vesicoureteral reflux but increase the risk of general anesthesia or surgical correc- recently a minimally invasive vesicoscopic approach has tion. There are few reports of primary hypospadias repair been used. Canon et al (page 269) from Columbus, Ohio in older patients. Dodson et al (page 278) from Baltimore, retrospectively reviewed their experience with 52 chil- Maryland retrospectively reviewed their experience from dren who underwent vesicoscopic repair and compared 1979 to 2002 with 31 male patients who underwent var- the results to those of 40 consecutive children who under- ious techniques of primary operative hypospadias repair went conventional open ureteral reimplantation. The at or after age 10 years. Median patient age at repair was vesicoscopic repair was done with the patient in the dor- 13 years and median followup was 14 months. The me- sal lithotomy position. Cystoscopy using CO2 insufflation atus was distal in 19 cases, mid shaft in 7 and proximal in was performed to assess the anatomy and allow for percutaneous fixation of the bladder to the anterior bladder

4. The overall complication rate was 48%, and the most This Month in Pediatric Urology common complications were fistula (32%), stricture (13%) wall.A5mmport was placed in the dome for the camera and 2, 3 mm ports were placed laterally. Pediatric feeding and hematoma (6%). These data suggest that delaying tubes were inserted into the ureters, and transtrigonal hypospadias repair until puberty results in a significantly ureteral reimplantation was performed. Of the 52 cases of higher complication rate. vesicoscopic repair 1 was converted to an open surgical procedure because of equipment malfunction and poor ORAL VERSUS INTRANASAL port placement. Overall, reflux resolved in 42 of the 46 (91%) patients in the vesicoscopic group and 31 of 32 DESMOPRESSIN FOR NOCTURNAL (97%) in the open reimplantation group. Mean operative ENURESIS time was 199 minutes for the vesicoscopic repair and 92 minutes for the open repair. Complications in the vesico- Desmopressin is the only medication approved by the scopic group included urinary leakage in the first case, Food and Drug Administration for primary nocturnal bladder calculi which passed in 1, and acute bilateral enuresis. The medication is available as a nasal spray ureteral obstruction and renal failure in 1. The authors (dosage 10 to 40 mcg) and an oral tablet (dosage 0.2 to conclude that vesicoscopic ureteral reimplantation is a 0.6 mg). The most serious complication of the medica- successful procedure with acceptable morbidity. Further tion is water intoxication, which can lead to hypona- refinement in the procedure seems justified. tremia. Robson et al (page 24) from Canada and Den- mark analyze the comparative safety of intranasal and oral formulations of desmopressin. A review of the lit- THE DURABILITY OF A erature between 1972 and 2005 revealed a total of 21 SINGLE ENDOSCOPIC clinical trials of desmopressin in children and no re- POLYTETRAFLUOROETHYLENE ports of hyponatremia. However, 48 case reports of hyponatremia in children with nocturnal enuresis were INJECTION FOR REFLUX published, all of whom had been treated with the in- Subureteral injection of polytetrafluoroethylene (PTFE) tranasal formulation. has been used in the past for vesicoureteral reflux. Yucel Analysis of post-marketing safety data revealed 151 et al (page 265) from Istanbul, Turkey retrospectively cases of hyponatremia, of which 145 occurred in children reviewed the charts of 38 patients with primary vesi- receiving the intranasal formulation, and seizures were coureteral reflux (unilateral 28, bilateral 10) who under- associated with hyponatremia in 80%. The recommended went a single subureteral injection of PTFE between 1989 dosage was given in 72% of the 145 cases and was un- and 1993. Followup routine voiding cystourethrography known in 16%. Of the 6 cases of hyponatremia, which performed at 1, 3 and 10 years after treatment revealed occurred with oral desmopressin, 4 were associated with reflux resolution in 73% of the patients. Median time to seizure. Potential risk factors were identified in 3 of the 6 reflux recurrence in the remaining 13 cases (grade I–II in cases. The authors conclude that there is a reduced risk of 5, grade III–V in 8) was 2 years. Of the 13 recurrences 10 hyponatremia with oral versus intranasal desmopressin. were detected following a febrile urinary tract infection They recommend avoiding high fluid intake in the and 3 grade I recurrences were asymptomatic. These data evening for patients treated with desmopressin, and suggest that ongoing clinical followup should be consid- prompt medical attention for those experiencing head- ered in children with reflux treated by endoscopic injec- ache, nausea or vomiting. tion.

0022-5347/07/1781-0005/0 5 Vol. 178, 5-6, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1016/j.juro.2007.04.017 6 THIS MONTH IN PEDIATRIC UROLOGY hsMnhi eiti Urology Pediatric in Month This MYOCYTE APOPTOSIS IN PRIMARY was 1 year (range 0 to 8.8 years), including 34 patients OBSTRUCTIVE MEGAURETERS younger than 1 year. Overall, 94% of the patients became continent and dry, including 11% who void frequently and In primary obstructive megaureter there is a thick sleeve 2% who void infrequently. The 3 girls with perisistent in- of muscle around the distal portion of the ureter, incontinence had a short urethra and large cecoureterocele. creased collagen deposition and dysregulated neuro- Pre-operative vesicoureteral reflux was noted in 33 patients modulation in the juxtavesical segment of the ureter. and was low grade at followup in 7. Of the 54 children 11 Payabvash et al (page 259) from Tehran, Iran analyzed (20%) had dysfunctional voiding. During the last 2 years the apoptotic changes of myocytes at the ureterovesical 17% of patients experienced 1 or 2 uncomplicated urinary junction of 16 children with primary obstructive mega- tract infections but no chemoprophylaxis was prescribed. ureter (mean age 21 months) and compared them to 19 The authors conclude that the majority of children control specimens taken from autopsy specimens. The treated with total reconstructive bladder surgery become authors found that the percentage of apoptotic myocytes continent and do not experience lower urinary tract was significantly higher in ureteral endings of children symptoms or recurrent urinary tract infections. with a megaureter (10.1%) versus controls (2.1%). In contrast, the numbers of CD31ϩ vascular elements and neu- KIDNEY FOLDING, THE “Y PLASTY” ral elements were significantly lower than those of control ureters. The authors conclude that induction of In some children with ureteropelvic junction (UPJ) ob- apoptosis in normal functioning myocytes and substitu- struction there is severe hydronephrosis with significant tion of fibrotic tissue may contribute to the pathogenesis parenchymal thinning and intrarenal dilatation of the of primary obstructive megaureter. collecting system. These patients may be at risk for secondary obstruction of the UPJ. Belman and Rushton ECTOPIC URETEROCELE (page 255) from Washington, D.C. retrospectively analyzed 5 patients with severe hydronephrosis secondary to Many children with an ectopic ureterocele undergo open a UPJ obstruction who underwent a kidney folding pro- lower urinary tract reconstruction. Beganovic et al cedure in addition to conventional pyeloplasty. All pa- (page 251) from Utrecht, The Netherlands performed a tients experienced significant reduction in hydronephro- long-term retrospective analysis of 54 children who un- sis and a dependent, funneled anastomosis. derwent total upper and lower urinary tract reconstructive surgery for ectopic ureterocele between 1988 and 2003. Specific outcomes addressed were continence and Jack S. Elder urinary tract infection. Median patient age at surgery Section Editor This Month in Investigative Urology

SINGLE TROCAR LAPAROSCOPIC nation has been applied in PDT, which easily depletes NEPHRECTOMY USING MAGNETIC tissue oxygen. Xiao et al (page 308) from Alberta, Canada determined ANCHORING if comprehensive treatment of the entire prostate could be achieved by interstitial PDT with intra-arterial (pros- To overcome the limitations imposed by fixed trocar tech- tatovesical artery) drug delivery and switched (pulsed) nology using laparoscopic surgery, Zeltser et al (page 288) interstitial light delivery. Lipid formulated QLT0074 from Arlington, Texas developed in prototype a novel (benzoporphyrin derivative 1,3-diene C,D-diethylene gly- adjunct laparoscopic system concept, that is a moveable, col ester A ring) was used as the intra-arterial photosen- lockable platform positioned intra-abdominally and sta- sitizer. Dog prostate glands were infused with QLT0074 bilized by an external permanent magnet placed on the via the prostatovesical arteries using fluoroscopic guid- abdominal skin. The design mandate was that the devel- ance. Immediately following infusion the prostate was oped technology should be able to deploy into the insuf- surgically exposed and 7 optical fibers with 1.5 cm cylin- flated abdomen through 1 existing 12 mm diameter trocar drical diffusers in after loading sheaths were inserted and then be moved into position in the peritoneum by into the prostate through a template. Light was delivered manipulating external magnets. The magnetic anchoring sequentially to optic fibers via a computer driven switch and guidance system concept was advanced to a working system to the prostate. The dogs were monitored for clin- prototype with a system of external magnetic anchors, an ical tolerance and urinary function. The prostate speci- This Month in Investigative Urology internal camera system and a hook cautery supported by mens were examined microscopically. Except for urinary an intra-abdominal robotic arm. This prototype system retention and mild hematuria no other perioperative com- was then evaluated in vivo in a porcine laparoscopic ne- plications were observed. Urodynamic examination did phrectomy model. Two nonsurvival porcine laparoscopic not reveal any deleterious bladder or urethral functional nephrectomies were successfully completed without com- effects. Average prostate volume decreased 71% at 3 plications via a single 15 mm transumbilical trocar using months and 56% after 6 months. Microscopic evaluation the prototype magnetic anchoring and guidance system revealed prostate glandular epithelial atrophy, stromal camera and the magnetically anchored robotic arm cau- fibrosis and mononuclear cell infiltration. Interstitial terizer. A conventional laparoscopic grasper was used for PDT using intra-arterial QLT0074 and pulsed light de- retraction through the 15 mm trocar after magnetic an- livery is safe and feasible for comprehensive destruction choring and guidance system deployment. The renal ar- of the canine prostate. Clinical trials are required to tery and vein were transected with a conventional Endo- determine its usefulness in patients. GIA® stapler introduced through the 15 mm trocar, and blood loss was minimal. Single trocar laparoscopic ne- INTRAURETHRAL MYOFIBER phrectomy using magnetically anchored instrumentation is technically feasible and demonstrates that intracorpo- IMPLANTS FORM INNERVATED real instrument manipulation may overcome the limita- MYOTUBES tions of current laparoscopic and robotic surgery by allowing unhindered intra-abdominal movement. This Transplantation of muscle precursor cells into the stri- single access technique may be used with natural orifice ated urethral sphincter is a potential new treatment for surgery approaches and it has the potential to realize stress urinary incontinence. The standard muscle precur- incisionless intra-abdominal surgery. sor cell grafting technique consists of an injection of cells that were originally harvested from a muscle biopsy by enzymatic digestion and then cultured under specific con- PROSTATE INTERSTITIAL ditions to eliminate nonmyogenic cells. However, there is PHOTODYNAMIC THERAPY USING AN now increasing evidence that these successive steps of muscle precursor cells preparation alter their myogenic INTRA-ARTERIAL PHOTOSENSITIZER potential in vivo. After enzymatic separation from their AND PULSED LIGHT DELIVERY parental myofibers satellite cells were found to be several thousand-fold less efficient in generating muscle. Taking Photodynamic therapy (PDT) is a dual selective experi- these recent concepts into consideration, Lecoeur et al mental treatment modality using light of a specific wave- (page 332) from Créteil, France investigated a novel method length to locally activate a photosensitizer accumulated of intraurethral muscle precursor cell transplantation in the target tissue, leading to photochemical destruction consisting of implanting freshly isolated myofibers with of the target tissue. A major obstacle to clinical PDT of their satellite cells. Pigs underwent baseline urodynam- the prostate is damage to adjacent structures, especially ics followed by endoscopic destruction of the striated ure- the rectum. To avoid adjacent normal tissue damage the thral sphincter located around the distal urethra. On day photosensitizer and light must be delivered selectively to 30 circular myofibers strips or adipocytes were implanted treat the target tissue/organ. To date continuous illumi- in the proximal urethra. On day 60 urodynamics were

0022-5347/07/1781-0007/0 7 Vol. 178, 7-8, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1016/j.juro.2007.04.016 8 THIS MONTH IN INVESTIGATIVE UROLOGY hsMnhi netgtv Urology Investigative in Month This performed and urethral cryosections were immuno- INFERTILITY AND stained for desmin (activated satellite cells), fast myosin HYPERGONADOTROPIC heavy chain/bungarotoxin (myotubes/acetylcholine receptors) and neurofilament/vesicular acetylcholine trans- HYPOGONADISM AS FIRST porter (nerve endings). Endoscopic injury abolished stri- EVIDENCE OF HEREDITARY ated urethral sphincter activity. Implantation of myofiber strips generated a pressure peak that was tonic and un- APOLIPOPROTEIN A-I AMYLOIDOSIS der neural control. Nerve endings connected to the ace- Systemic amyloidosis consists of a group of diseases char- tylcholine receptors of myotubes were observed on day 60. acterized by the progressive extracellular deposition of Adipocyte implantation resulted in no significant intra- soluble plasma proteins as insoluble fibrils, disrupting urethral pressure changes. Myofibers implanted in the tissue integrity, which leads to organ dysfunction. urethra regenerate as myotubes that exert tonic activity ApoA-I, the major component of high density lipopro- under neural control and are of potential clinical value. teins, can cause systemic amyloidosis at the presence of specific amino acid replacements. A total of 12 amyloido- hSMR3A AS A MARKER FOR genic apoA-I variants have been identified to date. The ERECTILE DYSFUNCTION natural history of the disease consists of progressive liver and kidney involvement with restrictive cardiomyopathy The Vcsa1 transcript (variable coding sequence a1 gene, observed in some variants. Recently an amyloidogenic also known as a submandibular rat 1 gene) is one of the variant of apoA-I associated with a predominantly spo- most down-regulated genes in the corpora of rats in 3 radic presentation, in which the leucine residue at posi- distinct models of erectile dysfunction (ED), including tion 75 is replaced by proline (Leu75Pro), was discovered. diabetic, age related and neurogenic ED models. Since In the first 2 series of patients in whom the diagnosis was gene transfer of plasmids expressing Vcsa1, or intracor- confirmed by genetic and immunohistochemical analyses, poreal injection of its mature peptide product sialorphin surgically treated gynecomastia was reported in a few into the corpora of aging rats was shown to restore erec- cases, suggesting testicular localization of the disease. tile function, it has been proposed that the Vcsa1 gene However, no additional studies were performed in these has a direct role in erectile function. To determine if subjects. similar genetic changes occur in the corpora of human Scalvini et al (page 344) from Brescia, Italy report a subjects with ED Tong et al (page 338) from New York, detailed characterization of apoA-I testicular amyloidosis New York identified a human homologue of Vcsa1 in a novel series of patients. The authors show that the (hSMR3A) and determined the level of expression of early deposition of amyloid in the testes leading to infer- hSMR3A in human patients. hSMR3A was identified as a tility is a peculiar feature of this form of the disease. Ten homologue of Vcsa1 by searching protein databases for patients presenting with infertility, gynecomastia, de- proteins with similarity. hSMR3A cDNA was generated creased libido, erectile dysfunction or a family history of and subcloned into the plasmid pVAX to generate pVAX- amyloidosis underwent clinical evaluation, hormone as- hSMR3A which was intracorporeally injected into aging says, semen analysis, ultrasonographic investigation of rats. The effect on erectile physiology was compared with the testicles, testicular biopsy and DNA sequencing of the controls treated with the empty plasmid. Total RNA was apoA-I gene. All patients showed azoospermia and 9 had extracted from human corporeal tissue obtained from increased testicular volume. Massive amyloid deposition patients undergoing previously scheduled penile surgery. was observed in all testicular biopsies and the Leu75Pro Patients were grouped according to normal erectile func- mutation of apoA-I was noted. Five patients showed hy- tion, ED and diabetes, and nondiabetics with ED. Quan- pergonadotropic hypogonadism and 5 had normal testos- titative reverse transcriptase polymerase chain reaction terone values with high gonadotropin levels. Nonobstruc- was used to determine expression levels of hSMR3A. tive azoospermia and macro-orchidism with or without Intracorporeal injection of pVAX-hSMR3A was able to hypogonadism may be caused by hereditary apoA-I amy- significantly increase the intracorporeal pressure in ag- loidosis in young patients. Testicular amyloidosis can be ing rats. The physiological effects were similar to previ- the first manifestation of this systemic disease. Specific ously reported effects of intracorporeal injection of pVAX- staining for amyloid deposits and genetic analysis of Vcsa1. More than 10-fold down-regulation in the apoA-I mutations are recommended in young, infertile expression of hSMR3A transcript was observed in the patients with macro-orchidism. Surveillance in asymp- corpora of patients with vs without ED. In patients with tomatic mutation carriers is suggested to evaluate the diabetes associated and nondiabetes associated ED opportunity to implement sperm retrieval and start an- hSMR3A expression was found to be down-regulated. drogen replacement therapy when necessary. These results suggest that hSMR3A can act as a marker for ED associated with diabetic and nondiabetic etiologies. Therapies that increase the hSMR3A gene and product expression could potentially have a positive impact on Anthony Atala erectile function. Section Editor Editorials

Getting Through it All

t’s been approximately 14 months since my diagnosis In a similar vein, my work at The Journal continued and approximately 9 months since I underwent ablative during those 14 months. I relied more on my Associate and I chemotherapy and a bone marrow transplant for treat- Section Editors, and the staff in Baltimore was essential. ment of acute myeloid leukemia. Friends and colleagues Some decisions were left to others but I continued to work on commonly ask me how I did, was I depressed, have I ac- “This Month in Clinical Urology Page,” selected guest edito- quired new insight into the physician-patient relationship rials and participated in monthly teleconferences with the and how was it on the other side, ie being the patient rather staff, and Associate and Section Editors. than the doc? I’d like to use this editorial page to comment I guess that’s how I got through it all. From the begin- on some of these questions. ning, I was concerned about my responsibilities and commit- First and foremost, I believe I am fortunate to have a ments. My medical care obviously had a priority and with wonderful family and group of friends who provide over- my physician’s support, I was always confident that I was on whelming support. A caring wife, 2 children and their the right track. The other work occupied my time, filled my spouses, several grandchildren and many friends are always days and often made me forget what I physically was going there for me. Daily calls, visits, e-mails and the many cards through. during those 14 months were greatly appreciated. What What was also interesting was my behaving in a manner surprised me was the hundreds of cards I received from similar to what I have observed in other physician friends patients I cared for over the years; all waiting for me to who have had a severe illness. They typically look upon their return to work and be their physician again. This serves as problem in the third person so when asked how they are a goal and I am sure will have much to do with my ultimate doing or feeling (and you just want to know only that), they recovery. typically respond with the results of their latest CT or blood Secondly, my professional life has been rewarding as test. I always thought it was interesting that physician well. I have chaired the Department of Urology at Case patients responded to their illness in that manner but was Medical Center since 1981 and have had the opportunity surprised when I found myself acting the same way. When and privilege to lead several national organizations, includ- asked how I was doing, I reported what my lab test results ing my terms as secretary and president of the American were, what chemotherapy I received, other clinical informa- Urological Association and my current role as the Editor of tion and often other data related to my illness. That, too, is The Journal of Urology®. I have also been active at Case another way of getting through it all. It was easier to look at Medical Center and University Hospitals in addition to my myself from the outside and in some respects remove myself from the gravity of the problem. other responsibilities. This is the third Editorial in this series on the subject of Throughout my treatment period, I made every attempt my illness. Hopefully, I will continue to do well and the to continue with these activities, although not with the in- readers of this Editorial, as well as the previous two,1,2 will tensity that I had when I was well. I tried to attend confer- come away with some insight that I gained during a difficult ences when I could, often by telephone, and remained an time. active participant in school and hospital programs. Depart- mental responsibilities were also met by pre-arranged Martin I. Resnick schedules and e-mails and, when necessary, responsibilities Editor were delegated to others because I realized from the beginning it would be impossible for me to do it all. Finally, my REFERENCES associates were most helpful in caring for my patients and 1. Resnick MI: Choices. J Urol 2006; 176: 2342. providing continued support during these difficult times. 2. Resnick MI: Observations. J Urol 2007; 177: 000.

0022-5347/07/1781-0009/0 9 Vol. 178, 9, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.04.011 ␤2 Microglobulin: A Surprising Therapeutic Target for Prostate Cancer and Renal Cell Carcinoma

he major histocompatibility complex (MHC) class I is onstrating that ␤2M supports the colonization and destruc- a heterodimeric cell surface protein that presents pro- tion of bone by RCC cells.2 T cessed antigenic peptides to cytotoxic (CD8ϩ) T lym- Yang et al demonstrated that antibodies that specifically phocytes. MHC class I is present on virtually all nucleated recognize ␤2M induce apoptosis in malignant cells but not cells and serves as a major component of the body’s viral normal cells.3 This study also identified interesting differ- surveillance mechanism. ␤2 microglobulin (␤2M) is a 12 ences in the behavior of membrane proteins in cancer and kDa, 100 amino acid protein MHC class I subunit that is normal cell membranes that might explain the differential thought to act primarily in intracellular assembly and sta- sensitivity to the ␤2M antibodies. Treatment of myeloma bilization of the complex at the cell surface. The cell associ- cells with ␤2M monoclonal antibodies resulted in the relo- ated form of ␤2M is not membrane anchored and therefore cation of MHC class I to lipid raft membranes, resulting in can be exchanged with circulating ␤2M, which is present at the recruitment and activation of the nonreceptor tyrosine low levels in serum, urine and other body fluids, but is kinase, Lyn and the signal transducing enzyme phospho- ␥ elevated in patients with kidney failure, autoimmune and lipase C- 2. Lipid rafts are cholesterol and sphingolipid-rich infectious diseases, and certain malignancies. Serum ␤2M patches of cell membranes that assume a liquid ordered levels are predictive of aggressive disease in some cancers state which is distinct from the more energetically dynamic 4 including renal cell carcinoma (RCC). condition characteristic of most of the plasma membrane. In this issue of The Journal an article by Nomura et al Lipid rafts can be thought of as coherent, moderately stable (page 292) continues the groundbreaking work from Leland structures that float upon the lipid sea. The lipid raft com- Chung’s laboratory on targeting cell surface ␤2M as a novel ponent of plasma membranes is believed to mediate signal means of anticancer therapy.1,2 Near-simultaneous 2006 re- transduction events by sequestering and excluding certain types of signaling molecules, such as cytokine activated reports from the Chung laboratory describe an unexpected role ceptors and their downstream mediators. Association of for ␤2M in cancer promotion. A similar conclusion was re- MHC class I with lipid rafts appears to be a major compo- ported by Qing Yi’s laboratory at M. D. Anderson Cancer nent of the apoptosis activation mechanism elicited by ␤2M Center at essentially the same time.3 The 2 groups used a antibodies because neither MHC class I nor Lyn were asso- wide range of experimental approaches to assess the role of ciated with the lipid raft membrane fraction in normal B ␤2M in malignancy. A noteworthy aspect to these reports is cells. These findings suggest that despite the absence of a that the Chung laboratory studies are on RCC and prostate transmembrane domain that crosses the lipid bilayer, ␤2M cancer while the Yi laboratory studies are on hematological is able to signal from a cholesterol-rich, membrane-proximal malignancies, principally myeloma. Taken together the re- signaling platform in response to antibody binding. The markable implication of the conclusions of the 4 studies is nature of the biochemical effect on the cell surface induced that targeting the identical cell surface molecule may be a by the antibody-target interaction, which both groups show therapeutic approach with potential widespread application is capable of triggering an apoptotic signal in tumor cells, is in the clinical treatment of solid as well as liquid tumors. unknown. The published data provide a broad range of evidence in The Nomura et al study demonstrates that the antibody ␤ support for 2M as a therapeutic target. In the first report in targeting approach against ␤2M works in RCC as well as it ␤ this series Huang et al identified 2M by protein purification does in myeloma. Analysis of signaling pathways down- and mass spectrometry as a protein capable of stimulating stream from antibody ligation of ␤2M by both groups indi- 1 bone specific gene activity in vitro. These investigators then cates that similar biochemical mechanisms are affected in went on to over express ␤2M in a series of human prostate multiple cell types (phosphoinositide 3’-kinase/Akt, Erk mi- cancer cell lines, and examine the consequences of this ma- togen activated protein kinase, jun N-terminal kinase and nipulation on growth in culture and tumor growth in vivo, as Bcl-xL/Bcl-2), suggesting that a general and widely con- well as on several downstream signal transduction mecha- served signaling web is being activated. nisms. It was found that ␤2M acts similarly to a prototypical These surprising preclinical data are very promising, and oncogenic factor capable of stimulating progression through may pave the way for an entirely new class of antibody based the cell cycle, enhanced growth in soft agar, more rapid pharmaceuticals for cancer control and eradication. The growth of xenografts in rodent hosts and the ability to colo- technology for development of therapeutic antibodies has nize bone. ␤2M also up-regulated angiogenic signaling, been commercialized for many years and over a dozen anti- partly by inducing elevated expression of the potent angio- body based drugs are now in clinical use, suggesting that genic factor vascular endothelial growth factor. Similar re- translating the ␤2M findings to the bedside may occur more sults were found in the RCC system by Nomura et al using rapidly than has been the case in studies of other important genetically engineered human RCC (SN12C) cells, and dem- tumor promoting proteins identified using in vitro studies

0022-5347/07/1781-0010/0 10 Vol. 178, 10-11, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.203 ␤2 MICROGLOBULIN AS THERAPEUTIC TARGET 11 and animal models.5 There is, however, a notable limitation 2. Nomura T, Huang WC, Zhau HE, Wu D, Xie Z, Mimata H et al: in targeting MHC class I for cancer therapy due to the Beta2-microglobulin promotes the growth of human renal frequent loss of cell surface HLA molecules during disease cell carcinoma through the activation of the protein kinase progression.6 Nevertheless, the possibility that targeting A, cyclic AMP-responsive element-binding protein, and vas- ␤2M may be effective in some settings against a range of cular endothelial growth factor axis. Clin Cancer Res 2006; malignancies suggests that this is clearly an exciting new 12: 7294. area of basic research with an unusually optimistic outlook 3. Yang J, Qian J, Wezeman M, Wang S, Lin P, Wang M et al: for clinical translation. Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies. Cancer Cell Michael R. Freeman 2006; 10: 295. Urological Diseases Research Center 4. Jacobson K, Mouritsen OG and Anderson RG: Lipid rafts: at a Departments of Urology, Surgery, and Biological crossroad between cell biology and physics. Nat Cell Biol Chemistry and Molecular Pharmacology 2007; 91: 7. Children’s Hospital Boston, Harvard Medical School 5. Mascelli MA, Zhou H, Sweet R, Getsy J, Davis HM, Graham M Boston, Massachusetts et al: Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development. J Clin Pharmacol 2007; Mar 22 [Epub REFERENCES ahead of print]. 1. Huang WC, Wu D, Xie Z, Zhau HE, Nomura T, Zayzafoon M 6. Chen HL, Gabrilovich D, Tampe R, Girgis KR, Nadaf S and et al: beta2-microglobulin is a signaling and growth-promot- Carbone DP: A functionally defective allele of TAP1 results ing factor for human prostate cancer bone metastasis. Can- in loss of MHC class I antigen presentation in a human lung cer Res 2006; 66: 9108. cancer. Nat Genet 1996; 13: 210. Upper Urinary Tract Cancer—Challenges for the Urologist

n this issue of The Journal (page 51) Holmang et al years. Interestingly there was no survival difference in com- present the natural history of treated upper urinary paring pT3 SCC and TCC, suggesting that the more ad- I tract (UUT) squamous cell carcinoma (SCC) in a study vanced stage of SCC explains the poor survival rate, rather population that was retrospectively identified from the than the histology itself. As the authors state, new treat- Swedish Cancer Registry from 1971 to 1998. The population ment modalities are urgently needed. Systemic therapy for included 943 malignant UUT tumors representing cases SCC of the bladder has not been effective.2 from 18 hospitals in western Sweden. The authors overcame Also in this issue Wong et al (page 178) report their the limitations of a pure registry based study (eg limited and experience at Peter MacCallum Cancer Center, Australia unreliable registry data) by reviewing hospital records and regarding the treatment of malignant ureteral obstruction. reevaluating pathological specimens. By including only The study population was retrospectively collected from a urothelial and squamous cell carcinoma the study popula- hospital database, and consisted of 102 patients treated for tion consisted of 743 patients with transitional cell carci- malignant UUT obstruction with antegrade stenting, retro- noma (TCC) and 65 patients with SCC. The SCC repre- grade stenting or percutaneous nephrostomy (PCN). The sented 8% of all cases, making this to our knowledge the population was diverse, including patients with various largest reported series of UUT SCC. types of malignancies and with various stages of disease. The authors compared the 2 patient groups, TCC and The majority of patients had a history of cancer yet in 16% SCC, and found that hematuria was less common in patients ureteral obstruction was the presenting symptom. with SCC. Only 5% of patients with SCC were asymptomatic The success and complication rates were as expected. compared to 19% of those with TCC, indicating that SCC PCN was the most common initial procedure and was asso- tumors were more advanced at diagnosis. Unlike TCC, ciated with a lower failure rate (1%) compared to retrograde which is more common in men, SCC was equally divided stenting (16%). The overall complication rate was high at between women (32) and men (33). 53% but major complications occurred in only 2 (2%) pa- The most striking difference between the 2 histological tients. There were no treatment related deaths. groups was tumor stage at diagnosis. Of SCCs 94% were pT3 The most interesting data deal with the prognosis of or pT4 whereas only 37% of TCCs were locally advanced. Of these patients. Of the patients treated with PCN only 10% patients with SCC 21% were not candidates for surgery due had the obstruction resolve after radiation or chemotherapy. to comorbidities or advanced disease. Interestingly the most The number of patients receiving active treatment was not common procedure for SCC was nephrectomy rather than reported. An attempt to internalize the stent was made in 37 nephroureterectomy. Nephrectomy was performed in 57% of of 77 patients who underwent PCN and was successful in patients with SCC and 32% of those with pT3 TCC. This 57%. Of their cumulative remaining lifetime 17.4% was finding highlights the importance of considering a urothelial spent in the hospital and 6 patients never left before dying. tumor in the differential of large invasive renal masses with The authors identified prognostic factors associated with frozen section analysis if the tumor might have arisen from poor survival after the decompression of the malignant ob- the urothelium. struction. The most important were metastasis, prior ther- In addition, bladder tumors were less common in patients apy, prior diagnosis of malignancy preceding the obstruc- with UUT SCC. The majority of SCCs were primarily soli- tion, and creatinine greater than 0.40 mmol/l. The presence tary advanced tumors, less often multiple tumors and not 1 of metastasis and a prior diagnosis of cancer were indepen- bilateral tumor, in contrast to TCCs which were more often dent prognostic factors in a multivariate analysis. noninvasive and occasionally multiple. It is tempting to Although to our knowledge there are no randomized tri- speculate on different pathways of tumorigenesis. In transi- als regarding the survival benefit of relieving ureteral ob- tional cell carcinogenesis the whole urothelium is suscepti- struction related to malignancy, this article suggests mini- ble to malignant transformation from the carcinogen.1 In mal benefit in overall survival in patients with poor contrast, SCC is speculated to originate from chronic irrita- prognostic factors. This finding is in line with previous re- tion or inflammation. ports. If we accept this idea, the key question is whether we Urinary lithiasis and the use of analgesics containing are improving the quality of life of patients with poor prog- phenacetin were the only etiological factors more common, nostic factors by decompressing the obstruction, or are we, in but not statistically significant, in patients with SCC. Inter- fact, prolonging a poor quality of life? estingly a history of radiation was more common in patients There is little in the literature on this subject. If there is with TCC (3.1% vs 11%, p ϭ 0.22). Unfortunately smoking pain associated with the obstruction, it is reasonable to was not included in the analysis, most probably due to believe that quality of life is improved after relief of the limited information from hospital records. obstruction. In other instances there seems to be no evidence The survival of patients with SCC was poor with a supporting the rationale for placing a stent. The patient and 7-month median survival and only 7.7% surviving 5 or more the family usually will advocate for relief of an obstruction

0022-5347/07/1781-0012/0 12 Vol. 178, 12-13, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.04.014 UPPER URINARY TRACT CANCER 13 and the clinicians will, with rare exception, comply without However, we still have an important responsibility to help a dialogue about the consequences of the procedure. support and inform the patient and family. Many times the This situation leads us to question the role of the urolo- optimal course of action is to encourage hospice care which gist in palliative medicine. Palliation is defined by the WHO may allow patients to spend their last days at home or in a as “an approach that improves the quality of life of patients setting more nurturing than a hospital. and their families facing the problem associating with life Peter J. Bostrom and Mark S. Soloway threatening illness, through the prevention and relief of Department of Urology suffering by means of early identification and impeccable Miller School of Medicine assessment and treatment of pain and other problems, phys- University of Miami ical, psychosocial, and spiritual.”3 This subject is thoroughly Miami, Florida discussed by Ok et al and their article should be required reading for all who care for patients with cancer.4 They indicate that the physician should commit to continuing care REFERENCES from the day of cancer diagnosis and that no patient should 1. Hafner C, Knuechel R, Stoehr R and Hartmann A: Clonality of be faced with abandonment of care. Rather the physician multifocal urothelial carcinomas: 10 years of molecular ge- should value palliation as an extension of the treatment netic studies. Int J Cancer 2002; 101: 1. process for those with advanced disease and not look at 2. Kastritis E, Dimopoulos MA, Antoniou N, Deliveliotis C, Chrisofos palliative care as a failure to cure. M, Skolarikos A et al: The outcome of patients with advanced In the current study a third of the patients had urological pure squamous or mixed squamous and transitional urothelial cancer and the rest had nonurological malignancies. We carcinomas following platinium-based chemotherapy. Anti- cancer Res 2006; 26: 3865. often find ourselves in the role of consultant. Should we 3. World Health Organization: Cancer Pain Relief and Palliative merely rely on our function as a technician either ordering or Care. Technical Report Series No. 804. Geneva, Switzerland: placing a stent, or should we take a more active role regard- World Health Organization 1990; p 11. ing the dying patient? Although this issue must be evaluated 4. Ok J-H, Meyers FJ and Evans CP: Medical and surgical pallia- individually, too often the clinicians withdraw from the dy- tive care of patients with urological malignancies. J Urol ing patient because we have no effective treatment to offer. 2005; 174: 1177. Evaluation of Nitrous Oxide Anesthesia for Endoscopic and Laparoscopic Urological Applications

alleary et al and El-Galley et al, the authors of arti- icant bowel distention that impairs the working space. In cles in this issue of The Journal (pages 184 and 225), this blinded prospective randomized study the authors dem- C should be congratulated on 2 accounts. These reports onstrated that subjective surgeon ratings of bowel distention are the result of well executed prospective randomized tri- were significantly worse with the application of N2O, and als. In addition, the authors focused on enhancing the pa- that the distention interfered with the progress of the pro- tient experience during what are already minimally invasive cedure in 25% of cases. These findings, if shared with our procedures. anesthesia colleagues, may help to further the concept of During the last 2 decades there has been an increased minimally invasive surgery by improving the quality of lapa- focus on the concept of minimally invasive surgery. As such, roscopic renal surgery while minimizing complications. patients no longer look to surgeons for a cure for disease, but The minimally invasive concept in urology has evolved rather expect that the disease will be managed effectively from a novelty and a luxury to a standard of care. Achieving with minimal discomfort and an expeditious convalescence. surgical objectives alone has lost acceptance among our pa- While these raised expectations can be difficult for surgeons tients, and a more educated public is demanding high qual- to achieve, we should perhaps use them as an impetus to ity results with minimal pain, a short hospital stay and an further minimize the perceived invasiveness of the proce- expedited convalescence. To continue exploring minimally dures, or to use novel techniques to improve the patient invasive concepts in a mature manner we will have to study experience during existing minimally invasive procedures. specific questions with well designed scientific trials as dem- Calleary et al explore the use of Entonox® during office onstrated in these 2 articles. In addition, to optimize the flexible cystoscopy in younger patients. Flexible cystoscopy overall patient experience with minimally invasive proce- is a valuable diagnostic and therapeutic modality commonly dures we will have to explore not only the technical proce- applied by urologists. Despite familiarity with flexible cys- dures themselves, but all aspects of surgery including anes- toscopy as well as the general belief that the procedure is thesia and analgesics, associated physiology and even well tolerated without anesthesia, the procedure has been psychological aspects of minimally invasive surgery. documented to result in noticeable patient discomfort.1,2 As emphasized by the authors, the value of lidocaine jelly in Jaime Landman this setting is controversial. Similarly Hruby et al evaluated Department of Urology transcutaneous electrical nerve stimulation in the setting of Columbia University Medical Center office flexible cystoscopy with limited success.3 In the cur- New York, New York rent article Calleary et al have nicely demonstrated that sedation with a combination of 50% nitrous oxide and 50% REFERENCES oxygen improved younger patients’ tolerance of flexible cystoscopy with minimal added morbidity. Using 2 metrics, 1. Kobayashi T, Nishizawa K, Mitsumori K and Ogura K: Instil- analogue pain scales and heart rate, the authors clearly lation of anesthetic gel is no longer necessary in the era of demonstrated improved patient tolerance, thus enhancing flexible cystoscopy: a crossover study. J Endourol 2004; 18: the minimally invasive nature of cystoscopy. 483. 2. Palit V, Ashurst HN, Biyani CS, Elmasray Y, Puri R and Shah El-Galley et al evaluated the effects of adding nitrous T: Is using lidocaine gel prior to cystoscopy justified? A oxide (N2O) during the harvest component of laparoscopic randomized prospective study. Urol Int 2003; 71: 389. donor nephrectomy. While there is conflicting evidence 3. Hruby G, Ames C, Chen C, Yan Y, Sagar J, Baron P et al: about bowel distention with nitrous oxide assisted anesthe- Assessment of efficacy of transcutaneous electrical nerve sia, many experienced urological renal laparoscopists be- stimulation for pain management during office-based flexi- lieve that the application of N2O results in clinically signif- ble cystoscopy. Urology 2006; 67: 914.

Techniques for Fluoroscopic Percutaneous Renal Access

Nicole L. Miller, Brian R. Matlaga and James E. Lingeman*,† From the Methodist Hospital Institute for Kidney Stone Disease, Indiana University School of Medicine and International Kidney Stone Institute, Indianapolis, Indiana

Purpose: Percutaneous nephrolithotomy has undergone considerable evolution since its introduction in the 1970s, which has been driven by advances in access techniques, instrumentation and endoscopic technology. Recent reports suggest an increase in the number of percutaneous stone treatments being performed. However, despite the increasing use of percutaneous nephrolithotomy a minority of urologists obtain their own access. We reviewed the techniques for performing safe and effective percutaneous renal access. Materials and Methods: A literature search using Entrez PubMed® was performed. All relevant literature concerning techniques for fluoroscopic percutaneous renal access published within the last 20 years was reviewed. Results: The success of percutaneous nephrolithotomy is critically dependent on achieving suitable percutaneous access. The ideal site of percutaneous puncture should be selected to maximize the use of rigid instruments, minimize the risk of complications and attain stone-free status. Familiarity with basic renal anatomy is essential to obtain access safely. Adherence to basic principles allows the establishment of percutaneous access in a straightforward and efficient manner. Certain clinical situations may require special access techniques. Conclusions: Percutaneous nephrolithotomy is the treatment of choice for complex stone disease. While the efficacy of percutaneous nephrolithotomy relies on the establishment of effective percutaneous access, there are considerable advantages for the urologist able to achieve access. Key Words: kidney; kidney calculi; nephrostomy, percutaneous; diverticulum; fluoroscopy

n the 3 decades that have passed since PNL was first We reviewed the techniques of successful PNL access described it has evolved into a safe and effective treat- achieved through more commonly used fluoroscopically I ment of patients with large or otherwise complex calcu- guided approaches. We also examined more specialized ac- lous disease. Morris et al recently reported that PNL has cess methods that may be required for the success of PNL in become an increasingly common intervention for patients special clinical situations. A complete review of the potential with stone disease.1,2 However, despite the increasing use of complications of PNL is beyond the intended scope of this PNL Lee et al reported that a minority of urologists, only review and complications are not discussed except as they 27% of those who were trained in percutaneous access, ac- relate to a specific access technique. tually gain their own access for PNL.3 One of the more common reasons given by respondents in this study was ANATOMICAL CONSIDERATIONS inadequate skills in the techniques of access. AND PUNCTURE SITE SELECTION The placement of percutaneous access into the intrarenal collecting system is one of the most critical aspects of PNL. Familiarity with basic renal anatomy is essential to obtain When done well, the remainder of PNL can be performed in access safely. In particular knowledge of the principal renal a straightforward, expeditious manner. However, when vascular structures and their relationships to the renal col- done poorly, PNL can be a struggle with complications be- lecting system can decrease the risk of problematic hemor- coming more frequent. In a recent study Watterson et al rhagic events. The main renal artery typically divides into examined access related complications during PNL when an anterior and a posterior division. The avascular field access was obtained by a urologist vs an interventional between the anterior and posterior divisions, known as radiologist.4 They concluded that, despite similar access dif- Brodel’s bloodless line, is the ideal point of renal entry. ficulties between the groups, access related complications Because of the orientation of the kidney in the body, entry through a posterior calix usually traverses this line. A pos- were less and stone-free rates were improved during urolo- terior calix is the preferred site of entry since it is usually gist acquired percutaneous access. easier to negotiate a wire out of the calix and into the ureter when the site of puncture is through a posterior rather than an anterior calix (fig. 1). Rarely it may be preferable to Submitted for publication July 7, 2006. obtain access through an anterior calix. This may be accom- * Correspondence: 1801 North Senate Blvd., Suite 220, Indianap- plished by adhering to the same principles as for a posterior olis, Indiana 46202 (telephone: 317-962-2485; FAX: 317-962-2893; caliceal approach. e-mail: [email protected]). † Financial interest and/or other relationship with Lumenis, Bos- Inadvertent puncture beyond the anterior aspect of the col- ton Scientific, Olympus and Karl Storz. lecting system risks vascular injury to the large anterior seg-

0022-5347/07/1781-0015/0 15 Vol. 178, 15-23, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.014 16 TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS

prone. The stone containing side is slightly elevated on a foam pad, which is a maneuver that brings the posterior calices into a more vertical position. The neck of the patient is placed in a neutral position with a chest roll positioned to facilitate ventilation. The upper extremity ipsilateral to the affected kidney is placed at 90-degree ﬂexion and the contralateral upper extremity is tucked at the side to allow the C-arm to be positioned as close to the patient as possible.

ACCESS TECHNIQUES While ultrasound and computerized tomography guidance have been described for percutaneous access,7,8 biplanar fluoroscopy is the most commonly used imaging method. FIG. 1. Preferred site for percutaneous access is through posterior Radiographic guidance of needle puncture into the collecting calix. This approach facilitates negotiation of wire out of calix and into ureter, and may decrease risk of vascular injury since access system for antegrade percutaneous access is routinely per- tract is created along avascular field between anterior and posterior formed using 1 of 2 techniques, including eye of the needle divisions of renal vasculature, known as Brödel’s bloodless line. and triangulation. There are still some urologists who favor Reprinted with permission from Lingeman JE, Lifshitz DA and Evan AP: Surgical management of nephrolithiasis. In: Campbell’s retrograde percutaneous access, especially when the kidney Urology, 8th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr and is mobile or malrotated. This involves retrograde placement AJ Wein. Philadelphia: WB Saunders Co 2002; vol 4, pp 3361–3451. of a ureteral catheter, followed by passage of a sharp wire through the catheter and out of the desired calix for access. mental vessels, which is a problematic complication since these Two nephrostomy systems (Hunter-Hawkins and Lawson) have been described to achieve retrograde percutaneous ac- vessels cannot be readily tamponaded with a nephrostomy 9,10 tube or occlusion balloon. Using 3-dimensional endocasts cess. Despite the feasibility of retrograde percutaneous Sampaio et al characterized the extent of vascular injury access this technique offers no advantage over antegrade from percutaneous puncture of the collecting system at var- percutaneous access, which enables more accurate and con- ious locations.5 Puncture through the infundibulum of the trolled creation of the nephrostomy tract. upper, middle and lower poles was associated with vascular injury in 67.6%, 38.4% and 68.2% of kidneys, respectively. Eye of the Needle Puncture through the fornix proved to be much safer and it As with most percutaneous access techniques, the eye of the was associated with a venous injury rate of less than 8% and needle technique requires fluoroscopy to monitor and guide no arterial lesions. Direct puncture into the renal pelvis the procedure. To this end a ureteral catheter is placed and injured large retropelvic vessels in a third of cases. There- the patient is positioned as described. With the C-arm in the fore, the preferred point of entry into the collecting system is 30-degree position an 18 gauge diamond tip access needle is along the axis of the calix, through the papilla. Aligning the positioned, so that the targeted calix, needle tip and needle access with the infundibulum also allows the most efficient hub are in line with the image intensifier, giving a bull’s-eye use of a rigid nephroscope and decreases the need to place effect on the monitor (fig. 2). In effect the surgeon is looking excessive torque on the rigid instruments, which may cause renal trauma and bleeding. Infundibular puncture should be avoided if possible, as should direct puncture of the renal pelvis with its increased risk of vascular injury, potential prolonged urinary leakage and easy tube dislodgment. Puncture for renal access should be medial to the posterior axillary line to avoid injury to the colon because the position of the colon is usually anterior or anterolateral to the most lateral part of the kidney.6 Medial puncture should also be avoided because it may traverse the paraspinal muscles increasing postoperative pain. Finally, puncture should not be performed too close to the rib because it may injure the intercostal nerve and vessels.

PATIENT POSITIONING Fluoroscopically guided percutaneous access requires opacification of the renal collecting system. Most commonly radiographic contrast medium is instilled via cystoscopically placed ureteral catheters. Cystoscopy may most easily be performed using rigid instruments and with the patient in a dorsal lithotomy position. Although it is less convenient, FIG. 2. Eye of needle technique for percutaneous access. Diamond flexible cystoscopy with the patient supine or prone may also tip 18 gauge access needle is positioned so that target, needle tip and needle hub are in line with image intensifier. Note character- be used. Following ureteral catheter placement a Foley cath- istic bull’s-eye radiographic appearance as surgeon looks down nee- eter is also routinely placed and the patient is positioned dle into targeted calix, hence, term eye of needle. TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS 17 down the needle into the targeted calix and, hence, the term capsule is entered final adjustments are made. Manipulat- eye of the needle. The needle is advanced in 1 to 2 cm ing the needle after entering the renal parenchyma is dis- increments using a hemostat to minimize radiation expo- couraged since this may displace the kidney and alter the sure to the surgeon. Continuous fluoroscopic monitoring is position of the targeted calix. performed to ensure that the needle maintains the proper trajectory. Needle depth is ascertained by rotating the C- TRACT DILATION arm to a vertical orientation. If the needle is aligned with the AND ACCESS ESTABLISHMENT calix in this view, the urologist should be able to aspirate urine from the collecting system, confirming proper position- Aspiration of urine verifies proper caliceal puncture. A ing. 0.038-inch hydrophilic nitinol core glidewire is then passed through the needle and into the collecting system. Triangulation Technique While various wires can be used as long as they have an Biplanar fluoroscopy permits the determination of caliceal atraumatic tip, we prefer the nitinol core glidewire for ob- orientation and selection of the optimal calix for entry. The taining initial access because it is quite maneuverable and preferred point of entry into the collecting system is along resists kinking. Some operators elect to obtain access using the axis of the calix, through the papilla. Aligning the access a 21 gauge puncture needle that accepts a 0.018-inch wire. If with the infundibulum also allows the most efficient use of a this instrumentation is chosen, transition dilators are nec- rigid nephroscope and decreases the need for excessive essary to upsize to a larger working wire. We prefer the 18 torque on the rigid instruments, which may cause renal gauge access needle because it can be torqued, is easily trauma and bleeding. stabilized and does not require an additional exchange to After the targeted calix is identified with fluoroscopy place a suitable working wire. orientation of the line of puncture is performed using a Under fluoroscopic guidance an attempt is made to ad- triangulation technique. The C-arm is moved back and forth vance the glidewire down the ureter. If the wire does not between 2 positions, that is 1 parallel and 1 oblique to the pass easily into the ureter, it can be coiled in the renal line of puncture. With the C-arm oriented parallel to the line pelvis. An 8Fr fascial dilator is passed into the calix, fol- of puncture adjustments are made in the mediolateral (left/ lowed by a 5Fr Cobra tipped angiographic catheter. The right) direction (fig. 3, A). The C-arm is rotated to the oblique angiographic catheter helps direct the glidewire toward the position and adjustments are made in the cephalad/caudad UPJ, facilitating placement of the wire down the ureter. (up/down) orientation of the line of puncture with care taken After the glidewire is positioned in the ureter it is exchanged not to alter the mediolateral orientation of the needle (fig. 3, for a stiffer, polytetrafluoroethylene coated working wire, B). To decrease radiation exposure to the surgeon the C-arm such as an Amplatz super-stiff wire. The glidewire should is angled away from the line of puncture with the image not be used as a working wire because its lubricious nature intensifier angled toward the head of the patient. Mainte- makes it prone to displacement. An 8Fr to 10Fr coaxial nance of needle orientation in 1 plane while making adjust- dilating system or dual lumen catheter is then used to place ments in the other plane is critical for preserving proper a second safety wire, usually a 0.035-inch straight removal orientation. To facilitate precise puncture the surgeon may core wire. It is imperative to have a safety wire in place rest 1 forearm on the torso of the patient, thereby stabilizing before proceeding with percutaneous tract dilation. the line of puncture and minimizing drift. Several methods of tract dilation are available, including After the proper orientation of the line of puncture is metal telescoping dilators, semirigid Amplatz dilators and obtained ventilation is suspended in full expiration. Retro- balloon dilators.11–13 Balloon dilators have been reported to grade instillation of contrast dye allows collecting system cause significantly less bleeding than sequential dilators14 opacification and distention. An 18 gauge diamond tipped because the radial force used to spread the renal paren- needle is advanced toward the desired calix in the oblique chyma is less traumatic than the shearing or cutting action position to gauge the depth of puncture. Before the renal of sequential Amplatz dilators or metal telescoping dilators.

FIG. 3. Triangulation technique for percutaneous access. Fluoroscopic C-arm is moved back and forth between 2 positions, including 1 parallel and 1 oblique to puncture line. A, with C-arm oriented parallel to puncture line adjustments with access needle (arrows) are made in mediolateral (left/right) direction. Inset, corresponding ﬂuoroscopic image. B, C-arm is rotated to oblique position and adjustments with access needle are made in cephalad/caudad (up/down) orientation of puncture line with care taken not to alter mediolateral needle orientation. Inset, corresponding ﬂuoroscopic image. 18 TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS

Sequential Amplatz or metal dilators may be useful in the passing a guidewire through the communication with the setting of extensive perirenal fibrosis from previous renal renal collecting system is usually impossible. surgery. However, an X-Force™ N30 nephrostomy balloon The surgical technique used in the percutaneous treat- dilation catheter (Bard Urological, Covington, Georgia) was ment of caliceal diverticulum and diverticular stones has recently introduced, which can achieve 30 atmospheres. varied. Some groups advocate dilation of the diverticular This may prove advantageous in the presence of flank scar- communication or creation of a neo-infundibulum to theo- ring. Alternatively a 4.5 mm fascial incising needle (Cook retically improve diverticular drainage and decrease the Urological, Spencer, Indiana) can be placed over the working risk of stasis.18,19,22,26–28 Unfortunately these techniques wire to facilitate balloon dilation. require prolonged nephrostomy tube drainage across the An Amplatz working sheath is placed following balloon infundibulum. Monga et al questioned the need for estab- dilation of the tract to 30Fr. Care should be taken to avoid lishing communication between the diverticulum and renal over advancement of the sheath because this may cause collecting system.21 They performed direct percutaneous bleeding and trauma to the renal parenchyma or collecting puncture of the diverticulum and fulguration of the diver- system. An Amplatz sheath is always preferred because it ticular lining without cannulation or dilation of the diver- creates an open, low pressure (below 16 H2O) system, ticular infundibulum. Obliteration of the diverticular cavity thereby decreasing the absorption of irrigant into the circu- was documented in all patients by contrast radiography. 15 lation. Further advantages of a working sheath are easy Our preferred technique involves a single stage percuta- insertion and removal of the nephroscope, a simple exchange neous approach that obviates placement of a ureteral cath- from rigid to flexible nephroscopy and the ability to grasp or eter or entrance into the renal collecting system.29 The pa- basket larger stone fragments. tient is placed prone with the side containing the caliceal While a percutaneous access tract is usually achieved via diverticulum elevated 30 degrees. A C-arm fluoroscopy unit the 2-step process described, the new Pathway™ balloon is used to visualize the diverticular calculi and a direct expandable percutaneous access sheath (Boston Scientific, infracostal puncture is performed in all cases using an 18 Natick, Massachusetts) allows simultaneous balloon tract gauge diamond tipped needle and the biplanar fluoroscopic dilation and access sheath placement.16 The potential ben- triangulation technique, as described previously. When ac- efits of this design are decreased operative time and tissue cess is achieved, a 0.035-inch J tipped removable core guide- trauma.17 However, more data are needed to support these wire is coiled inside the diverticular cavity. The major ad- conclusions. vantage of the removable core J wire is that the flexible distal end of the wire can be adapted to the size of the diverticulum, SPECIAL SITUATIONS while the wire proximal to the removed core remains rigid Caliceal Diverticulum/Obstructed Calix enough to function as the working wire. The lubricious nature PNL is an ideal treatment for caliceal diverticulum because of a hydrophilic wire, such as a glidewire, makes it prone to it allows stone removal and ablation of the diverticular cav- dislodgement, which can result in loss of access with manip- ity (fig. 4).18–22 This is particularly true for lower pole di- ulation of the wire. With the J wire in place an 8/10Fr verticula and those greater than 1.5 cm.23–25 PNL offers coaxial dilator is passed over the J wire in sequential fash- excellent stone-free rates (93% to 100%) and successful oblit- ion. The 8Fr dilator is removed and a second 0.035-inch J eration of the diverticular cavity (76% to 100%) with a single tipped removable core wire is curled inside of the diverticu- procedure.19,20,22 lum to be used as a safety wire. A special access technique is warranted when planning A balloon dilator is passed over the working wire and percutaneous treatment of a caliceal diverticulum or a calix dilation of the nephrostomy tract is performed (fig. 5). A with an obstructed infundibulum containing stone material. 30Fr Amplatz sheath is then advanced over the balloon Direct puncture of a caliceal diverticulum can be difficult dilator using fluoroscopic guidance. Special attention is when the diverticulum is small and/or located in the upper given to prevent over advancement of the balloon dilator and pole. Even when the diverticulum is successfully punctured, sheath to avoid traumatizing the opposite wall of the diver-

FIG.4.A, scout excretory urogram demonstrates multiple calculi overlying mid portion of left kidney. B, following intravenous contrast material administration these calculi were identiﬁed in left caliceal diverticulum. Special access technique is warranted when planning percutaneous treatment of caliceal diverticulum or calix with obstructed infundibulum containing stone material. TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS 19

Using this technique Kim et al reported an 85.7% stone- free rate (18 of 21 renal units).29 All 16 renal units imaged with excretory urography at 3 months revealed a reduction in diverticular size and 87.5% showed complete resolution of the diverticulum. The access technique described for caliceal diverticulum is easily adapted to treat kidneys in which the infundibulum of the desired calix of puncture is impassable, as commonly occurs with staghorn calculi.

Supracostal or Upper Pole Supracostal or upper pole percutaneous access is necessary in certain clinical situations (see Appendix). The main advantage of this access technique is that the line of puncture directly aligns with the renal axis. For this reason it is advantageous in cases of coexisting renal calculi and UPJ obstruction or impacted proximal ureteral calculi because it allows excellent visualization of the UPJ and proximal ureter for stone removal and/or antegrade endopyelotomy (fig. 6, A).30 Supracostal or upper pole access may also be necessary when a large stone burden is located in the upper FIG. 5. Percutaneous access technique for treating stones in caliceal calices, such as a complete staghorn calculus, or in the diverticulum. With initial 0.035-inch J tipped removable core wire (J wire) in place 8/10Fr coaxial dilator is used to curl second J wire presence of multiple stone containing lower pole calices (fig. inside diverticulum to be used as safety wire. Balloon dilator is 6, B).31–34 PNL for calculi occurring in a horseshoe kidney is passed over working wire and dilation of nephrostomy tract is often best accomplished through upper pole access due to performed. incomplete ascent of the kidney. Although the percutaneous technique is similar to that described for the lower pole, certain aspects of supracostal or ticulum. The balloon dilator has a tapered distal end that upper pole access are worthy of emphasis. The main risk of often precludes placement of the sheath directly into the a supracostal puncture is injury to the lung and pleura diverticular cavity unless the diverticulum is large. A 24.5Fr because the upper poles of the 2 kidneys lie immediately rigid offset nephroscope (Richard Wolf, Vernon Hills, Illi- anterior to the posterior portion of the 11th and 12th ribs, nois) without the external sheath is placed through the and can even be as high as the 10th rib.35 The risk of pleural Amplatz sheath in conjunction with normal saline irriga- injury is greatest during the inspiratory phase of respiration. An 11Fr alligator forceps is used to manually dilate the tion. Therefore, general anesthesia is essential to control tract as needed immediately adjacent to the diverticulum. respiratory movements during puncture. For supracostal After the tract is adequately dilated the offset nephroscope access the puncture site should be placed in the upper por- is gently advanced into the diverticular cavity. Careful in- tion of the intercostal space, just lateral to the paraspinal spection of the urothelium with the rigid nephroscope is muscles, and puncture above the 11th rib should be avoided performed in an effort to verify that a true diverticulum when possible (fig. 7). Occasionally the upper pole can be exists rather than a flattened renal papilla associated with accessed via a laterally situated tract between the tips of the an obstructed calix. Ultrasonic lithotripsy of existing diver- 11th and 12th ribs or even by an infracostal approach. This ticular calculi and fulguration of the diverticulum can then type of intercostal access has been shown to decrease the be performed via the established access. risk of pleural injury compared to a vertical supracostal

FIG. 6. KUB shows that supracostal or upper pole percutaneous access is advantageous in certain clinical scenarios. A, large left proximal ureteral calculus and lower pole renal calculus. Upper pole access allows excellent visualization of UPJ and proximal ureter for stone removal. B, left upper pole partial staghorn calculus. Supracostal or upper pole access would be beneﬁcial in this case to remove large stone burden in upper calices. 20 TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS

of pleural fluid while the patient is under anesthesia. If intraoperative fluoroscopy of the chest is normal, a formal chest radiograph in the recovery room is recommended only if the patient is symptomatic. Minor pleural effusions can be managed conservatively but larger effusions and significant pneumothorax, which are rare, require placement of a chest tube.40 Small pigtail type catheters are usually sufficient because lung injury is rare if puncture is performed in full expiration and they are more comfortable for the patient than larger chest tubes. In the absence of splenomegaly or hepatomegaly injury to the liver and spleen is extremely rare when the access puncture site is below the 12th rib. However, supracostal access can be associated with an increased risk of injury to the liver and spleen, particularly if puncture is performed during the inspiratory phase of respiration rather than the expiratory phase or the puncture is above the 11th rib.41,42 To decrease the risk of liver or spleen injury the skin puncture site should be located as far medial as possible, adjacent to the lateral border of the paraspinal muscles. Supracostal puncture is also associated with increased postoperative pain.35 This is particularly true when a nephrostomy tube is left through the upper pole tract. In these cases lower pole nephrostomy drainage via a nondilated puncture may be advantageous since it permits the benefit of a supracostal puncture, while minimizing patient discomfort from an intercostal nephrostomy tube.43 Tubeless upper FIG. 7. Landmarks for supracostal access. Puncture site (X) should pole access should be reserved for cases in which the surgeon be placed in upper portion of intercostal space, just lateral to paraspinal muscles. Adapted from Kim SC and Lingeman JE: Per- is confident that all stone material of interest has been cutaneous access to the urinary tract. In: Advanced Endourology: removed. The Complete Clinical Guide. Edited by SY Nakada and MS Pearle. Totowa, New Jersey: Humana Press 2006; pp 43–59. Nondilated Puncture The nondilated puncture technique is particularly useful as puncture but it can limit visualization of the renal pelvis, an adjunct to standard PNL techniques in certain clinical lower pole and UPJ.36 scenarios, such as in the presence of an eccentric calix that The use of an Amplatz working sheath is mandatory in is difficult to identify via the established access. In this patients with supracostal access to decrease the risk of situation needle puncture into the desired calix without hydrothorax. Pulmonary complications have been reported tract dilation can be helpful (fig. 8, A). After the desired calix in approximately 16% of cases with a need for intervention is punctured an attempt is made to pass a glidewire into the in 3% to 4%.32,33,35,37,38 Ogan et al reported the usefulness of renal pelvis, where it can serve as a road map to the area of intraoperative fluoroscopy for detecting clinically significant interest. Alternatively methylene blue, carbon dioxide or hydropneumothorax following supracostal access.39 This contrast material can be injected through the needle and the technique is advantageous because it allows the aspiration colored stream or gas bubbles may be used to guide a flexible

FIG. 8. Nondilated puncture technique is particularly useful when narrow infundibulum prevents advancement of nephroscope into calix. A, percutaneous Amplatz sheath is in place. Stone material is present in calix that could not be identified using flexible nephroscopy through rigid access sheath. Access needle is advanced using stone as target for puncture. B, after access needle is placed into desired calix contrast medium is instilled through needle to delineate caliceal anatomy. C, flexible nephroscope is guided into desired calix after instillation of contrast material via access needle that functions as road map for caliceal access and stone removal. Alternatively guidewire could be negotiated through infundibulum and back loading of flexible nephroscope or ureteroscope over guidewire into desired calix can be accomplished via push-pull technique. TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS 21 nephroscope into the desired calix (fig. 8, B and C). Occa- sionally a narrow infundibulum prevents advancement of the nephroscope into the calix. In this instance a flexible ureteroscope or balloon dilation of the infundibulum may be necessary. Back loading of the flexible nephroscope or ureteroscope over a guidewire into the desired calix can be accomplished via a push-pull technique.44 The advantage of this approach is that a nephrostomy tube is not necessary afterward. As mentioned, a nondilated puncture may also be useful for inserting a small diameter nephrostomy tube into a lower pole calix in cases of tubeless upper pole or multiple access. The technique reported by Kim et al involves puncture of the lower pole onto a flexible nephroscope inserted through the upper pole access and directed into the desired 43 lower pole calix. FIG. 10. Y puncture percutaneous access technique. A, when calculi are located in calices that are in parallel with or adjacent to calix of Multiple Access initial puncture that cannot be accessed with flexible nephroscope, Y puncture technique may be considered. B, after calix of initial In certain cases multiple access may be required during PNL. puncture is cleared of stone working sheath is retracted outside of In general multiple access PNL should be considered when a renal capsule and angled toward second targeted calix. Second calix contains a stone that is larger than 2 cm and cannot be puncture is made through working sheath. Attraction of Y puncture is that second puncture is created through same skin incision as approached with a rigid instrument via the primary access, or first puncture, minimizing cosmetic effects of PNL. Reprinted with if a calix contains stones of any size that cannot be reached permission from Lingeman JE, Lifshitz DA and Evan AP: Surgical with a flexible instrument via the primary access (fig. 9). In management of nephrolithiasis. In: Campbell’s Urology, 8th ed. Edited by PC Walsh, AB Retik, ED Vaughan Jr and AJ Wein. most situations the additional access may be performed during Philadelphia: WB Saunders Co 2002; vol 4, pp 3361–3451. primary PNL unless the procedure is unduly prolonged or bleeding is deemed excessive. If calculi are located in calices that are in parallel with or adjacent to the calix of initial minimizing the cosmetic effects of PNL. Patients with an ex- puncture, a Y puncture technique, in which the secondary cessively large stone burden or those with complex collecting puncture angles off of the initial nephrostomy tract, may be system anatomy may harbor a stone following PNL through considered (fig. 10). After the calix of initial puncture is cleared the initial access track that is inaccessible by a Y puncture of stone the working sheath is retracted outside of the renal technique. In these situations a more formal multiple access capsule and angled toward the second targeted calix. The sec- approach is required with a separate skin incision and sepa- ond puncture is made through the working sheath. One of the rate track, according to techniques described previously for attractions of the Y puncture is that the second puncture is primary access. created through the same skin incision as the first puncture, CONCLUSIONS PNL is the treatment of choice for complex stone disease. However, despite the increasing use of PNL a minority of urologists obtain their own access. Percutaneous access is the most critical factor in determining the safety and efficacy of PNL. For this reason and for patient comfort access is best achieved in the operating room by the urologist or the urologist working beside a radiologist. There is no major operation performed by urologists in which the success of the procedure depends upon another physician and PNL ideally should be no different. Urologist acquired or directed access ensures a 1-stage approach and allows the application of the various access techniques reviewed. Furthermore, recent data suggest that access related complications are less and stone-free rates are improved during urologist acquired percutaneous access.

APPENDIX Indications For Upper Pole Access FIG. 9. KUB reveals complete left staghorn calculus. Multiple access was necessary to render patient stone free with PNL. Stone Staghorn calculi analysis revealed magnesium ammonium phosphate (struvite) com- Large upper pole stone burden position. Multiple access PNL should be considered when calix Antegrade endopyelotomy contains stone that is larger than 2 cm and cannot be approached Large and/or impacted proximal ureteral calculi with rigid instrument via primary access or calix contains stones of Upper pole caliceal diverticulum Complex lower pole calculi any size that cannot be reached with ﬂexible instrument via pri- Horseshoe kidneys mary access. 22 TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS

management of caliceal diverticula containing calculi. Abbreviations and Acronyms J Urol 1986; 135: 225. KUB ϭ plain x-ray of the kidneys, ureters and 20. Jones JA, Lingeman JE and Steidle CP: The roles of extracor- bladder poreal shock wave lithotripsy and percutaneous nephrosto- PNL ϭ percutaneous nephrolithotomy lithotomy in the management of pyelocaliceal diverticula. UPJ ϭ ureteropelvic junction J Urol 1991; 146: 724. 21. Monga M, Smith R, Ferral H and Thomas R: Percutaneous ablation of caliceal diverticulum: long-term followup. J Urol 2000; 163: 28. REFERENCES 22. Shalhav AL, Soble JJ, Nakada SY, Wolf JS Jr, McClennan BL and Clayman RV: Long-term outcome of caliceal diverticula 1. Morris DS, Taub DA, Wei JT, Dunn RL, Wolf JS Jr and following percutaneous endosurgical management. J Urol Hollenbeck BK: Regionalization of percutaneous nephro- 1998; 160: 1635. lithotomy: evidence for the increasing burden of care on 23. Auge BK, Munver R, Kourambas J, Newman GE and Prem- tertiary centers. J Urol 2006; 176: 242. inger GM: Endoscopic management of symptomatic 2. Morris DS, Wei JT, Taub DA, Dunn RL, Wolf JS Jr and caliceal diverticula: a retrospective comparison of percu- Hollenbeck BK: Temporal trends in the use of percutaneous taneous nephrolithotripsy and ureteroscopy. J Endourol nephrolithotomy. J Urol 2006; 175: 1731. 2002; 16: 557. 3. Lee CL, Anderson JK and Monga M: Residency training in 24. Batter SJ and Dretler SP: Ureterorenoscopic approach to the percutaneous renal access: does it affect urological practice? symptomatic caliceal diverticulum. J Urol 1997; 158: 709. J Urol 2004; 171: 592. 25. Canales B and Monga M: Surgical management of the calyceal 4. Watterson JD, Soon S and Jana K: Access related complica- diverticulum. Curr Opin Urol 2003; 13: 255. tions during percutaneous nephrolithotomy: urology versus 26. Al-Basam S, Bennett JD, Layton ZA, Denstedt JD and Razvi radiology at a single academic institution. J Urol 2006; 176: H: Treatment of caliceal diverticular stones: transdiverticu- 142. lar percutaneous nephrolithotomy with creation of a neoin- 5. Sampaio FJ, Zanier JF, Aragao AH and Favorito LA: Intra- fundibulum. J Vasc Interv Radiol 2000; 11: 885. renal access: 3-dimensional anatomical study. J Urol 1992; 27. Auge BK, Munver R, Kourambas J, Newman GE, Wu NZ and 148: 1769. Preminger GM: Neoinfundibulotomy for the manage- 6. Lang EK: Percutaneous nephrostolithotomy and lithotripsy: ment of symptomatic caliceal diverticula. J Urol 2002; a multi-institutional survey of complications. Radiology 167: 1616. 1987; 162: 25. 28. Lang EK: Percutaneous infundibuloplasty: management of 7. Matlaga BR, Shah OD, Zagoria RJ, Dyer RB, Streem SB and calyceal diverticula and infundibular stenosis. Radiology Assimos DG: Computerized tomography guided access for 1991; 181: 871. percutaneous nephrostolithotomy. J Urol 2003; 170: 45. 29. Kim SC, Kuo RL, Tinmouth WW, Watkins S and Lingeman JE: 8. Osman M, Wendt-Nordahl G, Heger K, Michel MS, Alken P Percutaneous nephrolithotomy for caliceal diverticular cal- and Knoll T: Percutaneous nephrolithotomy with ultra- culi: a novel single stage approach. J Urol 2005; 173: 1194. sonography-guided renal access: experience from over 300 30. Lam HS, Lingeman JE, Mosbaugh PG, Steele RE, Knapp PM, cases. BJU Int 2005; 96: 875. Scott JW et al: Evolution of the technique of combination 9. Hunter PT, Hawkins IF, Finlayson B, Nanni G and Senior D: therapy for staghorn calculi: a decreasing role for extra- Hawkins-Hunter retrograde transcutaneous nephrostomy: corporeal shock wave lithotripsy. J Urol 1992; 148: 1058. a new technique. Urology 1983; 22: 583. 31. Aron M, Goel R, Kesarwani PK, Seth A and Gupta NP: Upper 10. Lawson RK, Murphy JB, Taylor AJ and Jacobs SC: Retrograde method for percutaneous access to kidney. Urology 1983; pole access for complex lower pole renal calculi. BJU Int 22: 580. 2004; 94: 849. 11. Alken P, Hutschenreiter G, Gunther R and Marberger M: 32. Munver R, Delvecchio FC, Newman GE and Preminger GM: Percutaneous stone manipulation. J Urol 1981; 125: 463. Critical analysis of supracostal access for percutaneous re- 12. Clayman RV, Surya V, Miller RP, Castaneda-Zuniga WR, nal surgery. J Urol 2001; 166: 1242. Amplatz K and Lange PH: Percutaneous nephrolithotomy. 33. Stening SG and Bourne S: Supracostal percutaneous nephro- An approach to branched and staghorn renal calculi. JAMA lithotomy for upper pole caliceal calculi. J Endourol 1998; 1983; 250: 73. 12: 359. 13. Kerlan RK Jr, Kahn RI and Ring EJ: Percutaneous renal and 34. Wong C and Leveillee RJ: Single upper-pole percutaneous Ͼ ϭ ureteral stone removal. Urol Radiol 1984; 6: 113. access for treatment of or 5-cm complex branched 14. Davidoff R and Bellman GC: Inﬂuence of technique of percu- staghorn calculi: is shockwave lithotripsy necessary? J En- taneous tract creation on incidence of renal hemorrhage. dourol 2002; 16: 477. J Urol 1997; 157: 1229. 35. Fuchs EF and Forsyth MJ: Supracostal approach for percu- 15. Saltzman B, Khasidy LR and Smith AD: Measurement of renal taneous ultrasonic lithotripsy. Urol Clin North Am 1990; pelvis pressures during endourologic procedures. Urology 17: 99. 1987; 30: 472. 36. LeRoy AJ, Williams HJ Jr, Bender CE, Segura JW, Patterson 16. Pathak AS and Bellman GC: One-step percutaneous nephro- DE and Benson RC: Colon perforation following percutane- lithotomy sheath versus standard two-step technique. Urol- ous nephrostomy and renal calculus removal. Radiology ogy 2005; 66: 953. 1985; 155: 83. 17. Goharderakhshan RZ, Schwartz BF, Rudnick DM, Irby PB and 37. Golijanin D, Katz R, Verstandig A, Sasson T, Landau EH and Stoller ML: Radially expanding single-step nephrostomy Meretyk S: The supracostal percutaneous nephrostomy for tract dilator. Urology 2001; 58: 693. treatment of staghorn and complex kidney stones. J En- 18. Bellman GC, Silverstein JI, Blickensderfer S and Smith AD: dourol 1998; 12: 403. Technique and follow-up of percutaneous management of 38. Narasimham DL, Jacobsson B, Vijayan P, Bhuyan BC, caliceal diverticula. Urology 1993; 42: 21. Nyman U and Holmquist B: Percutaneous nephrolithot- 19. Hulbert JC, Reddy PK, Hunter DW, Castaneda-Zuniga W, omy through an intercostal approach. Acta Radiol 1991; Amplatz K and Lange PH: Percutaneous techniques for the 32: 162. TECHNIQUES FOR FLUOROSCOPIC PERCUTANEOUS RENAL ACCESS 23

39. Ogan K, Corwin TS, Smith T, Watumull LM, Mullican MA, 42. Robert M, Maubon A, Roux JO, Rouanet JP and Navratil H: Cadeddu JA et al: Sensitivity of chest fluoroscopy compared Direct percutaneous approach to the upper pole of the kid- with chest CT and chest radiography for diagnosing hydro- ney: MRI anatomy with assessment of the visceral risk. pneumothorax in association with percutaneous nephrosto- J Endourol 1999; 13: 17. lithotomy. Urology 2003; 62: 988. 43. Kim SC, Ng JC, Matlaga BR, Lifshitz DA and Lingeman JE: 40. Ogan K and Pearle MS: Oops we got in the chest: fluoroscopic Use of lower pole nephrostomy drainage following endo- chest tube insertion for hydrothorax after percutaneous renal surgery through an upper pole access. J Urol 2006; nephrostolithotomy. Urology 2002; 60: 1098. 175: 580. 41. Hopper KD and Yakes WF: The posterior intercostal approach 44. Lingeman JE, Newmark JR and Wong MYC: Classification for percutaneous renal procedures: risk of puncturing the and management of staghorn calculi. In: Controversies in lung, spleen, and liver as determined by CT. AJR Am J Endourology. Edited by AD Smith. Philadelphia: WB Saun- Roentgenol 1990; 154: 115. ders Co 1995; pp. 136–144. The Comparative Safety of Oral Versus Intranasal Desmopressin for the Treatment of Children With Nocturnal Enuresis

W. L. M. Robson,* A. K. C. Leung and J. P. Norgaard From the Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada, Ferring International Science Center, Copenhagen, Denmark, and Department of Urology, Clinical Sciences, Lund University, Lund, Sweden

Purpose: Desmopressin is a well established and effective therapy for nocturnal enuresis. Water intoxication leading to hyponatremia is an infrequent but serious adverse event associated with desmopressin. We assessed the safety of desmopressin in children 18 years or younger with nocturnal enuresis with a focus on the relative safety of the oral compared with the intranasal formulation. Materials and Methods: Published data (MEDLINE®) from December 1972 to August 2006 and post-marketing safety data from December 1972 to June 2005 were analyzed. Results: A total of 21 clinical trials on desmopressin use in children with nocturnal enuresis were identified. There were no reports of hyponatremia. A total of 21 publications were identified that included 48 case reports of hyponatremia in children with nocturnal enuresis. In all case reports patients were treated with intranasal desmopressin. Post-marketing safety data included 151 cases of hyponatremia in children with nocturnal enuresis, of whom 145 were treated with intranasal desmopressin and 6 were treated with the tablet formulation. Prodromal symptoms of hyponatremia were identified as headache, nausea and vomiting. Conclusions: Data suggest that there is a decreased risk of hyponatremia with oral desmopressin compared with intranasal desmopressin. Identifiable and preventable risk factors for hyponatremia are inappropriately high fluid intake, administration of a larger than recommended dose, young age (less than 6 years) and concomitant administration of another medication. When desmopressin is prescribed, patients should be instructed to avoid high fluid intake when the medication is ingested, not ingest a higher than recommended dose and promptly discontinue the medication and seek assessment if headache, nausea or vomiting develops. Key Words: bladder, deamino arginine vasopressin, enuresis, hyponatremia, complications

esmopressin is a well established and effective METHODS therapy for NE. In the quarter century since ap- Data were collected from 2 primary sources. A MEDLINE D proval for this indication in 1980, numerous stud- search of the English language literature was done to iden- ies have demonstrated the efficacy and safety of desmo- tify clinical trials and case reports that included information pressin. The only serious adverse event associated with on the safety of desmopressin prescribed for the treatment of desmopressin is water intoxication, leading to hyponatre- children with NE. When pertinent nonEnglish language ar- mia.1 There is anecdotal evidence that the tablet formu- ticles were identified and the publication contained an En- lation of desmopressin is associated with a lower inci- glish abstract with sufficient information, these articles dence of hyponatremia than the intranasal formulations. were included in the review. The search included the years However, clinical studies that substantiate this sugges- from 1972, which is the year that the intranasal formulation tion are lacking. of desmopressin was introduced, to August 2006. The key We assessed the safety of desmopressin with a focus on words used for the search were safety, side effect(s), adverse the relative safety of the oral formulations, which include event(s), hyponatraemia, hyponatremia and water intoxica- a tablet and a lyophilisate, compared with the intranasal tion, combined with bedwetting, nocturnal enuresis, pri- formulations, which include droplets and a spray. Pub- mary nocturnal enuresis, secondary nocturnal enuresis, lished data (MEDLINE) were analyzed on the safety of DDAVP, desmopressin and Minirin®. The articles were re- desmopressin prescribed for the treatment of NE as well trieved and analyzed. as PMS adverse event data reported to Ferring Pharma- PMS data on file with Ferring Pharmaceuticals were ceuticals, which is the major manufacturer of desmo- analyzed to identify adverse event reports of hyponatremia. pressin. Data were available for review from December 1972 to June 2005. During these years Ferring Pharmaceuticals followed the same methodical and careful procedures to identify PMS adverse event data regardless of the drug or formulation. Submitted for publication August 23, 2006. In addition, a search of the Cochrane Database of Sys- * Correspondence: Suite 111, 4411 16th Ave. Northwest, Calgary, Alberta, T3B 0M3, Canada (telephone: ϩ1 403 202 2949; FAX: ϩ1 tematic Reviews was done using the key word desmopressin. 403 202 2948; e-mail: [email protected]). Retrieved articles were then searched for mention of the

0022-5347/07/1781-0024/0 24 Vol. 178, 24-30, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.015 SAFETY OF ORAL VERSUS INTRANASAL DESMOPRESSIN FOR NOCTURNAL ENURESIS 25 word hyponatraemia or hyponatremia to ensure that reports from clinical trials not listed on MEDLINE were not missed. For the purposes of this survey a child was defined as an individual younger than 19 years. Short-term use was defined as treatment for 6 months or less. Long-term use was defined as treatment for more than 6 months. Symptoms of headache, nausea or vomiting were defined as prodromal for hyponatremia.

RESULTS Published (MEDLINE) Data A total of 21 clinical trials on the short-term or long-term use of desmopressin for the treatment of children with NE were identified, which included 3,101 patients.2–22 No additional clinical trials were identified from the Cochrane Database of FIG. 1. Reported number of children with hyponatremia and noc- Systematic Reviews. Eight trials (38%) were initiated inde- turnal enuresis treated with desmopressin. PMS data included 145 2,3,5,7,9,11,15,20 children treated with intranasal formulation, of whom 21 were pendently of Ferring Pharmaceuticals, while included in publications identified in MEDLINE search, and 6 13 (62%) were supported by Ferring Pharmaceuticals. Five treated with tablet formulation. MEDLINE search included 48 of the latter sponsored trials were pivotal studies performed cases associated with intranasal formulation. for regulatory purposes6,10,12,18,21 and 8 were phase IV studies.4,8,13,16,17,19,22,23 Hyponatremia was not reported in any of these clinical trials. had nausea, vomiting or headache before the onset of a seizure 24–26,28,29,32,33,35–37,39–42,44 In the clinical trials of short-term and long-term use of or an altered level of consciousness. the intranasal or tablet formulations of desmopressin in The MEDLINE search did not reveal any case reports of children with NE the overall incidence of adverse events was hyponatremia in children with NE treated with the oral low. Reported adverse events associated with desmopressin formulations (fig. 1). treatment in children with NE were described as mild and transient, including headache, abdominal pain, nausea and PMS Data dyspepsia. In patients treated with the intranasal formula- Analysis of PMS data revealed 145 cases of hyponatremia tions reported adverse events also included nasal conges- associated with the use of intranasal formulations for the tion, rhinitis and epistaxis. In 2 studies there was no signif- treatment of NE in children (fig. 1).46 Of these 145 cases 21 icant difference between the reported incidences of adverse were in the MEDLINE database. Seizures associated with events in the treatment and control groups, and no associa- hyponatremia were reported in 115 cases (80%). A total of tion between the dose and the number of adverse events.10,12 129 patients, representing 97% of those on whom data were Few patients withdrew from treatment due to an adverse available, recovered from hyponatremia. Three patients event and no serious adverse events were reported in short- (2%) had not recovered at the time of the report and 1 (1%) term or long-term studies of the treatment of NE with the died. A 9-year-old girl experienced hyponatremia with sei- intranasal or tablet formulations of desmopressin. No clini- zures following strenuous exertion during warm weather. cally significant changes in mean serum sodium were re- Information on the dose of desmopressin, fluid intake and ported in long-term studies of the treatment of NE with the medical history was not available. Fluid intake was docu- intranasal formulations or tablet formulation.9,16,17 One mented as increased or excessive during or before treatment study described an increase in mean body weight,17 while in with desmopressin in 38 cases (26%). Of the patients 105 another mean body weight did not change throughout treat- (72%) ingested the recommended dose, 17 (12%) ingested a ment.9 higher than recommended dose and in 23 (16%) the dose was A total of 21 publications were identified that included not reported. A total of 41 patients (28%) were 5 to 6 years 48 case reports of hyponatremia in children with NE who old. The drug was administered to 14 children (10%) were treated with intranasal formulations of desmopressin younger than 5 years. Five patients (4%) who experienced (fig. 1).24–44 Ten publications provide data on the short-term hyponatremic seizures received imipramine in combination use of desmopressin24–29,31,38,40,42 and 6 provide data on with desmopressin. long-term use.30,33,35–37,39 Three publications describe a Analysis of PMS data revealed hyponatremia in 6 chil- mixture of long-term and short-term data,34,41,44 while 2 do dren with NE who were treated with the tablet formulation not mention the duration of desmopressin use.32,43 The table (fig. 1).46 Four of the 6 children (67%) experienced a seizure. lists pertinent clinical information from the 48 case reports. In 1 child a larger than recommended dose was suspected. Of these cases 36 (75%) involved seizures. Potential risk factors were identified in 3 of the 6 cases. One Excess fluid intake was identified as a contributing factor child had suspected psychogenic polydipsia and was also in at least 16 of the 48 cases (33%).26,27,34,35,37,38,40–43 Al- administered a higher than recommended dose. Two chil- though in the majority of cases a conventional dose of des- dren had a tendency to drink a lot of fluids and they were mopressin was prescribed, a higher than recommended dose concomitantly administered oxybutynin. All 6 patients re- might have been a factor in some cases.24,34,36,41 A weight gain covered fully. of 700 and 1,500 gm was recorded in 1 patient each.29,38 The In the short time that the new oral lyophilisate has been weight gain was believed to be a physical examination finding marketed there have been no reports of hyponatremia asso- consistent with hyponatremia.45 A total of 27 patients (56%) ciated with the formulation. 26 SAFETY OF ORAL VERSUS INTRANASAL DESMOPRESSIN FOR NOCTURNAL ENURESIS

Case reports of hyponatremia in children with NE treated with intranasal desmopressin Reference Age (yrs)—Sex Dose (␮g) Indication Seizure Sodium (mmol/l) Treatment Duration

Simmonds et al40 13—F 10–20 PNE Yes 120 4 days Bamford and Cruickshank25 6—M 20 PNE Yes 122 8 days Blanchard and Brossier27 5—M 20 NE Yes 117 5 wks Beach et al26 10—M 20 PNE Yes 118 3 days Muglia et al35 15—M 80 PNE No 124 7 mos Yaouyanc et al42 2—M 20 PNE Yes 118 6 wks Hamed et al30 10—M 40 PNE Yes 113 7 mos Kallio et al33 8—F 40 PNE No 120 2ϩ yrs Kallio et al33 11—M 20 PNE Yes 123 2 yrs, 2 mos, break, 1 day Hourthane and Salisbury31 8—F 40 NE Yes 119 2 days Guillaud et al29 4—M 20 SNE Yes 122 8 days Schwab et al38 6—M 10 NE Yes 125 3 days Robson et al37 16—F 40 NE Yes 128 9 mos Jensen and Hansen32 NM 40–50 NE Yes 125 NM Segal-Kuperschmit et al39 15—M NM PNE Yes NM 1 yr Donoghue et al28 10—M 40 PNE Yes 134 3 wks Apakama and Bleetman24 6—M 10 NE Yes 119 1 wks Lebl et al34 10—M 7 NE No 125 3 mos Lebl et al34 5—M 7 NE Yes 125 3 mos Lebl et al34 7—F 21 PNE No 125 1 yrs Lebl et al34 6—F 7 PNE No 120 2 yrs Lebl et al34 9—M 7 PNE Yes 123 Few days Lebl et al34 10—F 7 SNE Yes 113 2 wks Lebl et al34 11—M 7 SNE Yes 127 1 day Ragoschke-Schumm et al36 16—M 20 NE Yes 120 2ϩ yrs Thumfart et al41 5—M 30 SNE Yes 122 1 wk Thumfart et al41 6—M 10 PNE Yes 119 8 wks Thumfart et al41 6—M 10 PNE Yes 112 4 wks Thumfart et al41 6—M 10 PNE No 127 1 day Thumfart et al41 6—M 20 PNE Yes 129 1 day Thumfart et al41 6—M 20 PNE No 118 1 wk Thumfart et al41 8—M 20 PNE Yes 121 2 yrs Thumfart et al41 8—M 20 PNE Yes 122 2 wks Thumfart et al41 5—F 10 PNE Yes 126 2 wks Thumfart et al41 6—F 10 PNE Yes 120 1 day Thumfart et al41 6—F 40 PNE Yes 116 3 wks Thumfart et al41 8—F 30 PNE Yes 125 8 wks Thumfart et al41 9—F 20 PNE Yes 126 26 wks Dehoorne et al43 NM NM PNE Yes NM NM Dehoorne et al43 NM NM PNE Yes NM NM Dehoorne et al43 NM NM PNE Yes NM NM Dehoorne et al43 NM NM PNE No NM NM Dehoorne et al43 NM NM PNE No NM NM Ecoffey et al44 7—F 30 NE Yes 117 7 wks Ecoffey et al44 8—M 40 NE No 127 6 wks Ecoffey et al44 12—M 40 NE No 116 4 days Ecoffey et al44 5—M 20 NE Yes 115 1 wk Ecoffey et al44 9—F 10–40 NE No 121 1 yr (occasional)

DISCUSSION an injectable solution for intravenous, subcutaneous or in- tramuscular use introduced in 1981, an oral tablet formula- Desmopressin, also known as Minirin or DDAVP (1- tion introduced in 1987 and a rapidly acting, water-free oral deamino-8-arginine vasopressin), is a synthetic analogue of lyophilisate formulation introduced in 2005. Desmopressin has AVP. AVP regulates serum osmolality through the control of a level 1, grade A recommendation from the International water production by the kidney and it exerts an antidiuretic Consultation on Incontinence for the treatment of NE.49 effect mediated by renal V -receptors. AVP also has a pow- 2 The only serious potential adverse event that has been erful vasopressor effect mediated by vascular V -receptor. 1 reported in children with NE who were treated with desmo- Desmopressin is a selective V -receptor agonist and it has no 2 pressin is hyponatremia. Symptoms of hyponatremia in- effect on V1-receptors. As such, desmopressin retains the antidiuretic properties of AVP but it avoids unwanted vaso- clude headache, nausea, vomiting, altered consciousness 41 47 and seizure. pressor effects. In collecting duct cells V2-receptors stimulated by desmopressin increase water reabsorption directly Although data obtained from published clinical trials on via the insertion of aquaporin-2 type water channels into the the safety of desmopressin did not suggest any difference in apical cell membrane of collecting duct epithelial cells.48 overall safety between the intranasal formulations and the oral formulations of desmopressin, and did not reveal any Activated renal V2-receptors also increase sodium reabsorption, which increases medullary tonicity and enhances water cases of hyponatremia associated with any oral formula- reabsorption.48 tions, there were 48 case reports in the literature of this Desmopressin was originally introduced for the treat- adverse event with the intranasal formulations. All patients ment of central diabetes insipidus. The major current indi- recovered completely. cation for treatment with desmopressin is NE in children. PMS data included hyponatremia in 145 children with Desmopressin is commercially available in various formula- NE who were treated with intranasal desmopressin, of tions, including an intranasal solution introduced in 1972, whom 21 were included in the publications identiﬁed in the SAFETY OF ORAL VERSUS INTRANASAL DESMOPRESSIN FOR NOCTURNAL ENURESIS 27

MEDLINE search. Analysis of PMS data also showed 6 case antidiuretic activity of therapeutic doses of desmopressin reports of hyponatremia in children with NE treated with nasal spray and tablets lasts for 6 to 2447 and6to850 hours, the tablet formulation. respectively. A pharmacodynamic study was performed in Based on sales figures up to November 2005 approxi- children with primary NE treated with the oral lyophilisate mately 10 million children have been treated with desmo- formulation.18 This study revealed that the duration of an- pressin and it is estimated that 5 million have been exposed tidiuretic action increases with each increase in dose (fig. 2). to the intranasal and oral formulations, respectively.46 Al- For NE the most appropriate dose has a duration of action though the oral formulations have been available for a much that corresponds to the typical duration of sleep in a child. shorter time, exposure to intranasal and oral formulations is The typical duration of sleep for children between ages 6 and similar. This is probably because the oral formulations have 18 years is 11 and 8 hours, respectively.53 A dose of desmo- been marketed more extensively, especially in the United pressin that provides a longer duration of action would be States, and the international market for desmopressin in- likely to increase the risk of prolonged antidiuresis and creased substantially after the introduction of the tablet the risk of hyponatremia. When antidiuresis extends into formulation. Although a similar number of children have the following day, water is accumulated and not excreted been treated with each formulation, we identified 172 case before the next dose is taken.18 In support of this proposed reports (145 in PMS data plus 27 additional cases in the mechanism for hyponatremia Dehoorne et al reported a MEDLINE literature) of hyponatremia associated with prolonged duration of antidiuretic action in 18 children the intranasal formulations in children younger than 19 treated for NE with intranasal desmopressin in whom pro- years treated for NE and only 6 case reports of the tablet dromal symptoms or hyponatremia developed.43 The inves- formulation. As such, the risks associated with the intrana- tigators noted a significantly prolonged maximal urinary sal formulations would appear to be much higher. A possi- concentration period and delayed restoration of daytime di- bility to account for the smaller number of case reports with luting capacity in this population of children compared with the tablet formulation is that the medical community has those in a control group of 50 children with NE who were presumed that the medical literature contains a sufficient treated with the same desmopressin regimen (p Ͻ0.01). The number of case reports of hyponatremia associated with physiological mechanism is not known to explain why these desmopressin treatment per se and the occurrence with an 18 children had a prolonged duration of antidiuretic action oral formulation is no longer reportable. Another possibility but the other 50 did not. is that the tablet formulation has been available for a For the lyophilisate formulation the pharmacodynamic shorter period. Notwithstanding these possibilities, we be- study revealed that doses in the range of 120 to 360 ␮g lieve that there is a decreased risk with the oral (tablet and provide a duration of antidiuretic action of up to 10.2 lyophilisate) formulations. hours.18 Since the lyophilisate formulation has approxi- There are several reasons that might explain an in- mately 60% higher bioavailability than the tablet, an esti- creased risk with the intranasal formulations. Ingestion of a mate of a corresponding dose for a tablet might be 200 to 600 higher than recommended dose is more likely with an intra- ␮g. This is in the range suggested by pharmacodynamic nasal formulation. Some patients, parents or caregivers studies on tablets in adults, which revealed a duration of might feel unsure whether an adequate dose has been ad- antidiuretic action of 6 to 8 hours.50 However, to our knowl- ministered with an intranasal formulation and they might edge such data are not available for the intranasal formula- increase the dose to compensate for this uncertainty. An- other possible reason for this increased risk could be differences in pharmacodynamic profiles between the intranasal and oral formulations. Desmopressin is rapidly absorbed into the bloodstream regardless of the formulation. Ten ␮gof the intranasal formulation achieves the maximum plasma concentration within 1 hour of administration,50 while 400 ␮g of the tablet and 240 ␮g of the lyophilisate attain a maximum dose dependent plasma concentration within 2 hours.46 However, desmopressin tablets and the lyophilisate have a rapid onset of antidiuretic action with a decrease in urine production that is observed within 30 minutes following oral administration51 compared with 1 to 2 hours for intranasal desmopressin.47 The bioavailability of desmopressin in adults is approximately 3% after intranasal ad- ministration50 and 0.08% to 0.16% after a desmopressin tablet.50,52 The lyophilisate formulation has an average bioavailability that is approximately 60% higher than that of the tablet, that is the amount that reaches the circulation is approximately the same after the administration of 120 ␮g lyophilisate as after the administration of a 200 ␮g tablet.46 Until recently limited information existed on the pharmacodynamic response to desmopressin in children with NE FIG. 2. Mean osmolality with time after administration of different relative to the dose required to produce a useful antidiuretic doses of lyophilisate formulation of desmopressin in children with NE. Results revealed that duration of antidiuretic action increases effect. The doses used in children were extrapolated from with each increase in dose. Reproduced with permission from Black- studies in adults. Studies in healthy adults show that the well Publishing.18 28 SAFETY OF ORAL VERSUS INTRANASAL DESMOPRESSIN FOR NOCTURNAL ENURESIS

tions and the most appropriate dose for the desired duration Imipramine is known to decrease the seizure threshold.54 of antidiuresis with this formulation is unclear. The bio- The side effects of oxybutynin and methylphenidate include availability of intranasally administered desmopressin is dry mouth, which might lead patients to consume excess approximately 3%.50 Therefore, for the recommended dose fluid.29 Methylphenidate influences the central nervous range of 20 to 40 ␮gupto1.2␮g of medication are available. system, although it has no known effect on fluid ho- The bioavailability of the tablet is up to 0.16% and so, for the meostasis.55 It is possible that the distractibility and lack recommended dose range of 200 to 600 ␮g, 0.3 to 1.0 ␮gof of attention span common in some patients with ADHD the drug is available. As mentioned, the bioavailability of who are treated with methylphenidate might make these the lyophilisate is about 60% higher than that of the tablet individuals more susceptible to ingest an inappropriate and, therefore, for the recommended dose range of 120 to 360 amount of fluid.41 ␮ ␮ g, 0.3 to 0.9 g of the drug is available. Thus, oral formu- A coexistent disorder might also be a risk factor. Children lations appear to represent a safer alternative to intranasal with cystic fibrosis might be at increased risk, perhaps be- formulations because they have a similar onset of action, cause of abnormal sweat electrolyte losses or the increased lower bioavailability of the medication for the recommended risk of inappropriate antidiuretic hormone secretion associ- dose range, and a relatively predictable and practical dura- ated with the condition.56 In addition, children with ADHD tion of action that is compatible with the typical duration of might be at risk, as noted.26 Children with Prader-Willi sleep for children who are 6 to 18 years old.18,53 syndrome might also be at increased risk.37 These children Regardless of the formulation prescribed there are iden- have a voracious appetite and they often experience behav- tifiable and preventable risk factors for hyponatremia. An inappropriately high fluid intake before desmopressin ad- ioral problems, which might predispose them to an inappro- ministration is a key risk factor. Excess fluid intake was priately high fluid intake. We recommend that desmopressin identified as a contributing factor in 38 of the 145 PMS cases should be used with caution in patients with cystic fibrosis, (26%) that we identified. Other reviews and reports confirm ADHD or Prader-Willi syndrome. The medication should this risk factor. Robson et al identified an inappropriately not be administered during intercurrent clinical situa- high fluid intake in 5 of 10 cases (50%) reviewed.1 Thumfart tions that might otherwise affect fluid balance or in chil- et al identified an inappropriately high fluid intake in 4 of 12 dren with severe neurological or developmental problems cases (33%) on which fluid intake data were available.41 Lebl who might not be able to appropriately limit their evening et al attributed hyponatremia to an inappropriately high fluid intake. fluid intake in 2 of 7 children (29%) with NE who were We defined headache, nausea and vomiting as prodromal treated with intranasal desmopressin.34 Most recently symptoms. We recognize that headache, nausea and vomit- Ecoffey et al reported inappropriately high fluid intake in 4 of ing are signs of cerebral irritability and, therefore, they are the 5 cases (80%) reviewed.44 None of the groups reported the symptoms of hyponatremia. We chose these definitions be- duration of bioactivity of the administered desmopressin. cause from a practical clinical perspective the identification We recommend that fluid intake should be minimized on of prodromal symptoms might allow sufficient warning for a any evening that desmopressin is administered. A reason- patient, caregiver or physician to discontinue desmopressin able recommendation is to allow fluids as desired during therapy and prevent a seizure or altered level of conscious- dinner, minimize fluids to less than 240 ml (8 oz) after ness. Prodromal symptoms were common in patients in supper and not permit any fluids during the 2 hours preced- whom hyponatremia developed. Of the patients reported on 1 ing bedtime. These restrictions require modification for by Thumfart et al 8 (62%) experienced vomiting and 2 (15%) children who plays sports in the evening or who reside in hot experienced headache before the onset of hyponatremia.41 environments without air conditioning. Desmopressin Six of the 10 patients (60%) evaluated by Robson et al had a should not be administered on evenings when it is not prac- prodromal symptom before hyponatremia.1 Patients and tical or possible to restrict fluid intake. their caregivers should be advised that if headache, nausea The prescription or administration of a larger than rec- or vomiting develop, desmopressin treatment should be dis- ommended dose is another key risk factor. In the cases continued immediately and the child should be promptly reported by Thumfart et al 1 patient (8%) ingested a larger assessed. than recommended dose of desmopressin.41 Lebl et al spec- Finally, the completeness of PMS data should be consid- ulated that hyponatremia might have been due to the inges- ered. Although physicians are professionally obliged to re- tion of a larger than recommended dose in all 7 cases port suspected treatment related adverse events to the rel- reported.26 The drug should not be prescribed or taken in a higher than recommended dose. Hyponatremia might be evant pharmaceutical company or health authorities, not all more common early in the course of treatment with desmo- do so and adverse events in this respect are probably appre- pressin. Thumfart et al identified the first 3 weeks of treat- ciably underreported. However, the comprehensiveness of ment as a risk factor.41 Desmopressin is not recommended the data is somewhat immaterial since PMS data collection or approved for the treatment of NE in children younger methods were similar for the intranasal and oral formula- than 5 years. Thumfart et al identified young age as a risk tions, and the information remains useful and relevant in factor for hyponatremia.41 Concomitant administration of terms of the proportion of adverse events associated with another medication might be a risk factor. Robson et al each formulation. Therefore, the PMS data presented are identified concomitant administration of imipramine and believed to reliably substantiate the published data that we methylphenidate in 2 of the 10 cases (20%) that they re- reviewed. They indicate that hyponatremia in children with viewed.1 Of the 13 patients reported on by Thumfart et al 2 NE who are treated with desmopressin is more frequent (15%) were on oxybutynin and 1 (8%) was on methylpheni- with the intranasal formulations than with the tablet for- date.41 mulation. SAFETY OF ORAL VERSUS INTRANASAL DESMOPRESSIN FOR NOCTURNAL ENURESIS 29

CONCLUSIONS 6. Fjellestad-Paulsen A, Wille S and Harris AS: Comparison of intranasal and oral desmopressin for nocturnal enuresis. In the clinical trial setting desmopressin has proved to be an Arch Dis Child 1987; 62: 674. effective and well tolerated medication for children who 7. Kahan E, Morel D, Amir J and Zelcer C: A controlled trial of have NE with a low incidence of adverse events. Case re- desmopressin and behavioral therapy for nocturnal enure- ports and PMS data indicate that hyponatremia is an un- sis. Medicine (Baltimore) 1998; 77: 384. common but serious adverse event in children with NE. The 8. Matthiesen TB, Rittig S, Djurhuus JC and Norgaard JP: A optimal dose of desmopressin for NE is one that results in dose titration, and an open 6-week efficacy and safety study antidiuresis for approximately 8 to 11 hours, which is the of desmopressin tablets in the management of nocturnal enuresis. J Urol 1994; 151: 460. typical duration of sleep for a 6 to 18-year-old child. Any 9. Miller K and Klauber GT: Desmopressin acetate in children effect beyond this might lead to unwanted fluid retention with severe primary nocturnal enuresis. Clin Ther 1990; with a risk of hyponatremia. Therefore, for optimal safety 12: 357. the duration of action should be limited to no more than 12 10. Schulman SL, Stokes A and Salzman PM: The efficacy and to 16 hours, giving the body 8 to 12 hours to compensate for safety of oral desmopressin in children with primary noc- extra fluid retained. The data suggest that the risk of hypo- turnal enuresis. J Urol 2001; 166: 2427. natremia is greater in children treated with the intranasal 11. Shu SG, Lii YP and Chi CS: The efficacy of intranasal DDAVP compared with the oral formulations, probably because in therapy in children with nocturnal enuresis. Zhonghua Yi some children the duration of action of the intranasal for- Xue Za Zhi (Taipei) 1993; 52: 368. mulation (up to 24 hours) is longer than the typical duration 12. Skoog SJ, Stokes A and Turner KL: Oral desmopressin: a of sleep. We suggest that children with NE should be treated randomized double-blind placebo controlled study of effectiveness in children with primary nocturnal enuresis. with an oral rather than intranasal formulation of desmo- J Urol 1997; 158: 1035. pressin, especially since the duration of action of the oral 13. Terho P and Kekomaki M: Management of nocturnal enuresis formulations in the approved dose range is limited to ap- with a vasopressin analogue. J Urol 1984; 131: 925. proximately 10 hours. When desmopressin is prescribed, the 14. Terho P: Desmopressin in nocturnal enuresis. J Urol 1991; potential side effects and associated risk factors should 145: 818. be clearly explained to the patient and family. They should 15. Triantafyllidis A, Charalambous S, Papatsoris AG, Pa- be instructed to avoid an inappropriately high fluid intake pathanasiou A, Kalaitzis C, Rombis V et al: Management when the medication is received, not ingest a higher than of nocturnal enuresis in Greek children. Pediatr Nephrol recommended dose and promptly discontinue the medication 2005; 20: 1343. and seek assessment if headache, nausea or vomiting devel- 16. Tullus K, Bergstrom R, Fosdal I, Winnergard I and Hjalmas K: Efficacy and safety during long-term treatment of primary ops. monosymptomatic nocturnal enuresis with desmopressin. Swedish Enuresis Trial Group. Acta Paediatr 1999; 88: ACKNOWLEDGMENTS 1274. 17. Uygur MC, Ozgu IH, Ozen H, Ozen S, Toklu C, Ergen A et al: Klaus Olsen assisted with initial literature searches and Long-term treatment of nocturnal enuresis with desmo- Lene Holdrup provided feedback on the manuscript. pressin intranasal spray. Clin Pediatr (Phila) 1997; 36: 455. 18. Vande Walle J, Bogaert GA, Mattsson S, Schurmans T, Hoebeke P, Deboe V et al: A new fast-melting oral formulation of desmopressin (Minirin® Melt): a pharmacody- Abbreviations and Acronyms namic study in children with primary nocturnal enuresis. ADHD ϭ attention deficit hyperactivity disorder BJU Int 2006; 97: 603. AVP ϭ arginine vasopressin 19. Vertucci P, Lanzi C, Capece G, Fano M, Gallai V, Margari L NE ϭ nocturnal enuresis et al: Desmopressin and imipramine in the management NM ϭ not mentioned of nocturnal enuresis: a multicentre study. Br J Clin Pract PMS ϭ post-marketing safety 1997; 51: 27. PNE ϭ primary NE 20. Wille S: Comparison of desmopressin and enuresis alarm for SNE ϭ secondary NE nocturnal enuresis. Arch Dis Child 1986; 61: 30. 21. Wolfish NM, Barkin J, Gorodzinsky F and Schwarz R: The Canadian Enuresis Study and Evaluation—short- and REFERENCES long-term safety and efficacy of an oral desmopressin preparation. Scand J Urol Nephrol 2003; 37: 22. 1. 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Cohen LF, di Sant’Agnese PA, Taylor A and Gill JR Jr: The factors? J Urol 2005; 174: 294. syndrome of inappropriate antidiuretic hormone secretion 42. Yaouyanc G, Jonville AP, Yaouyanc-Lapalle H, Barbier P, as a cause of hyponatremia in cystic fibrosis. J Pediatr Dutertre JP and Autret E: Seizure with hyponatremia in a 1977; 90: 574. Historical Article

The Circumcision of Jesus Christ

Johan J. Mattelaer, Robert A. Schipper and Sakti Das* From the History Ofﬁce, European Association of Urology, Kortrijk, Belgium (JJM), Department of Urology, Jeroen Bosch Ziekenhuis, Hertogenbosch, The Netherlands (RAS), and the History Committee, American Urological Association, Linthicum, Maryland (SD)

Purpose: We study the controversies manifested in religious writings, art, sculpture and music as well as the theological disputes surrounding the circumcision of Jesus Christ. Materials and Methods: Data are derived from relevant historical and theological articles. Results: Jesus Christ was circumcised as a Jew on the 8th day after his birth. Until 1960 the Catholic church celebrated the day as Circumcision Day. In medieval times the holy foreskin was worshipped in many European churches. Conclusions: Christianity never condoned the ritual of circumcision and established the sacrament of baptism in its place. Key Words: circumcision, male; Christianity; foreskin; theology

CIRCUMCISION IN CHRISTIANITY compelled the Jacobites to abandon the ritual and adopt the sacrament of baptism. Circumcision was henceforth esus Christ was born as a Jew and, thus, was circum- regarded as a mortal sin.2 In Christian philosophy the spir- cised on the 8th day after his birth. “And when the itual circumcision of the heart triumphed over the physical J eight days were accomplished for the circumcising of circumcision of the foreskin. This was also the standpoint the child, his name was called Jesus, which was so named of later adopted by Luther and Calvin. the angel before he was conceived in the womb” (Luke, Until late in the 20th century January 1 was shown on chapter 2, verse 21). Notwithstanding the fact that Jesus calendars not as New Year’s Day but as the Feast of the was circumcised, Christianity never accepted this practice. Circumcision. The feast probably had its origins in Spain Although Jewish converts were allowed to be circumcised it during the late 5th century. When Spain later submitted to was forbidden for heathen converts. As early as 43 AD no the authority of the Western Empire and the Catholic less an authority than St. Peter adopted this pro-gentile church, the celebration of the feast spread throughout the position. “And when Peter was come up to Jerusalem, they rest of Western Europe and was included in the orthodox that were of the circumcision contended with him, saying, calendar.2 The Feast of the Circumcision was finally re- Thou wentest into men uncircumcised, and didst eat with moved from the Catholic calendar by the Second Vatican them.” (Acts of the Apostles, chapter 11, verses 2 to 3) Council in 1960. Similarly Paul wrote in his First Epistle to the Christians at Corinth (chapter 7, verses 18 to 19), “Is any man called THE CIRCUMCISION OF CHRIST being circumcised? Let him not become uncircumcised. Is IN THE HISTORY OF ART AND MUSIC any called in uncircumcision? Let him not be circumcised. Circumcision is nothing, and uncircumcision is nothing, but In light of this theological position it seems paradoxical that the keeping of the commandments of God is all.” This anti- uncircumcised Christian artists created so many images circumcision position was confirmed at the first Council of relating to the circumcision of Jesus in painting and sculp- Jerusalem in 48 AD and a new rite or sacrament was created ture (fig. 1). In Belgium alone there are no less than 54 listed to take its place: baptism. works in churches, museums and public buildings relating The first century of the new church was marked by constant to Christ’s circumcision, including paintings, grisaille, theological and dogmatic disputes between Christians and frescos, statues, altarpieces, stained glass windows and key- Jews on this difficult subject. The leaders of the early church stones. The icons of the Greek and Russian Orthodox were divided on the issue. In the Dictionnaire d’Archéologie churches also frequently contain circumcision images. Chrétienne et de Liturgie Father Henri Leclercq wrote, “The In the area of music there are fewer works relating to the faithful quickly came to regard circumcision as an eccentricity, circumcision of Jesus, although mention must be made of a bizarre and indecent act from which they felt far removed the “Missa Circumcisionis Domini Nostri Jesu Christi” com- and to which they did not intend to submit.”1 posed by Jan Dismas Zelenka (1679–1745), a court musician Nevertheless, the practice of circumcision remained in Vienna and Dresden. The original manuscript is pre- rooted in the Christian churches of the Jacobites in England served in the Sächsiche Landesbibliothek in Dresden. and the Copts in Ethiopia. The Council of Florence in 1442 REPRESENTATION OF THE CHILD CHRIST IN MEDIEVAL AND RENAISSANCE ART Submitted for publication September 1, 2006. * Correspondence: 1890 Via Ferrari, Lafayette, California 94549 In Byzantine and Roman art the child Christ is always (telephone: 925-639-5707; e-mail: [email protected]). dressed. However, from late medieval Flemish painters until

0022-5347/07/1781-0031/0 31 Vol. 178, 31-34, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.016 32 CIRCUMCISION OF JESUS CHRIST

In addition, the importance of the circumcision in the Renaissance lay in the fact that Christ shed his own blood. The blood was the proof of the incarnation just as it was a premonition of the Passion. What mattered was not the phallus but the wound.

THE RELIC OF THE HOLY FORESKIN OF CHRIST In the Middle Ages every tourist was a pilgrim and every pilgrim was somewhat of a tourist. Pilgrimage centers like Compostela and great abbeys were major attractions, and sacred relics and shrines acquired huge importance. Good relics could attract pilgrims and bring revenue from great distances, and the religious orders were quick to exploit this fact. Understandably the greatest value was attached to the relics of Christ himself. However, this presented something of a problem. Most saints left their bodies behind on earth when they died, thus there was an adequate supply of bones and other artifacts. Skulls were particularly prized. How- ever, Christ ascended into heaven in human form. This meant that the relic hunters had to make use of the parts of Christ’s body which he had lost before his death, such as his teeth, nails, tears, blood and, above all, his foreskin. This last item was particularly venerated and was known to the

FIG. 1. Gothic altarpiece panel in church of Sankt Wolfgang at Salzkammergut (Austria) painted by Michael Pacher (1430–1498). the Renaissance we see the Christ child completely nude and always uncircumcised.3 Although these painters must have been informed about circumcision because January 1 was a festivity day and they knew about circumcision in Jews and Moorish (Muslim) people, the Christ child was always depicted as uncircumcised (fig. 2). One reason for this depiction is the change in theology. The first Christians claimed for all the deity of Christ, while since the time of Augustine they claimed that Christ was perfect in divinity and in humanness, an actual God and an actual man, with a rational soul and body.3 A major reason for the Christ child not being shown circumcised must lie in the artist’s sense of the body’s perfection. Here artists would not infringe any more than they would deprive Eve of a navel, no matter what the learned might say.3 In view of the infinite merit which Christian doctrine attached to the circumcision of Christ, the refusal of artists in the Renaissance to acknowledge its visual effect remains an unexplained puzzle. Erasmus includes circumcision among the Jew- ish customs on which “we cry shame” (excremur). Perhaps this explains why Christian Renaissance artists did not represent the physical effect of circumcision when the subject was a reverend figure such as David or Christ. Depicting the nude infant Christ at any age they willingly paid the FIG. 2. Christ child completely nude and uncircumcised. Painting price of inaccuracy to spare the reverend body the blemish of by Hans Memling (ca. 1435–1494), Memlingmuseum, Bruges imperfection. (Belgium). CIRCUMCISION OF JESUS CHRIST 33

French as “Le Saint Prépuce,” to the English as “the Holy Foreskin,” to the Italians as “Santissimo Prepuzio” and to the Vatican as “Praeputium Domini.” The Spanish theologian and philosopher Francisco de Suarez (1548–1617) expressed the opinion that “after its circumcision, the foreskin of Christ was recovered and kept with great care and devotion by the Holy Virgin Mary.”4 Another version says that Holy Mary entrusted it with Mary Magdalena, and she later brought it to Saint Maximin-La Sainte Baume in the south of France where she was buried. The Swedish Saint Brigitta had a revelation in which she learned that Holy Mary had entrusted the holy foreskin with Saint John before her death. Other versions tell us that the holy prepuce fell into the caring hands of the apostles and from there it went to their successors. It finally emerged after centuries when an angel brought it to Charlemagne at Aachen (Germany), while a last story says it was a wedding gift to Charlemagne from the Byzantine Empress Irene. However, these startling assertions fail to explain how the Dominican scholar A. V. Müller, writing in 1907, could list no fewer than 13 separate locations, all of which claimed to possess the sacred foreskin as their holiest relic.5 We have been able to extend this list to 21 churches and abbeys, which at one time or another are reputed to have held Christ’s foreskin.6 Charroux, near Poitiers, France. The most famous center of pilgrimage related to the foreskin donated by the Emperor Charlemagne, who in turn had received it as a gift from the Empress Irene along with Christ’s sandals. The relic was described by Calvin, “Even the foreskin was shown by the monks of Charroux, who as a proof of its genuineness, declared that it yields drops of blood” (Calvin’s tract, vol. 1, pp. 296–304). The foreskin of Charroux was declared the only real one by Pope Clement VII (1523–1534). Coulombs, near Chartres, France. This “Saint Prépuce” FIG. 3. Reliquary for foreskin of Christ in church of St. Cornelius and St. Cyprian in Calcata. was famed for protecting women during childbirth. It was stolen in 1422 by the English King Henry V who believed it would help his French wife. The monks of Chartres were to the abbey by Charlemagne. Both relics were kept in the only able to recover it with great difficulty. same shrine, the “Capsa Magna.” It dates from the post- Sancta Sanctorum at the top of the famous Scala Santa, Carolingian period and was believed to be a gift from Pepin Rome, Italy. This relic was supposedly brought to Rome by of Aquitaine.8 Saint Brigida. It was stolen in 1527 during the siege of Rome Le Puy-en-Velay, France. During pilgrimages to Le Puy, by Charles V and was only rediscovered years later at Calcata the mother’s milk of the Blessed Virgin and the holy foreskin in the province of Viterbo. From that point Calcata itself be- were carried in procession through the streets in a kind of came a new center of pilgrimage. The relic was known as “La Christian fertility rite. Carna Vera Santa” (the True Flesh of the Most Holy). The Clermont, France. It was to this remote town that Saint reliquary containing the foreskin was carried in procession Austremoine, the patron saint of the Auvergne, brought the annually through the streets of Calcata until it was again holy foreskin and 2 fingernails of Christ’s right hand. stolen in 1983 (fig. 3). To date it has not been recovered.7 Paris, France. Saint Louis, King of France, built the San Giovanni in Laterano, Rome, Italy. In the early 12th magnificent Sainte-Chapelle to house his rich collection of century the holy prepuce was brought to Rome before Pope relics, including the holy foreskin. Innocent III. The Pope was asked to rule on the authenticity Hildesheim, Germany. Calvin wrote, “When this little but he declined the opportunity. book (on relics, published in 1543) was passing through the Antwerp, Belgium. In 1426 a fellowship was founded with press, I was informed of a third foreskin, which I had not the cumbersome name “The Fellowship of the Holy Foreskin mentioned, and which is displayed in Hildesheim.” of Our Dear Lord Jesus Christ in Our Lady’s Church in The remaining 11 locations include Notre-Dame-en- Antwerp.” A Flemish priest brought the holy foreskin to Vaux, Chalons-sur-Marne, France; Abbey of St.-Corneille, Antwerp after traveling to Jerusalem during the first cru- Compiègne, France; Metz, France; Santiago de Compostela, sade. However, the foreskin went missing during the icono- Spain; Langres, France; Besançon, France; Nancy, France; clastic riots of 1566.4 Boulogne, France; Chalon-sur-Marne, France; Fecamp, France Sainte-Foy de Conques, France. According to the and Vienna, Austria. However, the Vatican became increas- Chronique de Conques, a not wholly reliable source, the ingly less supportive of relics and in 1900 threatened excom- umbilical cord and the holy foreskin of Christ were donated munication to anyone who spoke of the holy foreskin. 34 CIRCUMCISION OF JESUS CHRIST

A THEOLOGICAL DEBATE FEMALE MYSTICI AND THE FORESKIN OF CHRIST Throughout the centuries many theologians concerned themselves with the thorny question of whether Christ was St. Catherine of Siena (1347–1380), 1 of the 2 female “doc- reunited with his foreskin before he ascended into heaven. tores” in the Catholic church during the Middle Ages, was Some argued that Christ must have taken his foreskin with widely revered for her “bridal purity and devotion.” To sym- him to heaven. Finally a consensus emerged that the pre- bolize her marriage with Christ she was reputed to wear the 5 puce was not more significant than the hair that had been foreskin of Jesus as a ring on her finger. This was depicted cut from Jesus’ head, or his nails or umbilical cord. Pope by several painters such as Peter Paul Rubens (Museum of Innocent III (1160/61–1216) decided not to become involved Fine Arts Houston) and Lorenzo Lotto (Accademia Carrara, and refused to judge who was right. According to him only Bergamo, Italy) as The Mystical Marriage of Catherine of Siena (fig. 4). The Austrian nun Agnes Blannbekin (1244– God would know the truth about such a delicate matter. 1315) also led a life devoted to the foreskin of Jesus. She was Anastasius Sinaita wrote in Quaestiones et Responsiones obsessed by the loss of blood and the pain which the re- (Questions and Answers), “We can be sure that he, having deemer had suffered during his circumcision.5 On one occa- voluntarily submitted himself to the act of circumcision, will sion when she was moved to tears by the thought of this have kept his foreskin, so that it could be restored to his suffering, she suddenly felt the foreskin on her tongue. body following his resurrection, thus allowing him to ascend McGinn explains that in late medieval times the festivity of to his heavenly father with a perfect body, entire and in- the circumcision of Jesus Christ was popular as a commem- 9 tact.” oration of the first bloodshed of our savior.10 Around the year 1150 Theophylactus made a similar argument that “It is useless to speculate what became of the CONCLUSIONS circumcised foreskin. We need not question where the scrip- tures themselves remain silent. We can assume, however, Born as a Jew, Jesus Christ was circumcised, and was de- that this body part, once removed, fell to the ground and picted as such in numerous paintings, sculptures and manu- made it holy, just as the water and blood which later flowed scripts. In the Catholic church Circumcision Day was cele- from his sacred side also made the ground holy. We must brated on January 1 until 1960. However, Christianity did conclude that our Lord preserved his undamaged foreskin not condone the practice of this rite but changed it to a new and restored it to his body following his resurrection, so that sacrament, that of baptism. In medieval times the holy he would once again become perfect” (Gospel of St. Luke, foreskin was worshipped in at least 21 Western European chapter 2).9 churches. Some theologians believed that to restore his per- The early Christian church was clearly interested in the fect body Christ was reunited with his foreskin after resurrection before ascending to heaven. question of what happened to the foreskin of Christ, but believed that the answer to this question was not deemed essential to the spiritual well-being of the faithful. Never- REFERENCES theless, during the 17th century the theologian Leo Allatius 1. Chebel M: Histoire de la Circoncision, Des Origines à Nos speculated (in an essay, De Praeputio Domini Nostri Jesu Jours (A History of Circumcision, from its Origins to the Christi Diatriba) that the holy foreskin may have ascended Present Day). Paris: Editions Balland 1992. into heaven at the same time as Jesus himself, and might 2. Maertens JT: Le Corps Sectionné (The Body Dissected). Paris: have become the rings of Saturn, then only recently ob- Aubier Montaigne 1978. 3. Steinberg L: The Sexuality of Christ in Renaissance Art and in served by the telescope. Modern Oblivion, 2nd ed., Revised and Expanded. Chicago: The University of Chicago Press 1996. 4. Van Gilst A and Kooger H: Kruisen, Relieken en Wonderen (Crosses, Relics and Miracles). The Netherlands: Uitgeverij Aspekt 2002. 5. Müller AV: Die hochheilige Vorhaut Christi im Kult und in der Theologie der Papstkirche (The Most Sacred Foreskin of Christ as a Cult Object and in the Theology of the Catholic Church). Berlin 1907. 6. Mattelaer JJ: Circumcision in Christianity. In: From Orna- mentation to Mutilation: Genital Decorations and Cultural Operations in the Male. Arnhem: Historical Committee of the European Association of Urology 2004. 7. Sorrentino F and Sorrentino M: Restoration of the prepuce. A historical review. Historical Committee of the European Association of Urology. 8. Gaborit-Chopin D and Taburet-Delahaye E: Le Trésor de Conques. Paris: Momum, Editions du Patrimoine 2001. 9. Heathcote W: Die Hochheilige Vorhaut (The Most Sacred Fore- skin). In: Aus den Vorhaut Akten. Der Grüne Zweig 128, Hrsg.Werner Pieper 1989.

FIG.4. Mystical Marriage of Catherine of Siena. Ring of foreskin of 10. McGinn BM: The presence of God (part III). In: The Flowering Christ is on her left middle ﬁnger. Painting by Lorenzo Lotto, 1523, of Mysticism: Men and Women in the New Mysticism, Accademia Carrara, Bergamo, Italy. 1200–1350. New York: Crossroad 1998; p 128. Oncology: Adrenal/Renal/Upper Tract/Bladder

Prognostic Impact of Tumor Size on pT2 Renal Cell Carcinoma: An International Multicenter Experience

Tobias Klatte, Jean-Jacques Patard, Rakhee H. Goel, Mark D. Kleid, Francois Guille, Bernard Lobel, Clement-Claude Abbou, Alexandre De La Taille, Jacques Tostain, Luca Cindolo, Vincenzo Altieri, Vincenzo Ficarra, Walter Artibani, Tommaso Prayer-Galetti, Ernst Peter Allhoff, Luigi Schips, Richard Zigeuner, Robert A. Figlin, Fairooz F. Kabbinavar, Allan J. Pantuck, Arie S. Belldegrun and John S. Lam*

From the Departments of Urology (TK, RHG, MDK, AJP, ASB, JSL) and Medicine (RAF, FFK), University of California, Los Angeles, Los Angeles, California, and the Department of Urology, Centre Hospitalier Universitaire Pontchaillou, Rennes (JJP, FG, BL), Centre Hospitalier Universitaire Henri Mondor, Créteil (CCA, ADLT), Centre Hospitalier Universitaire of Saint Etienne, Saint Etienne (JT), France, Medical School of University “Federico II,” Naples (LC, VA) and University of Padua, Padua (VF, WA, TPG), Italy, University of Magdeburg, Magdeburg, Germany (EPA), and University Hospital, Medical University of Graz, Graz, Austria (LS, RZ)

Purpose: The current tumor classification for renal cell carcinoma classifies pT2 tumors as larger than 7 cm in greatest dimension and limited to the kidney. We examined the current pT2 tumor classification of renal cell carcinoma and determined whether a tumor size cutoff exists that would improve prognostic accuracy. Materials and Methods: We studied 706 patients with pT2 renal cell carcinoma treated with surgical extirpation at 9 international academic centers. Data collected from each patient included age at diagnosis, gender, 2002 TNM (tumor, node, metastasis) stage, tumor size, nuclear grade, performance status, histological subtype and disease specific survival. Disease specific survival was evaluated with univariate and multivariate analysis. Results: Median followup was 52 months. Univariate Cox regression analysis showed a significant association of tumor size with disease specific survival (HR 1.11, p Ͻ0.001). An ideal tumor size cutoff of 11 cm was identified, which led to the stratification of 2 groups with respect to disease specific survival (p Ͻ0.0001) with 5 and 10-year survival rates of 73% and 65% for pT2 11 cm or less, and 57% and 49% for pT2 larger than 11 cm, respectively. The incidence of metastases was significantly greater in the larger than 11 cm group, while Eastern Cooperative Oncology Group performance status, Fuhrman grade and histological subtype were similar. Multivariate Cox regression analysis retained tumor size as an independent prognostic factor and as the strongest prognostic factor for patients with pT2N0M0 disease. Conclusions: Our data suggest that the current pT2 classification can be improved by subclassification into pT2a and pT2b based on a tumor size cutoff of 11 cm. Patients in the proposed pT2bN0M0 group are at higher risk for death from renal cell carcinoma and should be considered for adjuvant therapies. External validation is warranted before suggesting change to the TNM classification. Key Words: neoplasm staging, prognosis, neoplasm metastasis, classification

enal cell carcinoma accounts for approximately 3% of Accordingly, primary RCC limited to the kidney with a tu- all adult malignancies. In 2006 approximately 39,000 mor size greater than 7 cm is classified as pT2. Unlike pT1 R new cases and 13,000 deaths were to have resulted RCC, which is subdivided into pT1a (4 cm or smaller) and from RCC in the United States.1 About 30% of newly diag- pT1b (4 to 7 cm), all pT2 tumors are classified together nosed patients present with metastatic disease and metas- regardless of size. Although it has been well accepted that tases will eventually develop in 20% to 30% of patients tumor size is an important prognostic factor in RCC,4,5 few 2 undergoing curative nephrectomy for nonmetastatic RCC. efforts have been made to develop a subclassification for pT2 The methods to determine prognosis and select patients based on tumor size. Recently Frank et al proposed a sub- for postoperative therapy mainly rely on staging, which is classification into pT2a and pT2b based on a tumor size performed worldwide according the American Joint Commit- cutoff of 10 cm.6 However, other groups were not able to tee on Cancer (AJCC)/Union Internationale Contre le Can- 3 demonstrate that tumor size was a prognostic indicator cer (UICC) tumor, node, metastasis (TNM) classification. among patients with primary tumors limited to the kidney.7,8 Submitted for publication November 27, 2006. To determine the worldwide prognostic impact of tumor * Correspondence: Department of Urology, David Geffen School of size and, consequently, whether a tumor size cutoff exists Medicine at University of California-Los Angeles, 10833 Le Conte within pT2 RCC that improves the prognostic accuracy of Ave., 66-124 CHS, Box 951738, Los Angeles, California 90095-1738 (telephone: 310-794-6584; FAX: 310-206-5343; e-mail: jlam@mednet. the current TNM staging system, we collected data from ucla.edu). more than 700 patients at 9 international institutions.

0022-5347/07/1781-0035/0 35 Vol. 178, 35-40, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.046 36 TUMOR SIZE OF pT2 RENAL CELL CARCINOMA

PATIENTS AND METHODS In terms of followup and statistical analysis, patients were followed according to protocols established at each This retrospective study included 706 consecutive patients institution. The end point of this study was DSS, which was who were surgically treated for sporadic, unilateral pT2 computed from the date of surgery to the date of death or RCC at 9 international academic centers from 1984 to 2005. last followup. Death from RCC was considered the event, Surgical margins were negative in all cases. No patients while deaths from causes other than RCC were censored at received adjuvant therapy postoperatively. The centers in- the date of death. Survival curves were estimated using the cluded Centre Hospitalier Universitaire Pontchaillou, Kaplan-Meier method and compared using the log rank test. Rennes, France; Centre Hospitalier Universitaire Henri To identify an optimal cutoff for subclassification according Mondor, Créteil, France; North Hospital, Centre Hospitalier to tumor size, tree based recursive partitioning was per- Universitaire of Saint Etienne, Saint Etienne, France; Med- formed. To consider more than 1 variable simultaneously, ical School of University “Federico II”, Naples, Italy; Verona clinical and pathological parameters were evaluated using a University Hospital, Verona, Italy; University of Padua, multivariate Cox proportional hazard model to determine Padua, Italy; University Hospital of Magdeburg, Magde- those that were independently associated with DSS. All burg, Germany; University Hospital, Medical University of p values were 2-sided and p Ͻ0.05 was considered statisti- Graz, Graz, Austria; and the University of California, Los cally significant. Data were analyzed using the statistical Angeles Medical Center, Los Angeles, California, United software packages R (http://cran.r-project.org) and SPSS®. States. Patient records were reviewed in terms of clinicopathological data such as Eastern Cooperative Oncology Group performance status at initial presentation; T, N, and RESULTS M stage; tumor size; Fuhrman grade; and histological subtype. Radiographic, operative and pathology reports were Mean patient age at diagnosis was 58.2 Ϯ 12.8 years. Rad- used to assess the extent of disease. For preoperative radio- ical nephrectomy was performed in 685 patients (97%) while graphic evaluation patients underwent cross-sectional im- 21 underwent partial nephrectomy (3%). A total of 575 pa- aging (computerized tomography or magnetic resonance im- tients (81%) were diagnosed with nonmetastatic (N0M0) aging of the abdomen and pelvis, chest computerized disease, and lymph node and/or distant metastases were tomography or chest x-ray), serum electrolytes and liver present in 131 patients (19%). Patient and tumor character- function tests. istics are summarized in table 1. Pathological assessment of the nephrectomy specimens Mean tumor size was 9.8 Ϯ 2.4 cm for the entire cohort, was performed by a small group of experienced pathologists 9.7 Ϯ 2.4 cm for nonmetastatic and 10.2 Ϯ 2.6 cm for met- at each institution. T, N and M stage were determined astatic cases (p ϭ 0.04). Univariate logistic regression, ana- according to 2002 AJCC/UICC definitions.3 Tumor histology lyzing the association of tumor size and the risk of metasta- was classified according to the Heidelberg classification of ses at presentation, showed a risk ratio of 1.08 (95% CI renal cell tumors.9 Tumor grading was performed according 1.002–1.16, p ϭ 0.04), indicating that the risk of metastases to the Fuhrman grading scheme.10 The collected data were increased 8% for every 1 cm increase in tumor size. In labeled with their respective institution and pooled into 1 addition, there was a difference in tumor size among histo- database. logical subtypes (p ϭ 0.02). Mean tumor size for clear cell

TABLE 1. Patient and tumor characteristics pT2 Tumors 11 cm or Smaller pT2 Tumors Larger Than 11 cm Totals

No. pts 556 150 706 Mean pt age (SD) 59.0 (12.3) 55.5 (14.1) 58.2 (12.8) No. gender (%): Male 365 (66) 94 (63) 459 (65) Female 191 (34) 56 (37) 247 (35) No. ECOG-PS (%): 0 309 (65) 85 (63) 394 (65) 1 160 (34) 48 (35) 208 (34) 2 5 (1) 3 (2) 8 (1) No. N stage (%): N0 526 (95) 135 (90) 661 (94) N1 25 (4) 10 (7) 35 (5) N2 5 (1) 5 (3) 10 (1) No. M stage (%): M0 482 (87) 119 (79) 601 (85) M1 74 (13) 31 (21) 105 (15) No. Fuhrman grade (%): G1 51 (9) 13 (9) 64 (9) G2 329 (59) 84 (56) 413 (58) G3 151 (27) 39 (26) 190 (27) G4 25 (4) 14 (9) 39 (6) No. nonmetastatic (N0M0) (%) 464 (83) 111 (74) 575 (81) No. metastatic (N ϩ M0 or M1) (%) 92 (17) 39 (26) 131 (19) No. histological subtype (%): Clear cell 476 (86) 122 (81) 598 (85) Papillary 50 (9) 18 (12) 68 (10) Chromophobe 26 (5) 9 (6) 35 (5) Unclassiﬁed 4 (1) 1 (1) 5 (1) TUMOR SIZE OF pT2 RENAL CELL CARCINOMA 37

RCC (9.6 Ϯ 2.4 cm) was lower than papillary (10.2 Ϯ 2.8 cm), patients with pT2 greater than 11 cm the 1, 2 and 5-year chromophobe (10.7 Ϯ 2.5 cm) and unclassified RCC (10.8 Ϯ DSS rate was 72% Ϯ 7%, 43% Ϯ 8% and 14% Ϯ 6%, respec- 3.6 cm). Additionally, increasing tumor size was signifi- tively, with a median survival time of 23 months (fig. 2, B). cantly associated with poorer ECOG-PS (0—9.7 Ϯ 2.4 cm, Multivariate Cox regression was performed to identify 1 or greater—10.2 Ϯ 2.7 cm, p ϭ 0.02) but not with grade independent prognostic factors for DSS. To avoid over-fitting (p ϭ 0.35). of the regression model, tumor size was entered as a contin- During followup 187 patients (26%) died of RCC after a uous variable. Tumor size, ECOG-PS, M stage and Fuhrman median duration of 24 months (range 1 to 208). Median grade were retained as independent prognostic factors for followup for censored patients was 52 months (range 1 to DSS (table 2). For patients with nonmetastatic pT2 disease, 273). The 5 and 10-year DSS rate Ϯ SE for the entire cohort tumor size was the strongest predictor of death following was 70% Ϯ 2% and 62% Ϯ 3%, respectively. To analyze the nephrectomy. prognostic role of tumor size, univariate Cox regression A separate analysis for clear cell RCC (598) was also analysis was performed, and showed a significant associa- performed. Tumor size remained a prognostic factor in uni- tion between tumor size and DSS (p Ͻ0.001). The hazard variate Cox regression analysis (HR 1.10, 95% CI 1.04–1.16, ratio was 1.11 (95% CI 1.05–1.17), demonstrating that a 1 p ϭ 0.001). Patients with pT2 11 cm or less RCC had im- cm increase in tumor size is associated with an 11% in- proved survival compared to those with pT2 greater than 11 creased risk of death from RCC. To identify a cutoff for cm disease (p ϭ 0.001), with 5 and 10-year survival rates of tumor size, which optimally stratifies cases according to 72% Ϯ 2% and 63% Ϯ 3% for pT2 11 cm or less, and 58% Ϯ survival, tree based recursive partitioning was performed 5% and 48% Ϯ 5% for pT2 larger than 11 cm. In multivariate and demonstrated 11 cm as an ideal cut point. This cutoff led Cox regression analysis tumor size, ECOG-PS, M stage and to the stratification of 2 groups with respect to DSS Fuhrman grade were independent prognostic factors of DSS. (p Ͻ0.0001), with 5 and 10-year survival rates of 73% Ϯ 2% The survival difference between 11 cm or less and more than and 65% Ϯ 3% for pT2 11 cm or less, and 57% Ϯ 5% and 11 cm was still present in nonmetastatic disease (p ϭ 0.05), 49% Ϯ 5% for pT2 larger than 11 cm (fig. 1), respectively. In and tumor size, ECOG-PS and Fuhrman grade significantly addition, the incidence of lymph node involvement (p ϭ 0.04) impacted DSS in multivariate analysis. and distant metastases (p ϭ 0.03) was greater in the larger ϭ than 11 cm group, while ECOG-PS (p 0.53), Fuhrman DISCUSSION grade (p ϭ 0.15) and histological subtype (p ϭ 0.62) were similar. Interestingly, patients with a tumor size greater This international multicenter study reflecting the world- than 11 cm were significantly younger (p ϭ 0.01) (table 1). wide experience of patients with pT2 RCC treated with Because the prognostic value of primary tumor size is surgical extirpation demonstrates that tumor size is an im- different for nonmetastatic and metastatic RCC, we ana- portant prognostic factor, in particular for patients with lyzed both groups separately. For patients with nonmeta- nonmetastatic disease. Based on our data we propose a static disease (575), DSS was also different between the 2 subclassification of pT2 into pT2a and pT2b based on a groups (p ϭ 0.02). In these patients the 5 and 10-year DSS tumor size cutoff of 11 cm. In our study this cutoff was highly rates following nephrectomy were 84% Ϯ 2% and 76% Ϯ 3% associated with metastatic potential and DSS. Furthermore, for pT2 11 cm or less, and 75% Ϯ 5% and 67% Ϯ 6% for pT2 this finding may be helpful in identifying those patients at larger than 11 cm, respectively (fig. 2, A). For patients with higher risk for tumor recurrence and death from RCC, and metastatic disease (131) this subclassification also provided may facilitate individualized therapy and surveillance strat- prognostic information, although the survival difference was egies. not statistically significant (p ϭ 0.07). For pT2 11 cm or less The TNM classification for RCC has undergone system- the 1, 2 and 5-year DSS rate was 70% Ϯ 5%, 56% Ϯ 6% and atic modification since it was firstly recorded in 1974. Sim- 24% Ϯ 5% (median survival 31 months), respectively. For ilar to the Robson staging system, which categorizes organ confined (pT1/2) tumors as stage I, no tumor size cutoff was used in this first classification. In 1987 a tumor size cutoff of 2.5 cm was introduced to distinguish organ confined RCC. This cutoff was later increased to 7 cm and has not been changed since then.3 However, unlike the pT1 tumor classification, no subdivision exists for pT2 RCC. Consequently, smaller and larger pT2 tumors are classified together. For example, tumors 7.1 and 15 cm are classified in 1 category, indicating that the tumors share the same prognosis. How- ever, our data provide evidence that tumor size is an important prognostic factor in these groups and, therefore, we believe that subclassification of pT2 into pT2a and pT2b based on a cutoff of 11 cm would allow better stratification regarding prognosis. The prognostic relevance of tumor size has been studied by other groups. Bell was the first who observed the association between tumor size and risk of metastases.11 In his autopsy study only 1 of 39 patients (3%) with RCC 3 cm or FIG. 1. Kaplan-Meier survival estimates for pT2NallMall RCC, subclassified according to tumor size cutoff of 11 cm. Numbers of pa- less had metastatic disease. In contrast 66 of 84 patients tients at risk are indicated. (79%) with a tumor size greater than 5 cm had concomitant 38 TUMOR SIZE OF pT2 RENAL CELL CARCINOMA

FIG. 2. Kaplan-Meier survival estimates for nonmetastatic (N0M0) pT2 (A) and metastatic pT2 RCC (B), subclassified according to tumor size cutoff of 11 cm. Numbers of patients at risk are indicated. metastases. As previously stated a tumor size cutoff of 2.5 RCC.12 In this study with extended followup, tumor size was cm was introduced in the 1987 TNM classification to distin- an important prognostic factor. However, their cutoff anal- guish between pT1 and pT2 RCC. However, several studies ysis was limited to the tumor size interval between 2.5 cm revealed that this cutoff poorly predicted outcome. For ex- and 7.0 cm and they did not investigate a possible subclas- ample, Targonski et al studied different cutoff sizes of 2.5, sification for the 30 patients with pT2 RCC. Delahunt et al 5.0, 7.5 and 10.0 cm for pT1/2 RCC.7 Of these cutoffs 2.5 cm reported on 116 cases of pT1–2 RCC and demonstrated that had the poorest prognostic ability. Although they showed tumor size was an independent prognostic factor.4 In addi- that all other cutoffs improved accuracy in predicting sur- tion, these authors suggested that a continuous model may vival for all patients, they were not able to show that any of provide a more accurate estimate of the biological relations the cutoffs significantly substratified nonmetastatic disease. than a predictive model with dichotomized categories (cut- Nativ et al also did not observe differences in survival for offs). This proposal deserves further discussion because it is pT1/2 when classifying cases according to a tumor size cutoff clear that there is no true cutoff which perfectly substratifies of 5 cm.8 However, other groups were able to show that cases of organ confined primary RCC. Therefore, a continu- tumor size is an important prognostic factor for organ con- ous model may enhance the individual prognostic assess- fined RCC. Steiner et al reported on 198 patients with pT1–2 ment. However, it would complicate the definition of certain risk groups and their comparison. Thus, we believe that although it might decrease the individual prognostic accuracy, categorized classifications are the easiest predictive TABLE 2. Multivariate Cox regression analysis of DSS tools for survival. HR 95% CI p Value For pT2 RCC in particular, Frank et al analyzed 544 6 pT2NallMall patients from the Mayo Clinic database. Comparable with ECOG-PS: our study, they demonstrated the importance of tumor size 01 1 or Greater 1.92 1.37 2.71 Ͻ0.001 in these patients. They recommended a subclassification of Tumor size continuous 1.10 1.04 1.16 0.002 pT2 in pT2a and pT2b based on a cutoff of 10 cm (less than N stage: 01 10 cm, 10 cm or greater). Additionally, the study showed 1 or Greater 1.39 0.88 2.20 0.159 that this cutoff might be important in patients with pNx/ M stage: pN0 and pM0 disease. We also performed a statistical ex- 01 1 6.81 4.76 9.73 Ͻ0.001 amination of the 10 cm cutoff (data not shown) but could not Fuhrman grade: reproduce their findings. The log rank test was insignificant G1 1 for nonmetastatic disease (p ϭ 0.22) and only slightly sig- G2 1.08 0.57 2.05 0.813 G3 1.25 0.63 2.46 0.525 nificant when analyzing all patients together (p ϭ 0.025). G4 3.72 1.70 8.11 0.001 We conclude that both suggested cutoffs, less than 10 cm Subtype: Clear cell 1 and 11 cm or less, should be validated in further studies. Papillary 1.25 0.70 2.23 0.448 Although stage and grade are considered the most impor- Chromophobe 0.20 0.03 1.45 0.111 tant indicators for patients with nonmetastatic RCC, it re- Unclassified 0.55 0.08 4.06 0.560 pT2N0M0 mains difficult to predict which patients will experience ECOG-PS: recurrence and subsequently die of RCC.13–15 An important 01 tool is integrated staging, which comprises several prognos- 1 or Greater 1.99 1.24 3.19 0.004 Tumor size continuous 1.14 1.05 1.23 0.002 tic factors and, therefore, provides a more accurate predic- Fuhrman grade: tion of survival. Zisman et al developed the University of G1 1 G2 1.33 0.55 3.19 0.529 California, Los Angeles Integrated Staging System (UISS), G3 2.27 0.91 5.65 0.078 which stratifies surgically treated patients into 3 risk groups G4 3.76 1.05 13.45 0.041 of low, intermediate and high risk based on TNM stage, Subtype: 2 Clear cell 1 ECOG-PS and Fuhrman grade. Interestingly pT2N0M0 Nonclear cell 0.83 0.41 1.71 0.622 cases were all classified in the nonmetastatic intermediate Because of the small number of events in each group the histological risk group. The current study confirms that Fuhrman grade subtypes papillary, chromophobe and unclassified were summarized as does not have an important prognostic role for these patients nonclear cell in the analysis for pT2N0M0. and is not necessary for risk group assessment. However, TUMOR SIZE OF pT2 RENAL CELL CARCINOMA 39 our findings do indicate that ECOG-PS and tumor size pro- 2. Zisman A, Pantuck AJ, Wieder J, Chao DH, Dorey F, Said JW vide additional information. pT2N0M0 RCC may not repre- et al: Risk group assessment and clinical outcome algorithm sent a homogeneous group of patients who have an excellent to predict the natural history of patients with surgically prognosis comparable with a subgroup of pT1N0M0 RCC resected renal cell carcinoma. J Clin Oncol 2002; 20: 4559. and patients who have a greater risk of tumor recurrence 3. American Joint Committee on Cancer: Kidney. In: AJCC Can- and death from RCC. In addition to improving current clin- cer Staging Manual, 6th ed. New York: Springer 2002; pp ical and pathological classifications, it is notable that molec- 323–325. 4. Delahunt B, Kittelson JM, McCredie MR, Reeve AE, Stewart ular markers can enhance postoperative risk assessment. JH and Bilous AM: Prognostic importance of tumor size for Shvarts et al reported on a tissue microarray based study on 16 localized conventional (clear cell) renal cell carcinoma: as- 193 patients with nonmetastatic RCC. They observed that sessment of TNM T1 and T2 tumor categories and compar- p53 was the strongest prognostic factor for predicting recur- ison with other prognostic parameters. Cancer 2002; 94: rence after nephrectomy, in addition to T stage and ECOG- 658. PS. Taken together, improvements in staging and the wide- 5. Patard JJ, Dorey FJ, Cindolo L, Ficarra V, De La Taille A, spread use of molecular markers will pave the way for Tostain J et al: Symptoms as well as tumor size provide appropriate patient selection for adjuvant therapy. To date prognostic information on patients with localized renal tu- none of these therapies have been successful,17–19 but new mors. J Urol 2004; 172: 2167. targeted agents such as angiogenesis inhibitors or carbonic 6. Frank I, Blute ML, Leibovich BC, Cheville JC, Lohse CM, anhydrase IX antibodies are now available and under eval- Kwon ED et al: pT2 classification for renal cell carcinoma. uation in adjuvant settings. Data from our study suggest Can its accuracy be improved? J Urol 2005; 173: 380. that patients in the proposed pT2bN0M0 classification 7. Targonski PV, Frank W, Stuhldreher D and Guinan PD: Value should be considered candidates for these therapies. of tumor size in predicting survival from renal cell carci- Some limitations of our study need to be acknowledged noma among tumors, nodes and metastases stage 1 and and addressed. It was a retrospective study and conclusions stage 2 patients. J Urol 1994; 152: 1389. 8. Nativ O, Sabo E, Raviv G, Madjar S, Halachmi S and Mosko- drawn from a retrospective study are always limited. While vitz B: The impact of tumor size on clinical outcome in the primary tumor classification proposed here demon- patients with localized renal cell carcinoma treated by rad- strated an improvement in prognostic accuracy using our ical nephrectomy. J Urol 1997; 158: 729. patient population, external validation will be necessary in 9. Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, the future. In addition, we did not perform a review of all Delahunt B et al: The Heidelberg classification of renal cell pathological slides from 1 anatomical pathologist. However, tumours. J Pathol 1997; 183: 131. it is unlikely that our results were profoundly altered 10. Fuhrman SA, Lasky LC and Limas C: Prognostic significance through this approach since tumor staging was performed of morphologic parameters in renal cell carcinoma. Am J according to TNM classification and we expect the interob- Surg Pathol 1982; 6: 655. server variability to be low. Another consideration is that 11. Bell ET: A classification of renal tumors with observations on there was no standardization of whether a lymphadenec- the frequency of the various types. J Urol 1938; 49: 238. tomy was performed, and if so to what extent. Although 12. Steiner T, Knels R and Schubert J: Prognostic significance of there are many potential benefits of lymphadenectomy for tumour size in patients after tumour nephrectomy for lo- RCC that include more accurate staging, decreased local calised renal cell carcinoma. Eur Urol 2004; 46: 327. recurrence rates and improved survival, only limited data 13. Gelb AB: Renal cell carcinoma: current prognostic factors. Cancer 1997; 80: 981. support these potential benefits, and there is currently no 14. Lam JS, Shvarts O, Leppert JT, Figlin RA and Belldegrun AS: clear practice standard that has been established. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005; CONCLUSIONS 173: 1853. 15. Méjean A, Oudard S and Thiounn N: Prognostic factors of Our data suggest that the current pT2 classification can be renal cell carcinoma. J Urol 2003; 169: 821. improved by subclassification into pT2a and pT2b based on 16. Shvarts O, Seligson D, Lam J, Shi T, Horvath S, Figlin R et al: a tumor size cutoff of 11 cm. Patients in the proposed p53 is an independent predictor of tumor recurrence and pT2bN0M0 group are at higher risk for death from RCC and progression after nephrectomy in patients with localized should be considered for adjuvant therapies. External vali- renal cell carcinoma. J Urol 2005; 173: 725. dation is warranted before suggesting change to the TNM 17. Atzpodien J, Schmitt E, Gertenbach U, Fornara P, Heynemann classification. H, Maskow A et al: Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Abbreviations and Acronyms Renal Carcinoma Chemoimmunotherapy Group (DGCIN). DSS ϭ disease specific survival Br J Cancer 2005; 92: 843. ECOG-PS ϭ Eastern Cooperative Oncology Group 18. Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher performance status JP et al: Adjuvant high-dose bolus interleukin-2 for pa- RCC ϭ renal cell carcinoma tients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 2003; 21: 3133. 19. Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, REFERENCES Crawford ED et al: Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al: an Eastern Cooperative Oncology Group/Intergroup trial. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106. J Clin Oncol 2003; 21: 1214. 40 TUMOR SIZE OF pT2 RENAL CELL CARCINOMA

EDITORIAL COMMENT such trials in the future, or identify a subpopulation in these trials that may derive benefit from adjuvant therapy. This study represents a retrospective look at a large number As with many studies this publication raises almost as of patients across 9 different institutions and asks the ques- many questions as it answers. Important collaborative work tion, in patients with pathological stage T2 renal cell carci- like this needs to be continued and expanded to answer noma is there a size cutoff that helps predict those who have these and other questions before a revision of the TNM a higher risk of dying of disease. The authors conclude that staging system should be made. stage T2 disease could be substratified into a T2a and T2b subcategory based on a size cutoff of 11 cm. Peter E. Clark While the data presented support a statistically signifi- Department of Urologic Surgery cant difference in outcome between patients with T2 RCC Vanderbilt University Medical Center based on tumor size, some important questions need to be Nashville, Tennessee considered before any revision of the TNM system. The present study found that the size with the greatest discrim- REPLY BY AUTHORS inatory power was 11 cm. However, another recent study that looked at 544 patients with T2 disease concluded that There is no consensus as to a correct size cutoff for substrati- 10 cm was the best criteria (reference 6 in article). While the fying stage T2 disease. A point of our study, as well the study latter study differed in that it was a single institutional by Frank et al (reference 6 in article), is that the size of experience, nevertheless it raises the question, what is the organ confined renal tumors is an important prognostic fac- correct size cutoff? Other studies have not found an associ- tor for outcome. There is no doubt that environmental fac- ation with tumor size, for example those by Targonski et al tors, surgical demographics and/or tumor biology may have and Nativ et al (references 7 and 8 in article). These studies a role in determining outcome, but we attempted to evaluate were designed differently and were noticeably smaller in the prognostic value of tumor size in a subgroup of surgically size, reducing the statistical power to detect any difference resected renal tumors larger than 7 cm yet confined within that may exist, but they still raise the issue of external the capsule of the kidney. validation before modifying the TNM system. If the same The TNM system has undergone systematic revisions to criteria were applied to another region of the world, for mirror the improved results obtained in the management of example Asia, would the results be the same? What about RCC. It has been just 10 years since the cutoff size for stage other centers in the United States? Could these shed light on T1 disease was expanded from 2.5 to 7 cm, and this was not the correct size cutoff to use? without controversy. The substratification of T1 disease may Finally, there is a more overarching, philosophical ques- also soon be challenged because there are emerging data tion that needs to be addressed. Does the TNM staging that partial nephrectomy can be safely performed in pa- system need to be that fine tuned? Does microdissection of tients with larger tumors (greater than 4 cm) without sac- 1,2 risk add substantive value to the care of our patients? For rificing oncologic efficacy. example, in the current study if patients with lymph node Substratification of patients into risk groups is a common involvement or metastatic disease are excluded from analy- practice among our medical oncology colleagues. The use of sis (a group all can agree are high risk), then the difference risk groups attempts to select those patients most likely to in predicted disease-free survival at 5 and 10 years for benefit from a particular treatment. We agree that the on- patients based on a size cutoff of 11 cm is 84% vs 76% and going adjuvant trials, if positive, may provide some answers 75% vs 67%. These are statistically significant differences, as to which patients should receive these treatments, but but how much will they change what we actually do? Unlike studies such as ours will also provide guidance as to which the situation in T1 disease, where a substratification of 4 cm group of patients will benefit most from selection for entry impacts whether a surgeon may consider a partial rather into a clinical trial. than a radical nephrectomy, it is less clear how a substratification of T2 disease will change management. To a large 1. Patard JJ, Shvarts O, Lam JS, Pantuck AJ, Kim HL, Ficarra V degree this may hinge on the outcome of several ongoing et al: Safety and efficacy of partial nephrectomy for all T1 tumors based on an international multicenter experience. prospective randomized trials that are testing various adju- J Urol 2004; 171: 2181. vant therapies for RCC. If these trials are positive, then a 2. Leibovich BC, Blute ML, Cheville JC, Lohse CM, Weaver AL finer understanding of risk may be critical in deciding who and Zincke H: Nephron sparing surgery for appropriately should receive these therapies, but what if they are all selected renal cell carcinoma between 4 and 7 cm results in negative trials? Conversely, perhaps studies such as the one outcome similar to radical nephrectomy. J Urol 2004; 171: presented here can better define who should be entered into 1066. Comparison of 1,800 Laparoscopic and Open Partial Nephrectomies for Single Renal Tumors

Inderbir S. Gill, Louis R. Kavoussi, Brian R. Lane, Michael L. Blute, Denise Babineau, J. Roberto Colombo, Jr., Igor Frank, Sompol Permpongkosol, Christopher J. Weight, Jihad H. Kaouk, Michael W. Kattan and Andrew C. Novick* From the Glickman Urological Institute (ISG, BRL, JRC, CJW, ACN) and Department of Quantitative Health Sciences (DB, MWK), Cleveland Clinic, Cleveland, Ohio, and Departments of Urology, The Johns Hopkins Hospital (LRK, SP), Baltimore, Maryland, and Mayo Clinic (MLB, IG), Rochester, Minnesota

Purpose: Laparoscopic partial nephrectomy is an increasingly performed, minimally invasive alternative to open partial nephrectomy. We compared early postoperative outcomes in 1,800 patients undergoing open partial nephrectomy by experienced surgeons with the initial experience with laparoscopic partial nephrectomy in patients with a single renal tumor 7 cm or less. Materials and Methods: Data on 1,800 consecutive open or laparoscopic partial nephrectomies were collected prospectively or retrospectively in tumor registries at 3 large referral centers. Demographic, intraoperative, postoperative and followup data were compared between the 2 groups. Results: Compared to the laparoscopic partial nephrectomy group of 771 patients the 1,028 undergoing open partial nephrectomy were a higher risk group with a greater percent presenting symptomatically with decreased performance status, impaired renal function and tumor in a solitary functioning kidney (p Ͻ0.0001). More tumors in the open partial nephrectomy group were more than 4 cm and centrally located and more proved to be malignant (p Ͻ0.0001 and 0.0003, respectively). Based on multivariate analysis laparoscopic partial nephrectomy was associated with shorter operative time (p Ͻ0.0001), decreased operative blood loss (p Ͻ0.0001) and shorter hospital stay (p Ͻ0.0001). The chance of intraoperative complications was comparable in the 2 groups. However, laparoscopic partial nephrectomy was associated with longer ischemia time (p Ͻ0.0001), more postoperative complications, particularly urological (p Ͻ0.0001), and an increased number of subsequent procedures (p Ͻ0.0001). Renal functional outcomes were similar 3 months after laparoscopic and open partial nephrectomy with 97.9% and 99.6% of renal units retaining function, respectively. Three-year cancer speciﬁc survival for patients with a single cT1N0M0 renal cell carcinoma was 99.3% and 99.2% after laparoscopic and open partial nephrectomy, respectively. Conclusions: Early experience with laparoscopic partial nephrectomy is promising. Laparoscopic partial nephrectomy offered the advantages of less operative time, decreased operative blood loss and a shorter hospital stay. When applied to patients with a single renal tumor 7 cm or less, laparoscopic partial nephrectomy was associated with additional postoperative morbidity compared to open partial nephrectomy. However, equivalent functional and early oncological outcomes were achieved. Key Words: kidney; nephrectomy; laparoscopy; neoplasm recurrence, local; carcinoma, renal cell

he incidence of RCC has increased by 2.3% to 4.3% perioperative and early renal functional outcomes of the each year since the 1970s, resulting in more than initial experience with LPN to those of a mature series of T 35,000 new diagnoses and more than 12,000 deaths OPN in 1,800 patients with a single clinical T1 (7 cm or less) annually in the United States alone.1,2 More than 60% of renal tumor, as performed at 3 high volume centers. renal tumors are now detected incidentally.3 Incidentally detected renal masses are smaller and less likely to metas- tasize.4 OPN has been established to provide better preser- MATERIALS AND METHODS vation of renal function and equivalent oncological outcomes compared with radical nephrectomy in select patients.5–7 Patients LPN was developed recently, incorporating the funda- Information were recorded in prospective or retrospective mental principles of OPN.8–10 We present a comparison of kidney cancer registries in accordance with institutional review board guidelines. The records of all patients undergoing LPN at Cleveland Clinic (454) and The Johns Hopkins Submitted for publication November 14, 2006. Hospital (317) were reviewed along with those who under- Study received institutional review board approval. went OPN at Cleveland Clinic (595) and Mayo Clinic (434) * Correspondence and requests for reprints: Glickman Urological Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., A100, between January 1, 1998 and August 31, 2005. Inclusion Cleveland, Ohio 44195 (telephone: 216-444-5584; FAX: 216-445- criteria were patients with a single, localized, suspected 4396; e-mail: [email protected]). sporadic RCC 7 cm or less who were candidates for NSS. For another article on a related topic see page 288. Patients with familial syndromes, multifocal tumors, or ra-

0022-5347/07/1781-0041/0 41 Vol. 178, 41-46, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.038 42 LAPAROSCOPIC AND OPEN PARTIAL NEPHRECTOMY FOR SINGLE RENAL TUMORS diological evidence of locally advanced disease or metastases kidney loss]) and nonurological (cardiac, gastrointestinal, were excluded, resulting in a consecutive group of patients pulmonary, thromboembolic, incisional or other). with a clinical T1 renal tumor. A total of 23 patients with tumor characteristics that prompted intraoperative conver- Assessment of Renal sion from LPN to radical nephrectomy were excluded, as Function, Recurrence and Mortality were 2 in whom LPN was planned but no tumor was iden- An early decrease in renal function was determined by com- tified during laparoscopic renal exploration with intraoper- paring preoperative sCr with the lowest postoperative sCr ative ultrasonography. Patients undergoing radical nephrec- measured within 90 days of surgery (nadir). All cause mor- tomy because of intraoperative complications or a suspected tality was determined using the Social Security death in- positive margin were included, providing a total of 1,800 dex.13 Cancer specific deaths included death attributable to procedures for analysis, including 771 LPNs and 1,029 cancer by death certificate, patient chart or family member, OPNs. or death from any cause with evidence of cancer recurrence. Preoperative evaluation comprised medical history, physical examination, routine laboratory studies, including sCr and urinalysis, chest x-ray and abdominopelvic computer- Statistical Methods ized tomography or magnetic resonance imaging. Absolute Baseline patient and tumor characteristics were compared 14 indications for partial nephrectomy were bilateral disease, in aggregate using the O’Brien mean rank strategy. Mul- or tumor in a solitary functioning kidney or renal remnant, tivariate regression was used to model warm ischemia time, as defined by 10% or less function in the contralateral renal operative time, hospital stay and estimated blood loss. These unit. Imperative indications were baseline renal dysfunction outcomes were log transformed if the normality assumption (sCr 1.5 mg/dl or greater) or a condition that posed a current was violated. Estimates and the 95% CI of the adjusted or future risk to renal function, including hypertension, diabe- change or adjusted relative change in the outcome per unit tes mellitus, kidney stone disease, contralateral ureteropelvic change in each covariate were determined. Logistic regres- junction obstruction, multiple contralateral renal cysts or renal sion was used to model the adjusted OR of detecting cancer, artery stenosis. Elective partial nephrectomy was performed in of postoperative nonurological and urological complications, the presence of a normal contralateral kidney. of hemorrhage and of subsequent procedures. Poisson regression was used to model the adjusted relative rate of postoperative complications per patient. Restricted cubic Nephron Sparing Techniques splines were used to account for any nonlinear association The surgical techniques of LPN and OPN were similar and that any continuous variables had with the various out- 8,10,11 they have been detailed previously. Followup and con- comes. The probability of overall or cancer specific survival valescence data were obtained by telephone contact or pa- and local or distant recurrence 3 years after surgery in the tient completed questionnaires. Tumor size is reported as LPN and OPN groups was estimated using Kaplan-Meier the longest single dimension of the lesion, as measured by curves and compared using a log rank test statistic. A sig- the radiologist. Clinical tumor staging regarded tumors 4 cm nificance level of 0.05 was used and all p values were 2-sided or less as cT1a and tumors greater than 4 to 7 cm as cT1b. with no adjustments for multiple testing. Pathological staging was performed according to the 2002 UICC/American Joint Committee on Cancer TNM staging RESULTS system. When the tumor had been morcellated or pathological size was otherwise unavailable, clinical size was used to Clinical Features of Patients and determine pathological tumor stage. Tumors Treated With OPN and LPN LPN and OPN groups were significantly different in regard Complications to patient age, American Society of Anesthesiologists score, Complications were classified as intraoperative or postoper- performance status, symptomatic presentation, indication ative with attention to previously established criteria.12 In- for NSS, solitary kidney and preoperative sCr considered in Ͻ traoperative complications included significant injury to an aggregate (p 0.0001, table 1). Absolute indications in the adjacent organ, major vessel, ureter or pleura and conver- LPN and OPN groups included solitary functioning kidney sion for vascular injury or hemorrhage. Minor intraopera- (4.2% and 21.6% of cases), synchronous bilateral tumors tive complications, such as small pleural injury repaired (11.8% and 15.2%) and asynchronous bilateral disease (3.2% without the need for a chest tube, small opening of the ureter and 12.7%, respectively). Preoperative tumor characteristics repaired with a single stitch, incidental injuries to the liver, (size and depth) were also significantly different between the Ͻ spleen or bowel that needed minimal intraoperative atten- 2 groups (p 0.0001). Mean radiographic tumor size was 2.7 tion and vascular injuries repaired promptly and readily and 3.5 cm with tumors more than 4 cm (cT1b) comprising without hemodynamic compromise, were not tabulated since 8.8% and 31.4% of the LPN and OPN groups, respectively. reporting varied considerably among institutions. Any post- Central tumors, defined as infiltrating the renal paren- operative complication occurring within 1 month, and uro- chyma up to the collecting system or renal sinus, comprised logical complications and mortality within 3 months of 34.4% and 53.3% of cases, respectively. surgery were recorded. Postoperative complications were classified as urological (hemorrhage [necessitating interven- Operative Details tion or transfusion of3Uorgreater], urine leakage [drain- The techniques of LPN and OPN used at the centers in this age of greater than 50 cc daily for more than 1 week with study have been described previously.8,10,11 Notable differ- fluid biochemistry compatible with urine] and acute renal ences between the 2 procedures included ureteral catheter failure [resulting in any dialysis, ureteral obstruction or placement in 89.1% and 2.7%, and intraoperative ultra- LAPAROSCOPIC AND OPEN PARTIAL NEPHRECTOMY FOR SINGLE RENAL TUMORS 43

TABLE 1. Characteristics and perioperative data on 1,800 patients undergoing partial nephrectomy for single renal tumor No. Pts

LPN Mean age (range) 771 59.4 (19.0–87.0) No. men (%) 771 442 (57.3) Mean kg/m2 body mass index (range) 524 29.3 (16.2–75.0) No. American Society of Anesthesiologists score 3 or greater (%) 732 336 (45.9) No. Eastern Cooperative Oncology Group performance status 1 or greater (%) 771 11 (1.4) No. smoking history (%) 692 127 (18.4) No. symptomatic at presentation (%) 771 68 (8.8) No. indication (%): 771 Elective 370 (48.0) Imperative 279 (36.2) Absolute 122 (15.8) No. solitary kidney (%) 771 32 (4.2) Preop sCr: 759 Mean mg/dl (range) 1.01 (0.4–3.4) No. greater than 2.0 mg/dl 12 (1.6) No. central tumor (%) 771 265 (34.4) Clinical tumor size: 771 Mean cm (range) 2.7 (0.5–7.0) No. 4 cm or greater 68 (8.8) Mean mins warm ischemia time (range) 648 30.7 (4.0–68.0) Mean mins total operative time (range) 680 201 (25–610) Estimated blood loss: Mean cc (range) 759 300 (25–6,000) No. transfusion (%) 764 34 (4.5) Mean days hospital stay (range) 771 3.3 (1.0–42) Mean cm pathological tumor size (range) 508 2.6 (0.4–8.0) No. pathological diagnosis (%): 771 Benign kidney ﬁndings 215 (27.9) Renal cell Ca 554 (71.9) Other Ca 2 (0.26) Mean mg/dl postop nadir sCr (range) 728 1.18 (0.4–9.9) OPN Mean age (range) 1,029 61.6 (25.7–94.0) No. men (%) 1,029 724 (70.4) Mean kg/m2 body mass index (range) 717 29.4 (16.0–62.2) No. American Society of Anesthesiologists score 3 or greater (%) 525 398 (75.8) No. Eastern Cooperative Oncology group performance status 1 or greater (%) 903 133 (14.7) No. smoking history 1,009 417 (41.3) No. symptomatic at presentation (%) 1,029 345 (33.5) No. indication (%): 1,029 Elective 360 (35.0) Imperative 298 (29.0) Absolute 371 (36.0) No. solitary kidney (%) 1,029 222 (21.6) Preop sCr: 1,025 Mean mg/dl (range) 1.25 (0.4–6.9) No. 4 cm or greater (%) 66 (6.4) No. central tumor (%) 595 317 (53.3) Clinical tumor size: 1,029 Mean cm (range) 3.5 (0.6–7.0) No. 4 cm or greater 323 (31.4) Mean mins warm ischemia time (range) 461 20.1 (4.0–52.0) Mean mins total operative time (range) 449 266 (118–600) Estimated blood loss: Mean cc (range) 945 376 (10–3,300) No. transfusion (%) 1,028 52 (5.1) Mean days hospital stay (range) 1,029 5.8 (1.0–96) Mean cm pathological tumor size (range) 1,029 3.3 (0.13–9.0) No. pathological diagnosis (%): 1,029 Benign kidney ﬁndings 171 (16.6) Renal cell Ca 853 (82.9) Other Ca 5 (0.49) Mean mg/dl postop nadir sCr (range) 996 1.42 (0.5–11.9) sonography in 61.3% and 1.5% of LPNs and OPNs, respec- stant warm ischemia time for a patient undergoing LPN was tively. A transperitoneal approach was used in 78.5% of the 1.69 times (95% CI 1.62, 1.77) longer than that of a similar laparoscopic cases. Control of the renal vasculature was patient undergoing OPN (p Ͻ0.0001). Mean operative time for performed in 91.5% and 99.5% of the cases, respectively. LPN and OPN was 3.3 and 4.3 hours, respectively. On multi- Warm ischemia was used predominantly with cold ischemia variate analysis operative time for LPN was 0.78 times (95% used in only 10 LPNs and 15 OPNs. Mean warm ischemia CI 0.75, 0.81) that of OPN (p Ͻ0.0001, table 2). time was 30.7 and 20.1 minutes in the 2 groups, respec- Mean intraoperative blood loss was 300 and 376 cc with a tively. Multivariate analysis of select outcomes was per- blood loss of 1,000 cc or greater in 5.4% and 5.7% of LPNs formed using the covariates surgical approach, patient age, and OPNs, respectively. On multivariate analysis blood loss clinical tumor size, contralateral kidney function and bilat- in the LPN group was 0.80 times (95% CI 0.74, 0.87) that in eral disease status (table 2). With all other variables con- the OPN group (p Ͻ0.0001, table 2). Blood transfusions were 44 LAPAROSCOPIC AND OPEN PARTIAL NEPHRECTOMY FOR SINGLE RENAL TUMORS

parenchymal margin in 4, and vascular injury, bowel injury TABLE 2. Log transformed multivariable regression of select outcomes after LPN and OPN and tumor fracture in 1 each. Relative Increase Covariate (95% CI) p Value Postoperative Course The duration of hospitalization following LPN and OPN was Warm ischemia time: LPN vs OPN 1.69 (1.62, 1.77) Ͻ0.0001 3.3 and 5.8 days, respectively (table 1). On multivariate Clinical size 1.07 (1.05, 1.09) Ͻ0.0001 analysis hospital stay following LPN was 0.59 times (95% CI Age 0.999 (0.997, 1.00) 0.3426 0.56, 0.61) that of OPN (p Ͻ0.0001, table 2). A total of 192 Solitary 1.03 (0.96, 1.10) 0.4167 Bilat 1.05 (0.99, 1.10) 0.0952 (24.9%) and 198 postoperative complications (19.2%) oc- Operative time: curred in 18.6% and 13.7% of patients undergoing LPN and LPN vs OPN 0.78 (0.75, 0.81) Ͻ0.0001 Clinical size 1.04 (1.02, 1.05) Ͻ0.0001 OPN, respectively (see figure). On multivariate analysis the Age 1.00 (1.00, 1.00) 0.4455 rate of postoperative complications following LPN was 1.66 Solitary 1.02 (0.96, 1.08) 0.5583 times (95% CI 1.33, 2.05) higher than that following OPN Bilat 1.06 (1.01, 1.11) 0.0129 Hospital stay: (p Ͻ0.0001). The odds of nonurological and urological com- LPN vs OPN 0.59 (0.56, 0.61) Ͻ0.0001 plications were 1.53 (95% CI 1.12, 2.10) and 2.14 times (95% Ͻ Clinical size 1.05 (1.03, 1.07) 0.0001 CI 1.39, 3.31) greater for LPN than for OPN (table 3). Age 1.005 (1.003, 1.007) Ͻ0.0001 Solitary 1.06 (0.99, 1.13) 0.1071 In the overall series the number of patients who required Bilat 1.06 (1.01, 1.12) 0.0237 1 or more postoperative blood transfusions was 45 in the Intraop estimated blood loss: LPN vs OPN 0.80 (0.74, 0.83) Ͻ0.0001 LPN group (5.8%) and 35 in the OPN group (3.4%). Postop- Clinical size 1.12 (1.09, 1.14) Ͻ0.0001 erative hemorrhage after LPN in 32 cases (4.2%) was Age 1.00 (1.00, 1.00) 0.425 treated with conservative management in 13, embolization Solitary 1.08 (0.96, 1.14) 0.214 Bilat 1.07 (0.97, 1.12) 0.171 in 10, reexploration in 6 and nephrectomy in 3. Postopera- tive hemorrhage after OPN in 16 cases (1.6%) was treated with conservative management in 12, embolization in 3 and reexploration in 1. On multivariate analysis the odds of given to 4.5% and 5.1% of patients with LPN and OPN, postoperative hemorrhage after LPN were 3.52 times (95% respectively. A total of 14 (1.8%) and 10 (1.0%) intraopera- CI 1.82, 6.77) those of OPN (p Ͻ0.0001, table 3). tive complications occurred during LPN and OPN, including Urine leakage occurred in 24 patients in each group. 7 and 3 vascular, 2 and 6 ureteral, 2 and 0 organ (spleen and Following LPN management was nonoperative in 22 cases bowel), and 3 and 1 pleural injuries, respectively. Vascular (91.7%) and nephrectomy in 2 (8.3%). Following OPN man- injuries during LPN included renal artery occlusion leading agement was nonoperative in all 24 cases. The odds of un- to renal infarction in 2 cases, tear of the renal vein in 1, dergoing a secondary procedure for any reason in LPN cases lumbar vein in 1, a mesenteric vessel in 1 and unspecified were 3.05 times (95% CI 1.88, 4.94) those in OPN cases in 2. During OPN they included injury to renal arterial (p Ͻ0.0001, table 3). Overall 6 patients with LPN and 0 with branches in 2 cases and lumbar vein in 1. Ureteral injury during LPN was repaired with laparoscopic ileal ureter and ureteral stenting in 1 case each, and during OPN it was repaired primarily over a ureteral stent in 6. Multivariate TABLE 3. Multivariable logistic regression of select outcomes analysis of intraoperative complications could not be per- after OPN and LPN formed because of the small number of events. Covariate OR (95% CI) p Value In 22 planned LPNs (2.85%) and 0 planned OPNs the patient did not undergo the scheduled procedure (see figure). Ca detection: LPN vs OPN 0.64 (0.50, 0.81) 0.0003 A total of 16 LPN cases (2.1%) underwent open conversion Clinical size Nonlinear Ͻ0.0001 (15 OPNs and 1 radical nephrectomy) electively (4), or for Age 0.99 (0.98, 1.00) 0.0493 parenchymal hemorrhage (6), vascular injury (4), an uncer- Solitary 2.32 (1.45, 3.70) 0.0004 Bilat 0.85 (0.63, 1.15) 0.2982 tain margin (1) or tumor identification (1). Overall 7 patients Postop nonurological complications: with LPN (0.9%) and 0 with OPN underwent radical ne- LPN vs OPN 1.53 (1.12, 2.10) 0.0077 Clinical size 1.10 (0.98, 1.23) 0.0932 phrectomy (laparoscopic in 6 and open in 1) due to a positive Age Nonlinear Ͻ0.0001 Solitary 1.68 (1.09, 2.59) 0.0196 Bilat 0.81 (0.55, 1.19) 0.2860 Postop urological complications: LPN vs OPN 2.14 (1.39, 3.31) 0.0006 Clinical size 1.26 (1.09, 1.46) 0.0020 Age 1.00 (0.98, 1.02) 0.9166 Solitary 0.94 (0.51, 1.74) 0.8475 Bilat 1.98 (1.24, 3.17) 0.0041 Postop hemorrhage: LPN vs OPN 3.52 (1.82, 6.77) 0.0002 Clinical size 1.24 (1.00, 1.53) 0.0511 Age Nonlinear 0.1189 Solitary 0.72 (0.27, 1.90) 0.5089 Bilat 2.48 (1.28, 4.84) 0.0074 Any subsequent procedure: LPN vs OPN 3.05 (1.88, 4.94) Ͻ0.0001 Clinical size 1.44 (1.23, 1.68) Ͻ0.0001 Age 0.99 (0.97, 1.01) 0.3168 Solitary 0.97 (0.49, 1.90) 0.9284 Bilat 1.82 (1.09, 3.05) 0.0225 Select LPN and OPN intraoperative and postoperative outcomes LAPAROSCOPIC AND OPEN PARTIAL NEPHRECTOMY FOR SINGLE RENAL TUMORS 45

OPN underwent postoperative nephrectomy due to hemor- for other factors (tumor size, stage and grade) the log rank rhage in 3, and a positive margin, ureteral stricture and test indicated similar oncological outcomes (p not signifi- urine leakage in 1 each. cant). When comparing 514 LPNs and 676 OPNs, the Kaplan-Meier estimate of 3-year cancer specific survival was Renal Functional Outcomes 99.3% (95% CI 98.0, 100) and 99.2% (95% CI 98.4, 100), Renal functional outcomes were similar between the LPN respectively. At 3 years Kaplan-Meier estimates of local and OPN groups. For the entire cohort mean preoperative recurrence rates were 1.4% (95% CI 0, 2.8) and 1.5% (95% CI and nadir sCr was 1.01 and 1.18 mg/dl for LPN, and 1.25 and 0.4, 2.6), and the distant recurrence rates were 0.9% (95% CI 1.42 mg/dl for OPN, respectively (table 1). Preoperative and 0, 2.2) and 2.1% (95% CI 0.7, 3.4) in the LPN and OPN postoperative sCr associated with a solitary kidney was 1.24 groups, respectively. and 1.90 mg/dl for LPN in 29 patients, and 1.32 and 1.73 mg/dl for OPN in 212. This small statistical difference was DISCUSSION not believed to be clinically significant. Of the 602 patients with LPN and 542 with OPN who had normal baseline renal The open radical nephrectomy pioneered by Robson has function (sCr 1.4 mg/dl or less), 2 functioning kidneys and a been replaced with time by less radical alternatives, includ- unilateral tumor nadir sCr was 1.5 mg/dl or greater in 8.0% ing NSS and minimally invasive surgery, in appropriate 15 and 8.7%, and more than 2 mg/dl in 0.7% and 0%, respec- patients. In contemporary practice OPN has become the tively. Acute renal failure necessitating dialysis occurred in gold standard for a single small renal tumor with demon- 0.9% of patients in the 2 groups, including 0.7% (4 with LPN) strated oncological and improved renal functional outcomes 5–7 and 0.2% (1 with OPN) of patients with normal sCr, 2 that are similar to those of radical nephrectomy. Several functioning kidneys and a unilateral tumor. A total of 16 and minimally invasive types of NSS have emerged in the last 10 4 kidneys were lost after LPN and OPN (p not significant), years, including LPN and probe ablative treatments such as 16–18 such that 97.9% and 99.6% of patients, respectively, had a cryoablation and radio frequency ablation. Smaller stud- functioning kidney 3 months after surgery. ies have compared OPN and LPN, highlighting the potential risks and benefits associated with either approach.9,19 This study presents comparative data on 1,800 partial Pathological Outcomes nephrectomies performed at 3 major centers in patients with The mean pathological size of tumors treated with LPN and a single renal tumor 7 cm or less. The primary focus of this OPN was 2.6 and 3.3 cm with histologically confirmed cancer retrospective study is on perioperative and early renal func- in 556 (72.2%) and 858 (83.4%), respectively (table 1). On tional outcomes of the 2 techniques. Patients undergoing multivariate analysis the chance of detecting cancer with OPN were a higher risk group, as defined by greater age, LPN was 0.64 times (95% CI 0.50, 0.81) that of OPN inde- increased comorbidities, decreased performance status, Ͻ pendent of tumor size and all other covariates (p 0.0001, symptoms, decreased renal function and the indication for table 3). RCC of pathological stage higher than pT1a repre- NSS considered in aggregate (p Ͻ0.0001). Tumor character- sented 10.6% and 23.1% of tumors treated with LPN and istics (size, depth, bilaterality and solitary kidney) also in- OPN, respectively. In the 2 groups 61.8% and 72.2% of RCCs creased the perioperative and oncological risks. Multivariate were of conventional histology and 28.9% and 34.0%, respec- analyses revealed that patients undergoing LPN had de- tively, were Fuhrman grade III or IV. Positive surgical pa- creased operative time, shorter hospital stay and less blood renchymal margins were present in 22 (2.85%) and 13 loss (p Ͻ0.0001). Although the minor decrease in blood loss (1.26%) of the tumors removed by LPN and OPN, respec- was statistically significant, it was not believed to be clini- tively. Positive surgical margin rates for cancer were 1.6% cally relevant because absolute values in the 2 groups were for LPN and 1.0% for OPN. Of the 12 patients with LPN and small and intraoperative transfusion rates were also similar 10 with OPN who had a positive cancer margin 1 underwent in the 2 groups. However, LPN was also associated with prophylactic LRN 2 months later with no delayed recur- longer warm ischemia time and a higher rate of periopera- rence, while 1 with bilateral synchronous tumors who un- tive complications on multivariate analyses (p Ͻ0.0001). derwent OPN for 2 cm pT1a papillary RCC following radical Postoperative urological complications were more common nephrectomy for multiple large tumors had local and distant (OR 2.14) in the LPN group, particularly renal hemorrhage recurrence, and cancer specific mortality. No patient with (OR 3.52), of which most were managed nonoperatively. In LPN and no other with OPN who had a positive margin for addition, the severity of hemorrhage was higher after LPN, cancer showed any recurrence during a median followup of 1.9 as reflected by the greater number of patients who required years (range 0.1 to 5.6). In 1 patient with LPN the excised embolization (10 vs 3), reexploration (6 vs 1) and nephrec- specimen revealed no tumor but 30 months later the patient tomy (1 vs 0). The odds of secondary procedures for any underwent exploration for small bowel obstruction and a mass indication were 3.05 times higher after LPN. was found adjacent to the kidney. Excision of the mass and Early renal functional and oncological outcomes were nephrectomy were performed with findings of a Fuhrman similar between the LPN and OPN cohorts in this large, grade 4 clear cell RCC that did not involve the kidney. In this multi-institutional, 1,800 patient study. In regard to renal patient brain metastases subsequently developed. function, precise measurement of differential function with iothalamate scanning, the percent of renal parenchyma re- Oncological Outcomes moved and specimen weights were not available. Neverthe- Median followup was 1.2 (range 0 to 7.0) and 2.8 years less, only 0.9% of all patients in each group underwent (range 0 to 7.6) after LPN and OPN, respectively. Oncolog- dialysis for acute renal failure and renal dysfunction (sCr ical outcomes were analyzed at 3 years in the subgroup of 1.5 mg/dl or greater) was present postoperatively in less patients with a single pathological RCC. Without adjusting than 9% with normal baseline renal function in either group. 46 LAPAROSCOPIC AND OPEN PARTIAL NEPHRECTOMY FOR SINGLE RENAL TUMORS

In addition, only 2.1% and 0.9% of kidneys, respectively, 2. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor were lost within 90 days of surgery. Because the rates of A et al: Cancer statistics, 2005. CA Cancer J Clin 2005; ureteral injury, urine leakage, acute renal failure and kid- 55: 10. ney loss were comparable in the 2 groups, the increased 3. Janzen NK, Kim HL, Figlin RA and Belldegrun AS: Surveil- morbidity of LPN was due largely to the increased risk of lance after radical or partial nephrectomy for localized re- hemorrhage and potentially to the longer ischemic interval. nal cell carcinoma and management of recurrent disease. In regard to early oncological outcomes, 3-year cancer spe- Urol Clin North Am 2003; 30: 843. ciﬁc survival exceeded 99% for patients with a single RCC 4. Patard JJ, Dorey FJ, Cindolo L, Ficarra V, De La Taille A, Tostain J et al: Symptoms as well as tumor size provide treated with LPN or OPN. However, median followup was prognostic information on patients with localized renal tu- only 1.2 years for patients in the LPN group. mors. J Urol 2004; 172: 2167. We recognize the shortcomings of the current study as a 5. Lee CT, Katz J, Shi W, Thaler HT, Reuter VE and Russo P: retrospective, nonrandomized comparison. Moreover, the Surgical management of renal tumors 4 cm. or less in a OPN group was at higher risk for operative intervention contemporary cohort. J Urol 2000; 163: 730. because of a preponderance of larger tumors in less healthy 6. Lau WK, Blute ML, Weaver AL, Torres VE and Zincke H: patients. With increasing experience the indications for LPN Matched comparison of radical nephrectomy vs nephron- are being cautiously expanded at some centers to include sparing surgery in patients with unilateral renal cell carci- select patients with more central or larger tumors.20 It is noma and a normal contralateral kidney. Mayo Clin Proc understood that the open surgeons had more experience 2000; 75: 1236. with NSS than the laparoscopic surgeons. Considering the 7. McKiernan J, Simmons R, Katz J and Russo P: Natural history disparity in experience with NSS between the open and of chronic renal insufﬁciency after partial and radical ne- laparoscopic surgeons in this study the initial results of LPN phrectomy. Urology 2002; 59: 816. are encouraging and likely presage the expansion of current 8. Gill IS, Desai MM, Kaouk JH, Meraney AM, Murphy DP, eligibility criteria in the future. Sung GT et al: Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol 2002; 167: 469. CONCLUSIONS 9. Gill IS, Matin SF, Desai MM, Kaouk JH, Steinberg A, Mascha OPN is the reference standard for NSS in patients with a E et al: Comparative analysis of laparoscopic versus open suspected renal malignancy. LPN has emerged as a viable partial nephrectomy for renal tumors in 200 patients. alternative to OPN in appropriately selected patients. When J Urol 2003; 170: 64. applied to small renal tumors, LPN is associated with less 10. Link RE, Bhayani SB, Allaf ME, Varkarakis I, Inagaki T, blood loss and a shorter hospital stay but longer ischemia Rogers C et al: Exploring the learning curve, pathological outcomes and perioperative morbidity of laparoscopic par- time and more postoperative complications. Importantly re- tial nephrectomy performed for renal mass. J Urol 2005; nal function and early oncological outcomes are equivalent 173: 1690. in these cases. Selection of an individual for LPN or OPN 11. Novick AC: Renal-sparing surgery for renal cell carcinoma. should depend on the particular patient and tumor charac- Urol Clin North Am 1993; 20: 277. teristics, and the degree of laparoscopic expertise available 12. Campbell SC, Novick AC, Streem SB, Klein E and Licht M: at a given center. Currently OPN remains the preferred Complications of nephron sparing surgery for renal tumors. approach for more complicated renal neoplasms. J Urol 1994; 151: 1177. 13. Curb JD, Ford CE, Pressel S, Palmer M, Babcock C and ACKNOWLEDGMENTS Hawkins CM: Ascertainment of vital status through the National Death Index and the Social Security Administra- Christine Lohse, Wei Liao, Mary Federico, Mary Samplaski tion. Am J Epidemiol 1985; 121: 754. and Trisha Nemanic assisted with the database, Angela 14. O’Brien PC: Procedures for comparing samples with multiple Leschinsky, Kay Lawson Tucker and Diana Baker assisted endpoints. Biometrics 1984; 40: 1079. with followup and Ming Zhou assisted with pathological 15. Lane BR and Novick AC: Nephron-sparing surgery. BJU Int considerations. 2007; 99: 1245. 16. Gill IS: Five year outcomes of laparoscopic cryosurgical ablation of renal tumors. Unpublished data. 17. McDougal WS, Gervais DA, McGovern FJ and Mueller PR: Abbreviations and Acronyms Long-term followup of patients with renal cell carcinoma LPN ϭ laparoscopic partial nephrectomy treated with radio frequency ablation with curative intent. NSS ϭ nephron sparing surgery J Urol 2005; 174: 61. OPN ϭ open partial nephrectomy 18. Lane BR and Gill IS: 5-Year outcomes of laparoscopic partial RCC ϭ renal cell carcinoma nephrectomy. J Urol 2007; 177: 70. ϭ sCr serum creatinine 19. Schiff JD, Palese M, Vaughan ED Jr, Sosa RE, Coll D and Del Pizzo JJ: Laparoscopic vs open partial nephrectomy in con- REFERENCES secutive patients: the Cornell experience. BJU Int 2005; 96: 811. 1. Chow WH, Devesa SS, Warren JL and Fraumeni JF Jr: Rising 20. Frank I, Colombo JR Jr, Rubinstein M, Desai M, Kaouk J and incidence of renal cell cancer in the United States. JAMA Gill IS: Laparoscopic partial nephrectomy for centrally 1999; 281: 1628. located renal tumors J Urol 2006; 175: 849. Positive Margins in Laparoscopic Partial Nephrectomy in 855 Cases: A Multi-Institutional Survey From the United States and Europe

A. Breda,* S. V. Stepanian, J. Liao, J. S. Lam, G. Guazzoni, M. Stifelman, K. Perry, A. Celia, G. Breda, P. Fornara, S. Jackman, A. Rosales, J. Palou, M. Grasso, V. Pansadoro, V. Disanto, F. Porpiglia, C. Milani, C. Abbou, R. Gaston, G. Janetschek, N. A. Soomro, J. de la Rosette, M. P. Laguna and P. G. Schulam From the Department of Urology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (AB, SVS, JL, JSL, PGS); San Raffaele Hospital, Milan (GG), San Bassiamo Hospital, Bassano del Grappa (AC, GB), Vincenzo Pansadoro Foundation, Rome (VP), General Regional Hospital, Acqua Viva delle Fonti (VD), San Luigi Hospital, Turin (FP), and San Antonio Hospital, Padua (CM), Italy; New York University (MS) and St. Vincent’s Hospital (MG), New York, New York; Loyola University, Maywood, Illinois (KP); Martin-Luther University, Halle, Germany (PF); University of Pittsburgh, Pittsburgh, Pennsylvania (SJ); Fundaciò Puigvert, Barcelona, Spain (AR, JP), Henri Mondor Hospital, Creteil (CA) and Clinique Saint Augustin, Bordeaux (RG), France; Elisabethinen Hospital, Linz, Austria (GJ); The Freeman Hospital, High Heaton, Newcastle, United Kingdom (NAS); and Academic Medical Center, University Hospital, Amsterdam, The Netherlands (JdlR, MPL)

Purpose: Open partial nephrectomy has emerged as the standard of care in the management of renal tumors smaller than 4 cm. While laparoscopic radical nephrectomy has been shown to be comparable to open radical nephrectomy with respect to long-term outcomes, important questions remain unanswered regarding the oncological efficacy of laparoscopic partial nephrectomy. We examined the practice patterns and pathological outcomes following laparoscopic partial nephrectomy. Materials and Methods: A survey was sent to academic medical centers in the United States and in Europe performing laparoscopic partial nephrectomy. The total number of laparoscopic partial nephrectomies, positive margins, indications for intraoperative frozen biopsy as well as tumor size and position were queried. Results: Surveys suitable for analysis were received from 17 centers with a total of 855 laparoscopic partial nephrectomy cases. Mean tumor size was 2.7 cm (Ϯ0.6). There were 21 cases with positive margins on final pathology, giving an overall positive margin rate of 2.4%. Intraoperative frozen sections were performed selectively at 10 centers based on clinical suspicion of positive margins on excised tumor. Random biopsies were routinely performed on the resection bed at 5 centers. Frozen sections were never performed at 2 centers. Of the 21 cases with positive margins 14 underwent immediate radical nephrectomy based on the frozen section and 7 were followed expectantly. Conclusions: Early experience with laparoscopic partial nephrectomy in this multicenter study demonstrates oncological efficacy comparable to that of open partial nephrectomy with respect to the incidence of positive margins. The practice of intraoperative frozen sections varied among centers and is not definitive in guiding the optimal surgical treatment. Key Words: laparoscopy, nephrectomy, kidney neoplasms

he first suggestion of partial nephrectomy as treat- of partial nephrectomy as an accepted modality for the sur- ment for some cases of renal cell carcinoma was made gical treatment of selected renal cell masses.3–8 T in 1950.1 Since that time the advent of modern imag- More recently advances in laparoscopic technique have ing techniques such as ultrasound and computerized tomog- prompted studies examining the viability of LPN as an ac- raphy has resulted in increased detection of smaller, early ceptable alternative to OPN. Laparoscopic partial nephrec- stage renal masses, and has driven investigation into the tomy has been shown to be a technically feasible alternative feasibility and efficacy of partial nephrectomy as treatment to OPN with similar surgical efficacy as measured by posi- for some renal tumors. In 1981 it was shown that survival tive surgical margin rates in select cases.9–13 In this survey rates in patients treated with partial nephrectomy were no we evaluated the surgical and oncological efficacy of LPN at different than those of patients treated with radical ne- 17 centers in the United States and Europe. In addition, we phrectomy.2 More recent studies have also shown similar surveyed the indications for intraoperative frozen sectioning oncological outcomes between select patients treated with following LPN. partial vs radical nephrectomy, and triggered the emergence MATERIALS AND METHODS A survey was sent to 26 academic medical centers in the Submitted for publication November 27, 2006. United States and Europe that perform LPN. Records of * Correspondence: Department of Urology, University of Califor- patients who underwent LPN were reviewed retrospectively. nia, Los Angeles, 10833 Le Conte Ave., Los Angeles, California 90095(telephone:310-825-1172;FAX:310-825-2030;e-mail:abreda@ Laparoscopic approach was transperitoneal and/or extra- mednet.ucla.edu). peritoneal (table 1). The total number of LPNs performed,

0022-5347/07/1781-0047/0 47 Vol. 178, 47-50, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.045 48 POSITIVE MARGINS IN LAPAROSCOPIC PARTIAL NEPHRECTOMY

TABLE 1. Tumor characteristics and laparoscopic approach Center No. No. Cases Laparoscopic Approach Mean Tumor Size (cm) No. Exophytic Lesions No. Deep Lesions

1 68 Extraperitoneal 2.7 No response No response 2 56 Transperitoneal 2.5 No response No response 3 50 Transperitoneal 2.8 46 4 4 15 Transperitoneal 2.0 15 0 5 47 Transperitoneal No response 47 0 6 163 Both 2.8 120 43 7 25 Transperitoneal 3.0 No response No response 8 60 Both 3.3 46 14 9 23 Both 2.0 19 4 10 15 Both 2.4 15 0 11 34 Both 2.7 30 4 12 36 Extraperitoneal 4.0 No response No response 13 30 Transperitoneal 2.5 23 0 14 100 Transperitoneal 3.5 60 40 15 36 Transperitoneal 2.5 24 6 16 75 Transperitoneal 2.5 22 8 17 22 Transperitoneal 3.5 No response No response Overall 855 2.7 467 123 tumor size, tumor position, margin status, and indications margin rates in centers that performed 30 or less, 31 to 59, for intraoperative frozen biopsy were queried. We defined or 60 or more cases were 2.6%, 3.0% and 2.3%, respectively, exophytic tumors as those in which the lesion presented and there were no statistically significant differences among with more than 75% exophytic component. Deep tumors the 3 groups (p ϭ 0.93). were defined as having less than 15% of the lesion extending With respect to the frozen section indications 10 centers beyond the surface of the kidney. In addition, we queried the performed intraoperative frozen sections selectively, based real efficacy of the frozen section, particularly in guiding on clinical suspicion of positive margins on excised tumor. intraoperative management. Statistical comparisons among Two centers never performed frozen sections and 5 centers centers with varying case loads were made. Mean positive always performed random biopsies on the resection bed. Of margin rates among centers with 30 or less, 31 to 59, or 60 the 21 cases with positive margins 14 underwent immediate or more cases were compared using 1-way ANOVA for inde- radical nephrectomy based on the frozen section and 7 were pendent samples. followed expectantly. Of the 21 cases with positive margins on final pathology RESULTS we were able to obtain data on frozen sectioning from 6 cases (table 3). In 3 of these cases the final pathology corresponded There was a total of 855 LPN cases reported in suitable to the frozen section, whereas in the 3 other cases the final surveys received from 17 of the 26 centers. Data from 16 pathology did not correspond to the frozen section. Two centers, accounting for 808 cases, revealed a mean tumor tumors were preliminarily identified as RCC on frozen sec- size of 2.7 cm (range 2 to 4). One center (47 cases) did not tion with the patients undergoing radical nephrectomy report on tumor size. A total of 467 tumors (55%) were based on that result. Final pathology on both of those tumors described as exophytic and 123 (14%) as deep. Five centers revealed AML. One excised tumor was initially identified as did not report on tumor position accounting for a total of 260 having negative margins on frozen section but radical ne- cases (30%) (table 1). There were 21 cases with positive phrectomy was performed based on clinical suspicion of re- margins on final pathology, giving a mean positive margin maining cancer. Final pathology in that case revealed RCC. rate of 2.4% (range 0% to 8%, table 2). The mean positive DISCUSSION

TABLE 2. Positive margin rate Laparoscopic partial nephrectomy as a surgical approach for the management of renal tumors is becoming increasingly Center No. No. Cases No. Pos Margins standardized. Many contemporary studies have demon- 1680strated the feasibility, safety and efficacy of LPN.9–13 To our 2560 3502knowledge the current survey is the largest survey provid- 4150ing further evidence of the oncological efficacy of LPN as well 5470as the practice patterns and surgical efficacy. The positive 6 163 3 7252 8603 9230 10 15 0 TABLE 3. Intraoperative frozen section and final pathology 11 34 0 12 36 2 Case No. Frozen Section Final Pathology 13 30 1 1 RCC RCC 14 100 2 2 RCC RCC 15 36 3 3 RCC RCC 16 75 2 4 RCC AML 17 22 1 5 RCC AML Totals 855 21 (2.4%) 6 Neg RCC POSITIVE MARGINS IN LAPAROSCOPIC PARTIAL NEPHRECTOMY 49

tutions. Various techniques exist for intraoperative section- TABLE 4. Reported oncological efficacy of open and laparoscopic partial nephrectomy ing and previous studies have reported sectioning of the inked margins of the excised tumor itself14 or multiple ran- References No. Tumors No. Pos Margins (%) dom biopsies of the resection bed.9 We found that the tech- Laparoscopic: niques and indications for intraoperative frozen sectioning 12 Moinzadeh et al 100 2 (2) varied among participating centers. In our survey 10 centers Venkatesh et al13 121 3 (2.5) Link et al11 201 7 (3.5) performed intraoperative frozen sectioning of the excised Current series 855 21 (2.4) tumor selectively based on clinical suspicion of positive mar- Open: Thompson et al14 480 1 (0.8) gins, 5 centers always performed random biopsies of the Porpiglia et al10 30 1 (3.3) tumor resection bed and 2 centers never performed frozen Sutherland et al15 44 3 (6.8) sections. We also found that the results of intraoperative frozen sections, when performed, did not correlate well with final pathology. Of the 21 cases with positive margins on margin rate of 2.4% found in our survey is comparable to final pathology we were able to obtain data on frozen sec- that reported in contemporary studies on LPN11–13 and tioning from 6 cases. In 3 of the 6 cases the final pathology OPN (table 4).10,14,15 Three contemporary studies on LPN of RCC corresponded to the frozen section, and in the re- have reported a positive margin rate of 2%, 2.5% and 3.5% in maining 3 cases final pathology did not correspond to the 100, 121 and 201 cases, respectively. Mean tumor size in frozen section. Two tumors were preliminarily identified as those studies ranged from 2.6 to 2.9 cm.11–13 With regard to renal cell carcinoma on frozen section with the patients OPN a study of 46 patients by Sutherland et al in 2002 undergoing radical nephrectomy based on that result. Final revealed a positive margin rate of 6.8%.15 In 2005 Porpiglia pathology on both of those tumors revealed angiomyolipoma. et al reported a positive margin rate of 3.3% in 30 patients One excised tumor was initially identified as having nega- who underwent OPN10 and more recently Thompson et al tive margins on frozen section but radical nephrectomy was reported a positive margin rate of 0.8% in their experience performed based on clinical suspicion of remaining cancer. with OPN involving 480 cases.14 It is important to acknowl- Final pathology in that case revealed renal cell carcinoma. edge that mean tumor sizes in these studies were small, The discrepancy between intraoperative frozen section pa- ranging from 3.14 to 3.6 cm,10,14,15 and are similar to our thology and final pathology may be due to numerous factors reported mean tumor size of 2.7 cm. This similarity may including technical reasons such as missing remaining tu- indicate a potential influence of tumor size on attaining clear mor during random biopsy or pathologist error.16 In the 3 surgical margins. Our reported positive margin of 2.4% in cases we described with incorrect frozen section pathology, 855 cases with a mean tumor size of 2.7 cm suggests that sectioning of the inked margins was performed suggesting LPN has an oncological efficacy, as measured by positive pathologist error. In 2005 a study of intraoperative frozen margin rate, comparable to that of OPN for small (4 cm or section in 301 OPN cases demonstrated minimal clinical less) renal masses. significance in frozen sections.17 In that study frozen sec- Additionally, data with regard to tumor position were tioning revealed positive margins in 2 patients who subse- obtained from 12 centers in our survey, accounting for 590 quently underwent radical nephrectomy. Final pathology on cases. In the majority of those cases (79%) the tumor was the radical nephrectomy specimens revealed no residual tu- described as exophytic. It is worthwhile to note that there is mor. In addition, final pathology revealed 4 positive margins a selection of exophytic masses in 2 recent studies on OPN in samples in which the frozen section pathologies were which have reported exophytic or peripheral tumors in 66% negative. Our data similarly demonstrate that intraopera- and 70% of cases.10,14 tive frozen sectioning is not definitive and raises questions Previous studies on LPN were single center studies often about its value in guiding intraoperative management. Re- performed at centers of excellence and, thus, raised concerns cent studies examining the effect of margin size on disease about the ability of less experienced urological laparosco- progression in OPN have shown that margin size is irrele- pists to reproduce the technique.10 Data from this survey vant as long as the tumor bed is completely free of residual were acquired from 17 centers across the United States and tumor after the initial procedure.15,18 Interestingly, studies Europe allowing for urologists from diverse training back- examining long-term oncological outcomes of patients who grounds to participate and demonstrate the feasibility of underwent simple enucleation for renal masses suggest that oncological standards attained with the open approach. excision of a margin of healthy parenchyma is not required However, it is important to note that the surgeons who to obtain long-term cancer specific survival rates similar to participated in this survey are well trained in the laparo- those of radical nephrectomy.19,20 In these studies examina- scopic technique. The centers in this survey had variable tion of the renal surface was done to rule out enucleation bed case loads ranging from 15 to 163 cases. Mean positive infiltration but biopsies of the enucleation bed were rarely margin rates in centers that performed 30 or less, 31 to 59, performed.19,20 Data from this survey as well as prior data or 60 or more cases were 2.6%, 3.0% and 2.3%, respectively, demonstrating the inconclusiveness of intraoperative frozen and there were no statistically significant differences among sectioning,17 combined with the recent data showing that the 3 groups (p ϭ 0.93). Interestingly this finding may have simple enucleation can yield long-term survival rates com- many explanations. The absence of a trend may be the result parable to radical nephrectomy, lead us to question whether of surgeons becoming more comfortable with the procedure, intraoperative frozen sectioning is at all necessary during treating more challenging cases and, thus, not seeing a the surgical management of clinically typical renal masses. decrease in positive margins. Further studies examining the usefulness of frozen section- This survey also provided an opportunity to examine the ing in nephron sparing surgery are needed to determine if practice of intraoperative frozen sectioning at various insti- careful macroscopic examination of the tumor bed can yield 50 POSITIVE MARGINS IN LAPAROSCOPIC PARTIAL NEPHRECTOMY reliable data with regard to tumor infiltration. In additional, 11. Link RE, Bhayani SB, Allaf ME, Varkarakis I, Inagaki T, whether these data can reliably be used to guide intraoper- Rogers C et al: Exploring the learning curve, pathological ative management must be investigated. outcomes and perioperative morbidity of laparoscopic partial nephrectomy performed for renal mass. J Urol 2005; 173: 1690. CONCLUSIONS 12. Moinzadeh A, Gill IS, Finelli A, Kaouk J and Desai M: Lapa- roscopic partial nephrectomy: 3-year followup. J Urol 2006; The experience with LPN in this multicenter study demon- 175: 459. strates that LPN is a technically feasible option with onco- 13. Venkatesh R, Weld K, Ames CD, Figenshau SR, Sundaram CP, logical efficacy comparable to OPN with respect to the inci- Andriole GL et al: Laparoscopic partial nephrectomy for dence of positive margins in patients with small renal renal masses: effect of tumor location. Urology 2006; 67: masses. Before LPN can be considered the standard in 1169. nephron sparing surgery, further followup studies are re- 14. Thompson RH, Leibovich BC, Lohse CM, Zincke H and Blute quired to assess the adequacy of long-term cancer control. ML: Complications of contemporary open nephron sparing The practice of intraoperative frozen sections varies among surgery: a single institution experience. J Urol 2005; 174: centers and is not definitive in guiding the optimal surgical 855. 15. Sutherland SE, Resnick MI, Maclennan GT and Goldman HB: treatment. Does the size of the surgical margin in partial nephrectomy for renal cell cancer really matter? J Urol 2002; 167: 61. 16. Truong LD, Krishnan B and Shen SS: Intraoperative pathol- Abbreviations and Acronyms ogy consultation for kidney and urinary bladder specimens. Arch Pathol Lab Med 2005; 129: 1585. ϭ AML angiomyolipoma 17. Duvdevani M, Laufer M, Kastin A, Mor Y, Nadu A, Hanani J ϭ LPN laparoscopic partial nephrectomy et al: Is frozen section analysis in nephron sparing surgery ϭ OPN open partial nephrectomy necessary? A clinicopathological study of 301 cases. J Urol ϭ RCC renal cell carcinoma 2005; 173: 385. 18. Castilla EA, Liou LS, Abrahams NA, Fergany A, Rybicki LA, Myles J et al: Prognostic importance of resection margin REFERENCES width after nephron-sparing surgery for renal cell carcinoma. Urology 2002; 60: 993. 1. Vermooten V: Indications for conservative surgery in certain 19. Carini M, Minervini A, Lapini A, Masieri L and Serni S: renal tumors: a study based on the growth pattern of the Simple enucleation for the treatment of renal cell carci- cell carcinoma. J Urol 1950; 64: 200. noma between 4 and 7 cm in greatest dimension: progres- 2. Engen DE and Herr HW: Conservative management of renal sion and long-term survival. J Urol 2006; 175: 2022. adenoma v. adenocarcinoma. Br J Urol 1981; 53: 387. 20. Lapini A, Serni S, Minervini A, Masieri L and Carini M: 3. Belldegrun A, Tsui KH, deKernion JB and Smith RB: Efficacy Progression and long-term survival after simple enucle- of nephron-sparing surgery for renal cell carcinoma: anal- ation for the elective treatment of renal cell carcinoma: ysis based on the new 1997 tumor-node-metastasis staging experience in 107 patients. J Urol 2005; 174: 57. system. J Clin Oncol 1999; 17: 2868. 4. Campbell SC, Novick AC, Streem SB, Klein E and Licht M: Complications of nephron sparing surgery for renal tumors. EDITORIAL COMMENT J Urol 1994; 151: 1177. As anyone who has ever done a survey knows, it was a 5. Fergany AF, Hafez KS and Novick AC: Long-term results of nephron sparing surgery for localized renal cell carcinoma: formidable effort to obtain these 855 cases. And while this 10-year followup. J Urol 2000; 163: 442. study has the typical limitations of a survey such as retro- 6. Hafez KS, Fergany AF and Novick AC: Nephron sparing sur- spective data collection and missing responses, there is valu- gery for localized renal cell carcinoma: impact of tumor size able information here including the low positive margin on patient survival, tumor recurrence and TNM staging. rates with laparoscopic partial nephrectomy and the impre- J Urol 1999; 162: 1930. cise nature of intraoperative frozen sections for operative 7. Lerner SE, Hawkins CA, Blute ML, Grabner A, Wollan PC, guidance. Specimen orientation for the pathologist is not Eickholt JT et al: Disease outcome in patients with low obvious, and conversely areas of concern cannot be commu- stage renal cell carcinoma treated with nephron sparing or nicated in a timely fashion to the surgeon working under the radical surgery. 1996. J Urol 2002; 167: 884. duress of renal ischemia. Random biopsies of the resection 8. Uzzo RG and Novick AC: Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001; bed cannot be correlated with areas of concern on the re- 166: 6. sected specimen. The old adage to measure twice and cut 9. Allaf ME, Bhayani SB, Rogers C, Varkarakis I, Link RE, once is quite fitting for this procedure. Based on the results Inagaki T et al: Laparoscopic partial nephrectomy: evalua- of this study it seems that the urological community is tion of long-term oncological outcome. J Urol 2004; 172: heeding this well. 871. 10. Porpiglia F, Fiori C, Terrone C, Bollito E, Fontana D and Surena F. Matin Scarpa RM: Assessment of surgical margins in renal cell Department of Urology carcinoma after nephron sparing: a comparative study: University of Texas M.D. Anderson Cancer Center laparoscopy vs open surgery. J Urol 2005; 173: 1098. Houston, Texas Squamous Cell Carcinoma of the Renal Pelvis and Ureter: Incidence, Symptoms, Treatment and Outcome

Sten Holmäng,* Subodh M. Lele and Sonny L. Johansson From the Department of Urology, Sahlgrenska University Hospital Göteborg, Sweden (SH), and Department of Pathology and Microbiology, and Eppley Cancer Center, Nebraska Medical Center (SML, SLJ), Omaha, Nebraska

Purpose: Squamous cell carcinomas of the renal pelvis and ureter are rare. We report a large series of patients and compare it to patients with urothelial carcinoma. Materials and Methods: The initial material was comprised of 808 patients with renal pelvis or ureteral cancer. A review of the histopathological material and clinical records was performed. Results: Only 2 (4%) of 65 patients with squamous cell carcinoma had stage pTa/pT1/pT2 tumors compared to 460 (62%) of 743 patients with urothelial carcinoma. Median survival was much shorter for surgically treated patients with squamous cell carcinoma compared to those with urothelial carcinoma (7 vs 50 months). However, there was no significant difference in the disease specific 5-year survival rate between patients with squamous cell carcinoma and urothelial carcinoma in the same disease stage. Vascular invasion, microscopic solid tumor pattern and large tumor size had negative prognostic significance in multivariate analyses. Histopathological tumor type (squamous cell carcinoma or urothelial carcinoma) had no prognostic significance. Conclusions: The prognosis for squamous cell carcinoma is poor, but stage for stage the prognosis is not different between patients with urothelial carcinoma and squamous cell carcinoma of the renal pelvis and ureter. It can be presumed that high stage squamous cell carcinoma and urothelial carcinoma become symptomatic first at a time when the tumors already are large, deeply invasive and most often incurable. New treatment modalities are urgently needed to improve the poor prognosis in patients with advanced stage squamous cell carcinoma and urothelial carcinoma of the upper urinary tract. Key Words: carcinoma, squamous cell; ureter; kidney pelvis

umors of the renal pelvis are rare in comparison with result in cure but radiotherapy and systemic chemotherapy renal carcinoma and bladder carcinoma, which have a seem to have little benefit.3,9,12 We present a clinical and T 6 and 17 times higher incidence, respectively.1 Ure- histopathological review of 65 patients with SCC of the renal teral tumors are even more unusual with a reported inci- pelvis and ureter, and compare it to 743 patients with UC. dence at half that of renal pelvic carcinoma.1 The majority of renal pelvic and ureteral carcinomas are UC but 6% to 15% PATIENTS are SCC.2,3 It is presumed that chronic irritation of the urothelium may result in squamous metaplasia which later We used the Swedish Cancer Registry to identify all patients may develop into squamous cell carcinoma. Our current in western Sweden diagnosed with a malignant ureteral or knowledge of SCC is based on a few reports with up to 15 renal pelvic tumor between 1971 and 1998. A total of 943 patients as well as case reports, mostly without histopatho- patients were found. In 1998 the population in western 2–15 logical review. Sweden was 1.65 million. Patients with an upper urinary SCC is frequently associated with urolithiasis and hydro- tract tumor were treated surgically in 18 hospitals in the 3,11,12,14 nephrosis. It has been associated with paraneoplas- region. tic syndromes such as hypercalcemia, leukocytosis and thrombocytosis.4,6,7,10,13 A solid mass, hydronephrosis and calcifications are common radiological findings but nonspe- Clinical Review cific, which may explain why the diagnosis frequently is not The clinical records were reviewed in the hospitals where established before the histopathological examination of the the patients were treated and followed. Approximately 99% surgical specimen (fig. 1).3,5,6,9,12 Early metastatic spread is of the clinical records were available for review. Information common and the prognosis is poor with few patients surviv- about tumor size was taken from the pathology report or, if ing longer than 5 years.2–6,9,11,12 Surgery may sometimes absent, from the radiology reports. The diameter of the largest tumor was recorded in cases of multiple tumors. Information about the date for the initial symptom was Submitted for publication November 13, 2006. found in the clinical records. When the exact number of Supported by the Sahlgrenska University Hospital LUA. * Correspondence: Department of Urology, Sahlgrenska University days was uncertain it was approximated. For example, Hospital, S-413 45, Goteborg, Sweden (telephone: 0046313423309; 3 months was approximated to 90 days. Survival informa- e-mail: [email protected]; [email protected]). tion was obtained from the clinical records in the depart- See Editorial on page 12. ments of Urology, Surgery, Medicine and Oncology, and

0022-5347/07/1781-0051/0 51 Vol. 178, 51-56, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.033 52 SQUAMOUS CELL CARCINOMA OF RENAL PELVIS AND URETER

FIG.1. A, squamous cell carcinoma of the renal pelvis. Tumor is arising in renal pelvis, and extending to and inﬁltrating renal parenchyma. B, squamous cell carcinoma grade 2/4. Note nests of inﬁltrating squamous cells with hyperchromatic nuclei and prominent keratin production (H & E, reduced from ϫ200).

from the Cause of Death Registry of the Swedish National other histological patterns, mainly less than 10% UC. Micro- Board of Health and Welfare. papillary, lymphoepithelial, small cell and sarcomatoid patterns were occasionally identified. SCC was more common Histopathological Review among muscle invasive tumors (T2, T3, T4) and was present Recuts were made from the paraffin embedded blocks and in 64 (14.4%) of 445 patients. stained with hematoxylin and eosin if the original slides were unavailable or unreadable. Approximately 91% (858 of 943 cases) of the histopathological material was available for Etiology review. We excluded from analysis 50 patients with histo- Of 65 patients with SCC 8 (12.3%) compared to 41 (5.5%) of ϭ logical tumor types other than UC and SCC (mainly small 743 with UC (difference not significant, p 0.06) had a cell, sarcomatoid and undifferentiated carcinomas). Thus, history of previous surgery for urolithiasis or a staghorn the study population for the present report comprises 808 calculi, but information concerning this issue was incom- patients with UC or SCC verified by histopathological re- plete. A history of abuse of analgetics containing phenacetin view. The tumors were restaged according to the TNM sys- was documented in the clinical records of 5 patients (8%) tem of 1992, and graded according to the WHO classification of 65 with SCC and 20 patients (2.7%) of 743 with UC ϭ system of 1999 and to the WHO/International Society of (p 0.09). Of 32 women with SCC 1 (3.1%) had a history of Urological Pathologists Consensus Classification of 1998, external beam radiotherapy toward the abdomen or pelvic which is identical to the WHO 2004 classification sys- region as treatment for gynecological tumor as compared to ϭ tem.16–19 Squamous cell carcinomas were graded in a 32 (11%) of 290 women with UC (p 0.22). Only 1 male 4-grade system with grade 1—well differentiated, grade patient of 453 was treated with external beam radiotherapy 2—moderately differentiated, grade 3—poorly differentiated toward the abdomen before the diagnosis of an upper tract and grade 4—SCC with areas of undifferentiated carci- tumor. noma. Symptoms and Delay Statistics All stages. Local symptoms were more common in patients Fisher’s exact test was used for calculating differences be- with SCC compared to those with UC. The time from the tween groups for dichotomous variables. Time to event was appearance of the first symptom to surgery (delay) was 51.5 analyzed with survival analysis. Kaplan-Meier estimates days (median) for 50 of 55 patients with SCC treated with were calculated and formally tested with the log rank test surgery. Data were missing or uncertain in the remaining for categorical nonordered variables. Ordered and continu- patients. The median delay for 595 of 686 patients with UC ous variables were tested with Cox proportional hazard re- and available data were 80 days. gression. Stepwise proportional hazard regression was performed for multivariate purposes. All tests were 2-tailed and Stage pT3. There was no difference in delay between pa- conducted at a 5% significance level. tients with SCC and those with UC with stage pT3 tumors, at 68 days for 35 of 38 patients with SCC and 70 days for 166 RESULTS of 190 patients with UC treated with surgery. Incidence Of 808 patients 65 (8%) had SCC and 743 (92%) had UC. Age, Gender, Size, Side, Location and Multiplicity SCC was the only histological tumor type in 47 of the 65 All stages. The sex ratio in patients with SCC was almost 1:1 patients. A total of 18 patients with SCC had focal areas of but women comprised only 39% of those with UC (table 1). SQUAMOUS CELL CARCINOMA OF RENAL PELVIS AND URETER 53

surgical procedure was nephrectomy which was performed TABLE 1. Basic data on all stages in 32 of 56 patients treated surgically. The main reasons for SCC UC p Value nephrectomy rather than nephroureterectomy was that re- No. pts 65 743 nal cell carcinoma was suspected in 12 patients, a benign Age: condition was suspected in 4, a remaining tumor in the renal Median 72 70 Mean 68.9 69.3 0.78 area in 11 and poor general condition in another 5 patients. Range 39–89 25–94 A later ureterectomy was performed in 3 patients with SCC No. gender (%): but histopathology showed only ﬁbrosis. Initial treatment of Male 33 (51) 453 (61) 0.11 Female 32 (49) 290 (39) patients with stage pT3 disease is seen in table 3. No. initial symptoms (%): Macroscopic hematuria 28 (43) 446 (60) 0.09 Local 22 (34) 108 (15) Ͻ0.01 Bladder Cancer and Contralateral Tumors General 9 (14) 32 (4) Ͻ0.01 From distant metastases 2 (3) 6 (1) Of 42 patients with SCC stage pT3 disease 2 (5%) had None 3 (5) 143 (19) Ͻ0.01 bladder cancer preceding the diagnosis of an upper tract Data missing 1 (2) 8 (1) tumor and 1 (2%) had concomitant bladder cancer. Of 38 No. tumor side (%): Rt 34 (52) 354 (48) 0.6 patients treated surgically a subsequent bladder cancer de- Bilat 0 12 (2) veloped in 2 (5%). Contralateral upper tract tumors did not No. tumor multiplicity (%) 4 (6) 101 (14) 0.12 No. tumor location (%): develop in any patients. The corresponding ﬁgures for pa- Renal pelvis 45 (70) 473 (64) 0.56 tients with UC stage pT3 were 11 (5%) of 227 for a previous Ureter 16 (25) 210 (28) 0.33 bladder tumor, 11 (5%) of 227 for concomitant bladder tu- Both 4 (6) 60 (8) 0.81 Median tumor size (mm) 50 30 mor, 38 (20%) of 190 surgically treated patients for a subse- No. stage (%): quent bladder tumor and 5 (3%) of 190 for a contralateral pTa, pcis 0 347 (47) upper tract tumor. pT1 1 (2) 73 (10) Ͻ0.01 pT2 1 (2) 40 (5) 0.02 pT3 42 (65) 227 (31) Ͻ0.01 pT4 19 (29) 42 (6) Ͻ0.01 pTx 2 (3) 14 (2) 0.37 TABLE 2. Stage pT3 tumors SCC UC p Value

No. pts 42 227 Multiple tumors were more common in patients with UC. Age: Tumor diameter was larger in patients with SCC. Median 68.5 72 Mean 67.8 71.5 0.03 Stage pT3. Patients with stage pT3 SCC were younger Range 40–83 35–92 No. gender (%): than patients with UC stage pT3 (table 2). Patients with Male 22 (52) 127 (56) 0.74 SCC stage pT3 have on the average larger tumors and more Female 20 (48) 100 (44) No. initial symptoms (%): often tumors which show invasion into the kidney and peri- Macroscopic hematuria 18 (43) 145 (64) 0.02 renal tissues compared to patients with UC stage pT3. Local 13 (31) 32 (14) 0.01 General 7 (17) 13 (6) 0.02 From distant metastases 1 (2) 6 (1) Stage and Grade None 2 (5) 31 (14) 0.13 There were 10 patients with a SCC grade 2 tumor, 38 with Data missing 1 (2) 0 No. tumor side (%): a grade 3 and 15 with a grade 4 tumor. Data are missing for Rt 22 (52) 107 (48) 0.61 2 patients. There was no significant difference in prognosis Lt 20 (48) 116 (51) among patients with different grade disease. The majority of Bilat 0 1 Unknown 0 1 patients with UC had stage pTa and pT1 tumors but only 2 No. tumor location (%): patients had SCC of stage lower than pT3. Renal pelvis 27 (64) 159 (70) 0.47 Ureter 12 (29) 41 (18) 0.14 Both 3 (7) 27 (12) 0.59 Microscopic Tumor Patterns and Vascular Invasion Size (mm): Median 50 35 All stages. The tumor patterns in SCC were pure solid Mean 54 41 0.01 86%, mixed solid and papillary 14%, with no tumor having No./total No. tumor 3/42 (7) 33/227 (15) 0.32 papillary configuration only. The corresponding figures for multiplicity (%) No./total No. microscopic tumor UC were 15%, 23% and 62%, respectively. pattern (%):* Solid 34/41 (83) 69/222 (31) Ͻ0.01 Stage pT3. The microscopic tumor pattern for stage pT3 Solid ϩ papillary 7/41 (17) 121/222 (55) Ͻ0.01 Papillary 0 32/222 (14) 0.01 tumors is seen in table 2. Vascular invasion was equally No./total No. perirenal 26/30 (87) 137/182 (75) 0.24 common in SCC compared to UC. One patient with SCC had invasion (%)† tumor invasion into the renal vein and a tumor thrombus in No./total No. renal 28/30 (93) 142/182 (78) 0.50 invasion (%)† the caval vein. No./total No. perirenal ϩ renal 24/30 (80) 96/182 (53) 0.01 invasion (%)† No./total No. angiolymphatic 28/38 (74) 162/217 (75) 0.90 Treatment invasion (%)* There were 9 patients with SCC who did not undergo sur- No./total No. Nϩ and/or 18/42 (43) 63/227 (28) 0.07 ϩ gery due to poor general condition at the time of diagnosis (2 M (%) patients), distant metastases (3 patients) or a diagnosis first * Data are missing for some patients. at post mortem examination (4 patients). The most common † Renal pelvic tumors only. 54 SQUAMOUS CELL CARCINOMA OF RENAL PELVIS AND URETER

DISCUSSION TABLE 3. Treatment and outcome (stage pT3 only) SCC UC p Value The incidence of SCC in the renal pelvis and ureter was in agreement with that in previous studies reporting an inci- No. pts 42 227 2 No. initial treatment (%): dence between 6% and 15%. The proportion of SCC among Nephroureterectomy 13 (31) 111 (49) 0.04 muscle invasive upper urinary tract tumors was 14.4% Nephrectomy 20 (48) 61 (27) 0.01 Resection 4 (10) 17 (8) 0.75 which is not different from the proportion of SCC in patients Nephroureterectomy ϩ resection for 1 from western Sweden with muscle invasive bladder cancer bilat tumors which was 18.2%.20 There were almost as many female as Exploration 1 (2) 0 No surgery 4 (10) 37 (16) 0.35 male patients with SCC of the renal pelvis and ureter in No. later treatment (%): contrast to the ubiquitous dominance of men among patients Postop radiotherapy to renal fossa 2 (1) with UC in the upper urinary tract as well as in the bladder. Systemic chemotherapy 5 (12) 17 (8) 0.36 No. outcome (%): The proportion of female patients in previous publications Alive 5 (12) 32 (14) 1 on SCC has varied between 27% and 66% but it can be Dead of intercurrent disease 8 (19) 43 (19) Dead of tumor 29 (69) 152 (67) 0.86 explained by chance because the number of patients was 2–5 Mos postop survival: only between 11 and 15. Median 10 21 We found that a history of abuse of analgesics containing Mean 25 40 0.07 phenacetin or previous surgery for urolithiasis was more common among patients with SCC than it was among patients with UC, but that the difference was not statistically Outcome significant. The 12% incidence of staghorn calculi or previ- All stages. The outcome for patients with SCC was poor ous surgery for urolithiasis in the present report was much 14 with a median survival of only 7 months after surgery and lower than the 25% to 100% reported by other authors. only 5 patients (7.7%) surviving longer than 5 years. The The differences in the incidence of urolithiasis may be ex- median survival of patients with UC was 50 months and 306 plained by lack of information in this retrospective study. patients (41%) survived longer than 5 years (fig. 2, A). The Almgard et al reported on 2 female patients with ureteral 21 absolute majority of these long-term survivors had stage carcinoma 1 to 2 decades after pelvic radiotherapy. We pTa and pT1 UC. Only 1 patient of 19 with SCC stage pT4 identified as many as 33 patients with ureteral carcinoma survived past 5 years compared to 0 of 42 with UC stage pT4. and a history of pelvic radiotherapy for carcinoma of the Only 6 of 56 surgically treated patients with SCC were uterus, cervix uteri or ovaries 2 to 3 decades earlier, and this treated with systemic chemotherapy and they all died of will be the subject of a future study. Typically, most of these disease. The most common metastatic sites were the re- tumors were poorly differentiated UC and rarely SCC. gional lymph nodes, lungs, liver and the bone system. There There was a considerable and significant difference in was no difference in prognosis between patients with pure tumor size. SCCs were larger even when only stage pT3 SCC, and those with SCC and focal areas of other histolog- tumors were considered. The difference in size may explain ical types (74% and 71% died of disease, respectively). why local symptoms were more common in patients with SCC. On the other hand, macrohematuria was more com- Stage pT3. There was no significant difference between mon in patients with UC, which can be explained by the disease specific survival rates of patients with pT3 SCC and common papillary structure of these tumors leading to a pT3 UC (fig. 2, B). The difference was even smaller when larger surface area. only solid pT3 tumors were considered. The Kaplan-Meier Tumor grade had little prognostic value in our study. In estimated disease specific 5-year survival rate was 20% for 1990 Nativ et al performed DNA ploidy studies.8 The 3 patients with SCC and 29% for patients with UC (p Ͻ0.33, long-term survivors in the report had diploid tumors but the graph not shown). Univariate and multivariate analyses authors concluded that ploidy analyses were not indicated were performed for all patients with stage pT3 tumors. His- because they did not contribute to patient management. topathological tumor type (SCC or UC) had no significant Tumor stage had a strong prognostic value which is in agree- prognostic value for disease specific survival (table 4). ment with earlier reports. Patients with SCC stage T1–T2

FIG. 2. Comparison of disease speciﬁc survival in patients with SCC and UC. A, all patients. B, stage pT3 only. SQUAMOUS CELL CARCINOMA OF RENAL PELVIS AND URETER 55

TABLE 4. Analyses of factors of possible predictive value for disease speciﬁc survival of patients with stage pT3 tumors Univariate Multivariate HR (95% CI) p Value HR (95% CI) p Value

Vascular invasion 2.69 (1.75–4.13) Ͻ0.01 2.792 (1.706–4.569) Ͻ0.01 Tumor size 1.01 (1.00–1.02) Ͻ0.01 1.014 (1.007–1.020) Ͻ0.01 Papillary pattern 0.54 (0.39–0.77) Ͻ0.01 0.481 (0.321–0.720) Ͻ0.01 Ureteral tumor 1.39 (0.98–1.96) 0.06 1.692 (1.134–2.525) 0.01 Solid pattern 3.05 (1.65–5.66) Ͻ0.01 SCC or UC 1.43 (0.93–2.20) 0.1 100% SCC* 1.18 (0.92–1.52) 0.19 Renal pelvic tumor 0.78 (0.53–1.14) 0.19 Tumor No. 1.00 (0.58–1.71) 0.99 Bladder Ca† 1.02 (0.60–1.74) 0.94 Male gender 1.11 (0.80–1.54) 0.54 * Versus 50% to 100% SCC and 0% SCC. † Previous or concomitant.

tumors may be treated with radical surgery and have a good ACKNOWLEDGMENTS prognosis while those with more advanced tumors often have metastatic disease. Symptomatic residual tumor or Our colleagues in the departments of Urology, Surgery, Pa- local recurrence seem to occur in at least 50% of patients in thology and Oncology at the hospitals in western Sweden provided access to clinical records and the histopathological published series and case reports.6,11,13,14 material. If there is a benefit with neoadjuvant and adjuvant radiotherapy/chemotherapy in the treatment of SCC, it is probably small. Most patients in earlier reports as well as in our report treated with any of these modalities died of dis- Abbreviations and Acronyms ease within months.2–4,12 However, few patients were SCC ϭ squamous cell carcinoma treated with modern cisplatinum based regimes but out- UC ϭ urothelial carcinoma comes in such cases seem to have been equally poor.9,12 The nephroureterectomy rate in patients with SCC and UC was rather low which can be explained by the unselected REFERENCES nature of this report. We included all patients in a large geographic area with the diagnosis of a renal pelvic and 1. Cancer incidence in Sweden 2004. The National Board of ureteral carcinoma. The majority of prior publications have Health and Welfare. Centre for Epidemiology. Stockholm, come from University hospitals, often with a heavy bias for Sweden 2005. Available at www.socialstyrelsen.se. patient selection. 2. Blacher EJ, Johnson DE, Abdul-Karim FW and Ayala AG: Bladder tumors seem to be more unusual after surgery Squamous cell carcinoma of the renal pelvis. Urology 1985; for an upper tract SCC compared to an upper tract UC. This 25: 124. 3. Li MK and Cheung WL: Squamous cell carcinoma of the renal may explain why the value of regular followup cystoscopy pelvis. J Urol 1987; 138: 269. can be questioned, at least in patients with stage pT4 upper 4. Wagle DC, Moore RH and Murphy GP: Squamous cell carci- tract tumors because the prognosis is so poor. Contralateral noma of the renal pelvis. J Urol 1974; 111: 453. tumors after surgery for SCC are rare, thus there is not 5. Kinn A-C: Squamous cell carcinoma of the renal pelvis. Scand much motivation to perform routine followup urography. It J Urol Nephrol 1979; 14: 77. seems questionable to perform followup computerized to- 6. Gonzales RD, Barrientos A, Larrodera L, Ruilope LM, Leiva O mography of the abdomen due to the present lack of curative and Borobia V: Squamous cell carcinoma of the renal pelvis or palliative treatment for a patient with local recurrence. associated with hypercalcemia and the presence of para- thyroid hormone-like substances in the tumor. J Urol 1985; 133: 1029. 7. Lee M, Sharifi R and Kurtzman NA: Humoral hypercalcemia CONCLUSIONS due to squamous cell carcinoma of the renal pelvis. Urology 1988; 32: 250. The outcome for patients with SCC of the upper urinary 8. Nativ O, Winkler HZ, Reiman HM and Lieber MM: Squamous tract was poor with less than 10% alive after 5 years which cell carcinoma of the renal pelvis: nuclear deoxyribonucleic is in agreement with the results of previous studies.2,3,5,14,15 acid ploidy studied by flow cytometry. J Urol 1990; 144: 23. The comparison between advanced stage (pT3 and pT4) SCC 9. Nakamura K, Shiramizu M, Katsuoka Y and Baba S: Squa- and UC in the present report shows that the prognosis is mous cell carcinoma of ureter extending into renal vein. equally poor for the 2 tumor types. A reasonable assumption Urology 1992; 40: 458. is that solid SCC and UC rapidly invade the underlying 10. Morita T, Izumi T, Shinohara N and Tokue A: Squamous cell carcinoma of the ureter with marked leukocytosis produc- tissue, and first present with symptoms when they already ing granulocyte colony-stimulating factor. Urol Int 1995; are incurable. The treatment delay may seem long but it is 55: 32. 22 not different from the delay in bladder cancer. It seems 11. Cadeddu JA and Jarrett TW: Hypercalcemia associated with unlikely that a shorter delay would alter the poor prognosis. squamous cell carcinoma of the renal pelvis. J Urol 1998; Thus, new treatment modalities are urgently needed. 160: 1798. 56 SQUAMOUS CELL CARCINOMA OF RENAL PELVIS AND URETER

12. Kimura T, Kiyota H, Asano K, Madarame J, Yoshino Y, Miki K neoplasms of the urinary bladder. Bladder Consensus et al: Squamous cell carcinoma of the renal pelvis with Conference Committee. Am J Surg Pathol 1998; 22: 1435. inferior vena caval extension. Int J Urol 2000; 7: 316. 18. Mostofi FK, Davis CJ and Sesterhenn IA: World Health 13. Er Ö, Coskun HS, Altinbas M, Akgun H, Cetin M, Eser B et al: Organization International Histological Classification of Rapidly relapsing squamous cell carcinoma of the renal Tumours: Histological Typing of Urinary Bladder Tu- pelvis associated with paraneoplastic syndromes of leuko- mours, 2nd ed. New York: Springer-Verlag 1999. cytosis, thrombocytosis and hypercalcemia. Urol Int 2001; 19. Eble JN, Sauter G, Epstein JI and Sesterhenn IA: World 67: 175. Health Organization Classification of Tumours: Pathology 14. Busby JE, Brown GA, Tamboli P, Kamat AM, Dinney CPN, and Genetics of Tumours of the Urinary System and Male Grossman HB et al: Upper urinary tract tumors with non- Genital Organs. Lyon: IARC Press 2004. transitional histology: a single-center experience. Urology 20. Holmäng S, Hedelin H, Anderström C, Holmberg E and 2006; 67: 518. Johansson SL: Prospective registration of all patients in a 15. Perez-Montiel D, Wakely PE, Hes O, Michal M and Suster S: geographical region with newly diagnosed bladder carcino- High-grade urothelial carcinoma of the renal pelvis: clini- mas during a two-year period. Scand J Urol Nephrol 2000; copathologic study of 108 cases with emphasis on unusual 34: 95. morphological variants. Mod Pathol 2006; 19: 494. 21. Almgard LE, Freedman D and Ljungqvist A: Carcinoma of the 16. Hermanek P and Sobin L: TNM Classification of Malignant ureter with special reference to malignancy grading and Tumors: Renal Pelvis and Ureter, 4th ed. New York: prognosis. Scand J Urol Nephrol 1973; 7: 165. Springer-Verlag 1992; p 151. 22. Holmäng S and Johansson SL: Impact of diagnostic 17. Epstein JI, Amin MB, Reuter VR and Mostofi FK: The World and treatment delay on survival in patients with renal Health Organization/International Society of Urological Pa- pelvic and ureteral cancer. Scand J Urol Nephrol 2006; thology consensus classification of urothelial (transitional cell) 40: 479. Urine Telomerase Activity for the Detection of Bladder Cancer in Females

Sara Bravaccini,* Maria Aurora Sanchini, Anna Maria Granato, Roberta Gunelli, Oriana Nanni, Dino Amadori, Daniele Calistri and Rosella Silvestrini From the Istituto Oncologico Romagnolo (SB, MAS, AMG, ON, DC, RS) and the Department of Urology (RG), Morgagni-Pierantoni Hospital, Forlì, and the Istituto Scientiﬁco Romagnolo per lo Studio e la Cura dei Tumori (DA), Meldola, Italy

Purpose: Previous studies have shown that telomerase activity in bladder washings and voided urine represents an important noninvasive tool for bladder cancer diagnosis. With the present case-control study conducted on 212 women, including 144 healthy individuals and 68 patients, at first diagnosis of bladder cancer we confirmed previously obtained diagnostic results and improved the accuracy of this diagnostic assay. Materials and Methods: Telomerase activity was evaluated by quantitative telomeric repeat amplification protocol assay and expressed as arbitrary enzymatic units. Results: At the best overall cutoff of 50 arbitrary enzymatic units sensitivity was 87% and specificity was 66%. A breakdown analysis as a function of age showed a higher assay accuracy in women younger than 75 years (sensitivity 91% and specificity 69%) compared to older women (sensitivity 64% and specificity 59%). Conclusions: Other reasons in addition to age may account for the lower specificity in women with respect to men. In particular, a high number of telomerase positive nonurothelial cells in urine from females could be responsible for false- positive telomeric repeat amplification protocol results. Urine telomerase activity detected by telomeric repeat amplification protocol appears to be a good diagnostic tool in females although it is more accurate in younger than in older women. Key Words: telomerase, urine, urinary bladder neoplasms, diagnosis

lthough bladder cancer has a multiplicity of causes terized by high specificity but unsatisfactory sensitivity, es- including chemical, professional and biological fac- pecially for low grade, early stage tumors.3 Cystoscopy has a A tors as well as personal habits, a genetic predisposi- higher diagnostic accuracy but is an expensive and invasive tion involving alterations of detoxification enzymes is be- procedure requiring at least local anesthesia.4 coming increasingly evident.1 The multiplicity of these The search for an accurate, noninvasive and easily man- factors is reflected by the varying distribution of bladder ageable examination for bladder cancer diagnosis has been cancer worldwide as a function of lifestyle and industrial- intensively pursued in recent years. Exfoliated cells in urine ization. Bladder cancer incidence increases with age and is 3 bladder cancer represent an important, easily accessible 2 to 7-fold higher worldwide in men than in women. However, source of material for noninvasive tests. The diagnostic rel- the lower incidence in women is negatively counterbalanced evance of several markers has also been investigated such as by a shorter median survival for women compared to men. urinary human complement factor H related protein (BTA This higher mortality rate could be due to the higher per- stat® and BTA TRAK®), fibrinogen degradation products, centage of advanced tumors at first diagnosis, a greater nuclear matrix protein, cytokeratin 8 and 18 fragments frequency of unfavorable histologies and possibly to a thin- (UBC rapid and UBC immunoradiometric assays), and chro- ner bladder wall, especially in elderly women, which favors mosome alterations detected by fluorescence in situ hybrid- extravesical spread of tumor cells. ization.5,6 The sensitivity of these markers ranges from 65% As for every type of cancer early diagnosis allows for to 75% and specificity is high at approximately 90%. How- timely and often decisive measures to be taken. The current ever, some perplexities arise as to the wide variability in the gold standard for the diagnosis of bladder cancer consists of accuracy of results among the different studies.3 urine cytology and cystoscopy, used singly or sequentially. Among the markers proposed to improve diagnostic sen- Cytology is an inexpensive, noninvasive procedure charac- sitivity in urine, increasing attention has been focused on the role of telomerase activity for bladder cancer detection.7 Submitted for publication November 2, 2006. Telomerase is the enzyme that governs chromosomal length Study protocol received local Independent Reviewer Board ap- and, although it is switched off in almost all somatic cells, it proval from each center. is present in virtually all tumors. The 3 main components of Supported by Istituto Oncologico Romagnolo, Forlì and the National Research Council (Grants 02.00082.ST97 and 03.00073.ST97), Rome, the enzyme are human telomerase RNA, telomerase associ- Italy. ated protein 1 and human telomerase reverse transcriptase, * Correspondence: Istituto Scientifico Romagnolo per lo Studio e la the last of which has a key role in telomerase activation. Cura dei Tumori, Via P. Maroncelli 34/36, 47014 Meldola, Italy (telephone: 39 0543 739226; FAX: 39 0543 739221; e-mail: The most commonly used system for the detection and [email protected]). quantification of telomerase enzyme activity in various

0022-5347/07/1781-0057/0 57 Vol. 178, 57-61, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.025 58 TELOMERASE ACTIVITY FOR BLADDER CANCER DIAGNOSIS tumor types is the TRAP assay.8,9 However, TA can also be Urine Samples easily determined qualitatively or quantitatively using dif- Voided urine from healthy individuals and from patients ferent adaptations of the conventional TRAP assay such as (50 ml), the latter specimens collected immediately before TRAP scintillation proximity assay, TRAP-ELISA, fluores- cystoscopy, was used for cytological examination. Cell quan- cent TRAP assay, TRAP hybridization protection assay, tification and composition were analyzed by flow cytometry stretch polymerase chain reaction assay, real-time quanti- on 7 ml samples, and TA was determined by TRAP assay on tative TRAP, luminometric hybridization assay and bio- 3 ml samples. Urine samples were immediately stored at 4C luminescence link with TRAP. We used the TRAP assay and, when possible, processed as batched samples within 1 developed by Wright et al,9 and added a reference curve to to 3 hours or maintained at Ϫ80C for a maximum of 12 the internal standard to obtain more accurate and reproduc- months. All determinations were performed blindly with ible results for the diagnosis of bladder tumors.10 respect to the case-control status. Previous studies have shown that the quantitative TRAP assay performed in bladder washings and voided urine11 Cytological Examination represents an important noninvasive tool for diagnosis.12 Of the 68 patients 30 (44.1%) had positive urine cytology, 26 Sanchini et al also demonstrated in a case-control study that (38.2%) had negative cytology and 5 (7.4%) had suspicious this test is more accurate in males than in females.10 A cytology. The cytological samples were not assessable in 7 recent study by the same authors focusing on males con- (10.3%) patients. firmed the diagnostic accuracy of the test in the overall series of individuals, as well as in those with nonassessable Urine Cell Composition urine cytology or with low grade, early stage tumors. It also Samples were submitted to flow cytometric analysis using highlighted a higher accuracy in younger compared to older an automatic system (Sysmex UF 100, Sysmex Corp., Tarry- individuals.13 In the present case-control study we con- town, New York) specific for the quantitative and qualitative firmed the diagnostic results obtained in women and im- determination of cell components. proved the accuracy of the test, mainly in terms of specificity, by identifying factors responsible for false-positive TRAP Assay results.10 Cell protein extraction and TRAP assay were performed as previously described.10,14 Cells from 3 ml of urine were ϫ METHODS pelleted by centrifugation (850 g 10 minutes at 4C) within 1 to 3 hours of urine sample collection, washed once in Case Series phosphate buffered saline, re-sedimented by centrifugation The case-control study was conducted on 212 women includ- (2,300 g ϫ 5 minutes at 4C) and stored at Ϫ80C until use or ing 144 healthy individuals and 68 patients at first diagnosis for a maximum of 12 months. The pelleted cells were resus- of bladder cancer. Because bladder cancer incidence in- pended in 200 ␮l lysis reagent and left on ice for 30 min- creases with age and available treatments such as endovesi- utes.14 cal instillation are also used for older patients, we explored Cell lysates were centrifuged (10,000 g ϫ 20 minutes at TRAP diagnostic accuracy in individuals with a wide age 4C) and the supernatant extracts were stored at Ϫ80C. range. Patients 39 to 91 years old (median age 70) were Aliquots of each urine sample containing 1 ␮g of protein recruited from the Urology Departments of Pierantoni- lysate were used for the TRAP assay. Two microliters of Morgagni Hospital (Forlì) and Infermi Hospital (Rimini) polymerase chain reaction product were evaluated using a from January 2004 to March 2006. Healthy women from the 3100-Avant Genetic Analyzer (Applied Biosystems, Foster same age range (median 63 years) were recruited during the City, California) according to supplier instructions. Telomer- same period, including younger ones from hospital person- ase products were evaluated on fluorescence electrophero- nel and older ones from family members of staff. All individ- grams and the area underlying the different peaks was uals underwent clinical and cytological examinations to ex- calculated. To obtain semiquantitative levels of TA an inter- clude the presence of bladder cancer or any symptomatic nal telomerase assay standard (25 attograms9), amplified by inflammatory disease of the urogenital tract. Before urine the same 2 primers used for the TA assay, was included in sample collection none of the patients received locoregional the TRAP buffer. Serial dilutions of protein extract of a or systemic treatment. Tumors or suspicious lesions were human bladder cancer line (MCR)10 corresponding to 10, 30, resected and the final diagnosis of bladder cancer was con- 100, 300, 1,000 and 3,000 cells were analyzed in each assay, firmed by histological examination. and used as the reference curve. To obtain quantitative On the basis of World Health Organization criteria 6 evaluations of TA the areas of each sample were also nor- (8.8%) patients had grade I, 29 (42.6%) had grade II, 28 malized to the 150 bp ITAS peak. The relative TA per cell for (41.2%) had grade III tumors and 1 patient had an in situ each urine sample is presented as the percentage of the ratio carcinoma. Grading information was not available for 4 pa- of TRAP ladder/ITAS per cell vs the value of MCR, and tients. Moreover, 44 (64.7%) tumors were nonmuscle inva- expressed in AEUs. All experiments were performed in du- sive (stage Ta, Tis, T1) and 21 (30.9%) were muscle invasive plicate and, when variations were greater than 15% as ob- (stage T2, T3, T4). Information was not available for the served in approximately 10% of cases, a third analysis was remaining 3 (4.4%) cases. performed. TA was expressed as a continuous variable in all The study protocol was approved by the local Indepen- the analyses. dent Reviewer Board of each center. All participants were informed about the aim of the study and provided written Statistical Analysis informed consent. Anagraphic data and medical history Sample size was defined on the basis of results from our were recorded on study entry. previous study, which showed an 86% sensitivity and 71% TELOMERASE ACTIVITY FOR BLADDER CANCER DIAGNOSIS 59

ROC curves of telomerase activity. A, overall series AUC is 0.806 (95% CI 0.745–0.867). B, age subgroups AUC is 0.852 (95% CI 0.792–0.912) for women younger than 75 years and 0.629 (95% CI 0.436–0.821) for women 75 years old or older. specificity for the subgroup of females using the 50 AEU between patients with nonmuscle invasive (66.5 AEUs) and cutoff.10 For the 68 patients with bladder cancer and 144 muscle invasive (77 AEUs) tumors. The diagnostic accuracy healthy women in the present study we predicted the 95% CI of TA was analyzed as a continuous variable by the ROC to be Ϯ 8% with respect to the single estimated value for curve. In the overall series the area under curve was 0.806 sensitivity and Ϯ 7% for specificity. (95% CI 0.745–0.867) (part A of figure). The diagnostic accuracy of TA was analyzed as a contin- Sensitivity and specificity of TA levels were defined for uous variable using the ROC curve,15 constructed by calcu- different cutoff values in the 40 to 60 AEU range, with lating the true positive (sensitivity) and false-positive (1- sensitivity varying from 91% (95% CI 82–96) to 68% (95% CI specificity) rates at several cutoff values to identify the value 56–77) and specificity varying from 55% (95% CI 47–63) to with the best sensitivity and specificity. Sensitivity, speci- 78% (95% CI 70–84) (table 1). In particular, at the best ficity and relative 95% CI were calculated for the most overall cutoff of 50 AEUs, sensitivity was 87% (95% CI discriminant cutoff values. 77–93) and specificity was 66% (95% CI 58–73). A break- The relationship between urine TA and histological grade down analysis as a function of age showed a higher TRAP and stage were analyzed using the median test. For all tests assay accuracy in females younger than 75 years compared ϭ a 2-sided p 0.5 was regarded as significant. Data analyses to older individuals (part B of figure). In particular, at the 50 were performed with SAS® release 8.0. All statistical anal- AEU cutoff sensitivity was 91% (95% CI 81–96) and 64% yses were performed at the Unit of Biostatistics and Clinical (95% CI 35–85) (p ϭ 0.013), and specificity was 69% (95% CI Trials of Istituto Oncologico Romagnolo (Forlì, Italy). 59–77) and 59% (95% CI 43–72) (p ϭ 0.235) for the 2 subgroups, respectively. Analysis performed according to age RESULTS decades or tertile and quartile criteria did not highlight an The median TA value was 35 AEUs (range 0 to 195) in age discriminant. Furthermore, sensitivity was not signifi- healthy individuals and 68 AEUs (range 0 to 267) in patients cantly different in the grade or stage tumor subgroups (table 2). (p Ͻ0.0001). The statistically significant difference was lim- More importantly, 88% sensitivity and 65% specificity were ited to the subgroup of individuals younger than 75 years for observed in the 50% of individuals with negative or nonas- whom the median TA value was 35 AEUs (range 0 to 171) in sessable cytology. healthy women (103) and 75 AEUs (range 0 to 267) in In identifying the possible factors that have a confound- patients (57) (p Ͻ0.001). In the older subgroup the median ing role in TRAP diagnostic accuracy we considered the TA value was still higher in patients (11) than in healthy adequacy of urine samples (table 3). Telomerase assay women (41) (41 AEUs), but the difference did not reach showed extremely high accuracy starting from small sam- statistical significance. ples containing a minimum of 100 epithelial cells. Moreover, urine TA did not significantly differ between patients with grade 1 to 2 (median value 69, range 0 to 148) and grade 3 (median value 71, range 16 to 188) tumors, or TABLE 2. Sensitivity of urine telomerase activity at the 50 AEU cutoff

TABLE 1. Diagnostic accuracy of urine telomerase activity by % Sensitivity TRAP assay No. Pts (95% CI) AEU Cutoff % Sensitivity (95% CI) % Speciﬁcity (95% CI) Grade: G1 6 83 (44–97) 40 91 (82–96) 55 (47–63) G2 29 90 (74–96) 45 90 (80–95) 60 (52–67) G3 28 86 (68–94) 50 87 (77–93) 66 (58–73) Stage: 55 81 (70–88) 71 (63–78) Ta, Tis, T1 44 84 (71–92) 60 68 (56–77) 78 (70–84) T2, T3, T4 21 95 (75–99) 60 TELOMERASE ACTIVITY FOR BLADDER CANCER DIAGNOSIS

identifying low grade lesions. The analysis of other specific TABLE 3. Diagnostic accuracy as a function of epithelial cellularity of urine samples markers such as antiapoptotic survivin, which has been shown to have good specificity and tumor stage and grade No. Cells % Sensitivity % Specificity related sensitivity, could improve the diagnostic accuracy of Overall 87 66 telomerase activity.20 On the other hand, the determination 100 or More 89 68 of chromosomal alterations by fluorescence in situ hybrid- More than 1,000 87 68 More than 5,000 87 69 ization could represent a second level diagnostic approach More than 10,000 100 68 for unmasking false-positive TRAP results and increasing specificity, especially in elderly women.

DISCUSSION ACKNOWLEDGMENTS Telomerase is an enzyme delegated to maintaining telomere Gráinne Tierney reviewed the manuscript, and Arialdo length. It is active in almost all human tumor histotypes, Vernocchi, Giuliana Amadori and Carla Fabbri assisted including bladder cancer, leading to the assumption that one with sample collection. of the requirements for cell immortalization, and possibly carcinogenesis, may be the activation of telomerase.16 Therefore, it represents a promising marker for the detec- Abbreviations and Acronyms tion and prognosis of cancer. Comparative analyses of vari- AEUs ϭ arbitrary enzymatic units ous screening tests for bladder cancer diagnosis have shown ITAS ϭ internal telomerase assay standard that telomerase has the highest combination of sensitivity TA ϭ telomerase activity and specificity with respect to urine cytology and other bio- TRAP ϭ telomeric repeat amplification protocol chemical markers.17 As the primary end point of the present study we confirmed the 50 AEUs observed in our pilot study as the best REFERENCES cutoff in terms of overall accuracy as already observed for 10,13 1. Negri E and La Vecchia C: Epidemiology and prevention of males. Moreover, similar high sensitivity of the TRAP bladder cancer. Eur J Cancer Prev 2001; 10: 7. assay was observed for the grade and stage tumor subgroups 2. Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer 11 as already reported by other authors. At the same time we statistics, 2002. 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Babjuk M, Kostirova M, Mudra K, Pecher S, Pecher S, Smolova age range with respect to the pilot study, we demonstrated H et al: Qualitative and quantitative detection of urinary that diagnostic accuracy in women, as observed for males human complement factor H-related protein (BTA stat and especially in terms of specificity, also decreases as age in- BTA TRAK) and fragments of cytokeratins 8, 18 (UBC creases. The higher number of viable and telomerase posi- rapid and UBC IRMA) as markers for transitional cell tive nonurothelial cells, such as epithelial cells from the carcinoma of the bladder. Eur Urol 2002; 41: 34. lower genital tract or inflammatory elements, especially in 6. Laudadio J, Keane TE, Reeves HM, Savage SJ, Hoda RS, Lage the elderly, could be responsible for false-positive TRAP JM et al: Fluorescence in situ hybridization for detecting results. 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Science 1994; 266: 2011. represent a limit for the TRAP assay because maximum test 9. Wright WE, Shay JW and Piatyszek MA: Modifications of a accuracy had already been obtained in urine samples with telomeric repeat amplification protocol (TRAP) result in as few as 100 epithelial cells.19 increased reliability, linearity and sensitivity. Nucleic Acid Res 1995; 23: 3794. 10. Sanchini MA, Bravaccini S, Medri L, Gunelli R, Nanni O, CONCLUSIONS Monti F et al: Urine telomerase: an important marker in the diagnosis of bladder cancer. Neoplasia 2004; 6: 234. The TRAP assay requires a small amount of urine, and is 11. Gelmini S, Crisci A, Salvadori B, Pazzagli M, Selli C and Orlando noninvasive, inexpensive and easy to perform. It is also an C: Comparison of telomerase activity in bladder carcinoma objective, reproducible test that permits quantitative evalu- and exfoliated cells collected in urine and bladder washings, ation of TA. 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samples by assaying for the presence of telomerase activity. 17. Ramakumar S, Bhuiyan J, Besse JA, Roberts SG, Wollan PC, Cancer 1998; 82: 708. Blute DJ et al: Comparison of screening methods in the 13. Sanchini MA, Gunelli R, Nanni O, Bravaccini S, Fabbri C, detection of bladder cancer. J Urol 1999; 161: 388. Sermasi A et al: Relevance of urine telomerase in the diag- 18. Oestreicher N, White E, Malone KE and Porter PL: Hormonal nosis of bladder cancer. JAMA 2005; 294: 2052. factors and breast tumor proliferation; do factors that affect 14. Fedriga R, Gunelli R, Nanni O, Bacci F, Amadori D and cancer risk also affect tumor growth? Breast Cancer Res Calistri D: Telomerase activity detected by quantitative Treat 2004; 85: 133. assay in bladder carcinoma and exfoliated cells in urine. 19. Iwao T, Hiyama E, Yokoyama T, Tsuchida A, Hiyama K, Neoplasia 2001; 3: 446. Murakami Y et al: Telomerase activity for the preoperative 15. Deeks JJ: Systematic reviews in health care: Systematic re- diagnosis of pancreatic cancer. J Natl Cancer Inst 1997; 89: views of evaluations of diagnostic and screening tests. BMJ 1621. 2001; 323: 157. 20. Weikert S, Christoph F, Schrader M, Krause H, Miller K and 16. Moriarty TJ, Ward RJ, Taboski MA and Autexier C: An anchor Muller M: Quantitative analysis of survivin mRNA expres- site-type defect in human telomerase that disrupts telo- sion in urine and tumor tissue of bladder cancer patients mere length maintenance and cellular immortalization. and its potential relevance for disease detection and prog- Mol Biol Cell 2005; 16: 3152. nosis. Int J Cancer 2005; 116: 100. A Phase III, Multicenter Comparison of Hexaminolevulinate Fluorescence Cystoscopy and White Light Cystoscopy for the Detection of Superﬁcial Papillary Lesions in Patients With Bladder Cancer

H. Barton Grossman,* Leonard Gomella,† Yves Fradet, Alvaro Morales, Joseph Presti,‡ Chad Ritenour, Unyime Nseyo§ and Michael J. Drollerʈ on behalf of the PC B302/01 Study Group From the University of Texas M. D. Anderson Cancer Center (HBG), Houston, Texas, Kimel Cancer Center, Thomas Jefferson University (LG), Philadelphia, Pennsylvania, Stanford Cancer Center (JP), Palo Alto, California, Emory Clinic (CR), Atlanta, Georgia, McGuire Veterans Affairs Medical Center (UN), Richmond, Virginia, Department of Urology, Mount Sinai Medical Center (MD), New York, New York, and L’Hotel-Dieu de Québec, Centre Hospitalier Universitaire de Québec (YF), Québec, Province de Québec and Kingston General Hospital (AM), Kingston, Ontario, Canada

Purpose: We compared hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer. Materials and Methods: A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination. Results: Noninvasive pTa tumors were found in 108 of 196 evaluable patients (55.1%). In 31 patients (29%) at least 1 more tumor was detected by HAL than by white light cystoscopy (p Ͻ0.05). Six of these patients had no lesions detected by white light, 12 had 1 lesion detected by white light and more than 1 by HAL, and 13 had multiple Ta lesions detected by the 2 methods. Conversely at least 1 more tumor was detected by white light cystoscopy than by HAL cystoscopy in 10 patients (9%, 95% CI 5–16). Tumors invading the lamina propria (T1) were found in 20 patients (10.2%). At least 1 additional T1 tumor was detected by HAL but not by white light cystoscopy in 3 of these patients (15%), while at least 1 more T1 tumor was detected by white light cystoscopy than by HAL cystoscopy in 1 patient (5%, 95% CI 0–25). Detection rates for Ta tumors were 95% for HAL cystoscopy and 83% for white light cystoscopy (p ϭ 0.0001). Detection rates were 95% and 86%, respectively, for T1 tumors (p ϭ 0.3). HAL instillation was well tolerated with few local or systemic side effects. Conclusions: HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined. Key Words: bladder; carcinoma, papillary; fluorescence; cystoscopy; 5-aminolevulinic acid hexyl ester

ancer of the bladder is common in men and women, recurrence rates, prolong intervals to recurrence and possi- and the lifetime risk of the disease is greater than bly decrease progression rates. C 3%.1,2 Recurrence rates for patients with Ta and T1 The current standard for diagnosing bladder cancer and tumors are high at 50% to 75% at 20 years,3 highlighting the monitoring for recurrence is by white light cystoscopy. Al- need to improve endoscopic visualization of bladder tumors though it is generally recognized that cystoscopy can fail to and their more complete eradication. This could decrease detect carcinoma in situ, cystoscopy is considered to be effective for detecting papillary tumors. Recent studies suggest that porphyrin based fluorescence Submitted for publication November 8, 2006. cystoscopy may improve the endoscopic detection of bladder Study received approval from the relevant Institutional Review tumors.4–6 This technique involves inspecting the bladder Board at each center. mucosa with blue light following the instillation of a precur- Supported by PhotoCure ASA, Oslo, Norway. * Financial interest and/or other relationship with PhotoCure and sor of a photoactive porphyrin, such as HAL. This substance GE Healthcare. is converted to porphyrins that preferentially accumulate in † Financial interest and/or other relationship with PhotoCure and neoplastic cells, resulting in red fluorescence when illumi- American Urological Association. 7,8 ‡ Financial interest and/or other relationship with Novocea and nated with blue light. Recent studies suggest that fluores- Medidiom. cence cystoscopy may be more sensitive than white light § Financial interest and/or other relationship with Laserscope. cystoscopy for detecting bladder tumors and it is also well ʈ Correspondence and requests for reprints: Department of 9 Urology, Mount Sinai Medical Center, 1 Gustav Levy Pl., Box tolerated with no local or systemic side effects. We com- 1272, New York, New York 10029 (telephone: ϩ1 212-241-8711; pared HAL fluorescence cystoscopy with white light cystos- FAX: ϩ1 212-876-3246; e-mail: [email protected]). copy for detecting bladder cancer in a multicenter trial with For another article on a related topic see page 301. the aim of establishing whether HAL could detect more Ta

0022-5347/07/1781-0062/0 62 Vol. 178, 62-67, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.034 FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR PAPILLARY LESION DETECTION 63 and T1 papillary tumors than conventional white light cys- taken from urothelium that appeared normal under white toscopy. and blue light. All histology and biopsy samples were examined by 2 reference pathologists and a local pathologist METHODS blinded to whether the samples were taken under white or blue light. Papillary lesions were classiﬁed as Ta—papillary Study Design urothelial neoplasia without evidence of invasion, T1—pap- Investigators at 18 centers in the United States participated illary urothelial neoplasia invading the lamina propria or T2 in an open label, comparative, controlled (within patient), to T4—muscle invasive urothelial carcinoma. The 1997 phase III multicenter study. The study was done in accor- UICC/American Joint Committee on Cancer system10 was dance with Good Clinical Practice and the Declaration of used for staging. Papillary lesions were graded using the Helsinki, including the most recent amendment (Edinburgh, 1973 WHO system.11 The reference urological pathologists Scotland, 2000). Written approval was obtained from the jointly reviewed and agreed on each case while blinded to relevant Institutional Review Board at each center. the clinical setting, including patient age, gender or history.

Patient Population The study involved 311 patients with suspected or verified Efficacy Variables bladder cancer who were at least 18 years old. All patients We evaluated the number of patients with Ta and T1 pap- provided written informed consent. Patients had to fulfill at illary lesions in whom at least 1 additional papillary lesion least 1 of certain inclusion criteria, including a history of or was detected by HAL or white light cystoscopy. We also earlier (prior) detection of multiple bladder lesions, a blad- evaluated the detection rates for Ta and T1 lesions using der lesion more than 3 cm in diameter, a Ta or T1, or grade HAL and white light cystoscopy (the number of lesions de- 2 or 3 bladder tumor, positive urine cytology or recurrent tected by 1 procedure divided by the total number of lesions bladder cancer at followup examination. Patients were ex- detected using the 2 types of cystoscopy), the grade and cluded from study if they had gross hematuria or porphyria, stage of additional papillary lesions seen by HAL cystoscopy, if they had a known allergy to HAL or a similar compound, the location of the additional papillary lesions seen by HAL if they had participated in another clinical trial within the cystoscopy, and the false detection rates by HAL and white last 30 days, if they were pregnant or lactating, or if they light cystoscopy (the number of biopsied lesions with benign had received bacillus Calmette-Guerin or intravesical che- histology with 1 procedure divided by the overall number of motherapy within the previous 3 months. A further 93 pa- lesions seen with the same cystoscopy procedure). tients were excluded since they were training patients at centers new to the technique. Results in the first 5 patients at each center without experience with the technique were Safety Variables included only in safety set analysis and not in the efficacy Patients were monitored for adverse events for 7 days. Other study set. This was to provide training for clinicians unfa- safety evaluations included a limited physical examination miliar with HAL cystoscopy. and the measurement of vital signs (pulse rate, and systolic and diastolic blood pressure), hematological (hemoglobin, Cystoscopy red and white blood cell counts, and platelet count) and Patients underwent bladder instillation with 50 ml of a 2.0 biochemical parameters (aspartate aminotransferase, ala- mg/ml (8 mM) solution of HAL hydrochloride in phosphate nine aminotransferase, creatinine, blood urea nitrogen, buffered saline (Hexvix®) through a standard catheter. The ␥-glutamyl transferase, total bilirubin, sodium, potassium, solution was retained for at least 1 hour before cystoscopy. albumin, chloride and calcium) at baseline and 24 hours After the HAL solution was evacuated the bladder was in- after HAL instillation. spected by white light cystoscopy with a D-light system xenon arc lamp (Karl Storz™) providing the light source. Lesions or suspicious areas were classified as flat or papil- Data Analysis lary and mapped onto a bladder chart. The lesions were also Efficacy variables were analyzed using the FAS of patients recorded by video. The bladder was then inspected by HAL (ITT). This was composed of all 196 patients who underwent fluorescence cystoscopy using a band filter on the xenon arc HAL instillation, whose bladder was inspected using white lamp to supply blue light (wavelength 380 to 450 nm). Le- light and fluorescence cystoscopy, and who had evaluable sions or suspicious areas were again classified, mapped and data for histology. It excluded the first 5 patients for each recorded by video. The 2 cystoscopy procedures were per- investigator with no previous experience with HAL cystos- formed sequentially by the same investigator to avoid vari- copy, representing a total of 93 training patients. However, ability and fluorescence cystoscopy was always performed safety variables were analyzed using the safety set, which after white light visualization. Biopsies were taken only was composed of all 298 patients who underwent HAL in- after the 2 visualizations were completed to avoid biopsy stillation and had at least some safety data available. induced bleeding that might interfere with subsequent visu- SAS® software was used to tabulate summary statistics alization and diagnosis. and analyze data. The 1-sided binomial test was used to assess clinical relevance with level of significance considered Histology at p Ͻ0.05. A 1-sided test was believed to be appropriate Papillary lesions were resected and collected for histological instead of the more usual 2-sided approach because as HAL examination. In addition, biopsies were taken of all flat fluorescence cystoscopy is intended to be used as an add-on lesions and suspicious areas. As the control, 1 biopsy was to white light and not a replacement. 64 FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR PAPILLARY LESION DETECTION

TABLE 1. Patient demographics in safety and FAS populations Characteristic Safety FAS

No. pts 298 196 Mean Ϯ SD age 67 Ϯ 11 67 Ϯ 11 No. sex (%): M 223 (75) 148 (76) F 75 (25) 48 (24) Mean Ϯ SD ht (cm) 173 Ϯ 9.9 173 Ϯ 9.7 Mean Ϯ SD wt (kg) 83 Ϯ 18 82 Ϯ 17 No. ethnic group (%): White 274 (92) 187 (95) Ta grade 2 TCC on bladder floor under white light illumination (A) Black 15 (5.0) 5 (2.6) and using HAL fluorescence cystoscopy (B). Lesion was only visible Asian (Indian) 1 (0.3) 1 (0.5) under blue light. Asian (Oriental) 1 (0.3) — American Hispanic 4 (1.3) 2 (1.0) Other 3 (1.0) 1 (0.5) binomial test p Ͻ0.05). Six of these patients had no tumor detected by white light and the tumor was only detected RESULTS using HAL cystoscopy. In comparison, at least 1 more tumor was detected by white light cystoscopy than by HAL cystos- Patient Population copy in 10 patients (9%, 95% CI 5–16). The figure shows an A total of 311 patients were enrolled, of whom 298 under- example. went HAL instillation. These 298 patients formed the safety In 12 of the patients with HAL detected tumor only 1 set. A further 102 patients were excluded from the ITT tumor was detected by white light cystoscopy, while multiple population for certain reasons, including 93 who were train- tumors were detected by HAL cystoscopy. The remaining 13 ing patients, 3 in whom no cystoscopy was performed, 2 in patients had 2 to 4 tumors but in each at least 1 additional whom blue light analysis was not performed and 4 with no tumor was detected using HAL cystoscopy. Table 3 lists the valid histology results. Therefore, the ITT group consisted of number of patients in whom Ta tumors were detected by 196 patients. Patient characteristics were similar in the 2 HAL or white light cystoscopy according to the number of populations (table 1). Table 2 shows the history of bladder tumors detected per patient. It appeared that white light cancer in the ITT population. detected more single tumors than HAL cystoscopy (table 3). However, some of these patients actually had multiple tu- Patients With Additional mors that were not seen with white light but were detected Papillary Tumors Detected by HAL by HAL cystoscopy. Noninvasive Ta tumors were found in 108 patients (55.1%) Lamina propria invading tumors (T1) were found in 20 and 54 had multiple tumors. In 31 of these patients (29%, patients (10.2%). No new patient was found to have disease 95% CI 20–38) at least 1 more Ta tumor was detected by through detection by HAL cystoscopy alone. At least 1 more HAL cystoscopy than by white light cystoscopy (1-sided T1 tumor was detected by HAL cystoscopy than by white light cystoscopy in 3 patients (15%, 95% CI 3–38), while at least 1 more tumor was detected by white light cystoscopy

TABLE 2. Bladder cancer history in 196 FAS patients than by HAL cystoscopy in 1 patient (5%, 95% CI 0–25). This apparent difference was not significant (p ϭ 0.3). Table 4 History lists the number of patients in whom T1 tumors were de- Diagnosis tected by HAL or white light cystoscopy according to the Primary 62 (32) Recurrent 133 (68) number of tumors detected per patient. Missing 1 (0.5) No. verified by histology (%): No 48 (24) Detection Rates Yes 79 (40) A total of 218 Ta tumors were detected by HAL and white Not applicable 69 (35) light cystoscopy, of which 207 (95%, 95% CI 81–97) were No. verified by urine cytology (%): Positive 69 (35) detected by HAL cystoscopy and 181 (83%, 95% CI 77–88) Negative 106 (54) Missing 21 (11) No. verified by other means (%): No 11 (5.6) TABLE 3. Patients in whom Ta lesions were detected by HAL or Yes 126 (64) white light cystoscopy by number of lesions detected Not applicable 59 (30) No. 3 or More recurrences (%): HAL White Light No 124 (63) Yes 72 (37) No. Ta lesions detected (No. pts/%): No. chemotherapy for bladder Ca (%): 0 8/7.4 6/5.6 No 147 (75) 1 46/42.6 59/54.6 Yes 49 (25) 2 25/23.1 24/22.2 Bacillus Calmette-Guerin for bladder Ca (%): 3 16/14.8 11/10.2 No 119 (61) 4 7/6.5 3/2.8 Yes 77 (39) 5 3/2.8 3/2.8 Yrs since first diagnosis:* 6 1/0.9 0 Mean Ϯ SD 3.3 Ϯ 4.5 7 2/1.9 2/1.9 Median 2.0 No. Ta tumors 207 181 Range 0–24 No. pts with tumor 100 102 * In 185 patients. Ta lesions were detected in 108 patients. FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR PAPILLARY LESION DETECTION 65

TABLE 4. Patients in whom T1 lesions were detected by HAL or TABLE 6. Site of additional Ta and T1 lesions detected by HAL white light cystoscopy by number of lesions detected but not white light cystoscopy HAL White Light No. Ta (%) No. T1 (%) Total No.

No. T1 lesions detected (No. pts/%): Bladder neck 1 (2.7) 0 1 0 1/5.0 1/5.0 Trigone 3 (8.1) 1 (33.3) 4 1 17/85.0 19/95.0 Ureteral orifice 1 (2.7) 1 (33.3) 2 2 2/10.0 0 Posterior floor 9 (24.3) 0 9 No. T1 tumors 21 19 Lat wall: No. pts with tumor 19 19 Rt 4 (10.8) 0 4 Lt 4 (10.8) 0 4 T1 lesions were detected in 20 patients. Cranial wall 1 (2.7) 0 1 Dome 9 (24.3) 1 (33.3) 10 Anterior bladder 5 (13.5) 0 5 were detected by white light cystoscopy (p ϭ 0.0001). The Totals 37 3 40 total number of T1 tumors detected by the 2 types of cystoscopy was 22, of which 21 (95%, 95% CI 77–100) were detected by HAL cystoscopy and 19 (86%, 95% CI 65–97) were was mild in 110 cases and moderate in 19. Table 7 lists other detected by white light cystoscopy (p ϭ 0.3). adverse events occurring in more than 2% of patients. In 20 patients (7%) a total of 23 serious adverse events Grade and Location of Additional Lesions were reported but none were definitely related to HAL in- Table 5 shows the grade of additional Ta or T1 lesions stillation. One patient died of an aortic aneurysm during the detected by HAL cystoscopy and not by white light cystos- study, an event unrelated to HAL instillation. copy. Table 6 shows the locations of the additional lesions. Hematological parameters showed no significant change Of particular interest are the 8 grade 3 lesions (Ta in 5 and other than those expected following cystoscopy, including a T1 in 1) that were only detected by HAL fluorescence cys- slight decrease in hemoglobin and red blood cell levels, and toscopy and were overlooked during inspection with white an increase in white blood cell levels. No significant changes light. in biochemistry variables, vital signs or the results of physical examination were observed. False Detection Rates The false detection rate at the biopsy level was 39% (95% CI DISCUSSION 35-43) for HAL cystoscopy and 31% (95% CI 27-36) for white HAL cystoscopy detected at least 1 more Ta lesion than light cystoscopy. Biopsies were taken from all suspicious flat white light cystoscopy in 29% of patients and it detected at lesions (possibly carcinoma in situ) and papillary lesions. least 1 more T1 lesion in 15% of patients. In contrast, white Therefore, the false detection rates represent the proportion light cystoscopy detected at least 1 more Ta and T1 lesion of these biopsies that were judged by the investigator to be than HAL cystoscopy in 9% and 5% of patients, respectively. suspicious (not necessarily papillary lesions) but were sub- There was no obvious trend as to the location of these tumors sequently found to be nonmalignant. When analyzed by in the bladder. In patients with Ta or T1 disease at least 1 institution, it appeared that some investigators may have more Ta or T1 lesion was detected by HAL cystoscopy in a been more aggressive in taking biopsies of any mucosal statistically significant proportion of patients (p Ͻ0.05). abnormality, thus, possibly accounting for the high false detection rates tabulated in the entire group.

TABLE 7. Adverse events reported by more than 2% of 298 safety Safety Results set patients and relationship to HAL instillation Of the 298 patients in the safety set 240 (80.5%) reported a No. Treatment Related (%) total of 800 adverse events. However, only 19 of these adverse events (2.4%) were considered to be related to HAL Adverse Event No. Pts (%) Mild or Moderate Severe instillation. Most adverse events were mild or moderate and Hematuria 129 (43.3) 7 (2.4) 0 resolved spontaneously. A total of 38 adverse events were Dysuria 53 (17.8) 8 (2.6) 0 Bladder spasm 43 (14.4) 17 (5.7) 4 (1.3) rated as severe in intensity but only 11 (29%) of them were Nausea 42 (14.1) 6 (2.0) 0 considered to be related to HAL instillation, including penile Unspeciﬁed pain 30 (10.1) 3 (1.0) 0 Bladder pain 29 (9.7) 16 (5.4) 3 (1.0) infection, blood in the urine, penile pain, bladder pain, blad- Headache 25 (8.4) 12 (4.0) 0 der spasm and urinary frequency. Hematuria was the most Urinary retention 25 (8.4) 8 (2.6) 0 common adverse event, occurring in 43.3% of patients. This Pubic pain 21 (7.0) 0 0 Urinary frequency 21 (7.0) 1 (0.3) 1 (0.3) Post-procedural pain 19 (6.4) 0 0 Abdominal pain 17 (5.7) 1 (0.3) 0 Blood in urine 15 (5.0) 0 1 (0.3) TABLE 5. Grade of additional Ta or T1 lesions detected by HAL Pelvic pain 13 (4.4) 0 0 but not white light cystoscopy Vomiting 12 (4.0) 3 (1.0) 0 Insomnia 11 (3.7) 3 (1.0) 0 No. Lesion Grade (%) Penile pain 11 (3.7) 0 1 (0.3) Lesion Type G1 G2 G3 Total No. Urinary urgency 10 (3.4) 0 0 Hypotension 9 (3.0) 0 0 Ta 25 (67.6) 7 (18.9) 5 (13.5) 37 Pharyngolaryngeal pain 7 (2.3) 0 0 T1 0 0 3 (100) 3 Back pain 7 (2.3) 1 (0.3) 0 Lower abdominal pain 7 (2.3) 1 (0.3) 0 Totals 25 7 8 40 Constipation 7 (2.3) 2 (0.7) 0 66 FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR PAPILLARY LESION DETECTION

As confirmed by biopsy, detection rates supported the Because other randomized studies showed that HAL flu- primary efficacy findings. The mean detection rate for Ta orescence cystoscopy is capable of detecting more tumors lesions was 95% for HAL cystoscopy compared with 83% for than white light,4–6,9 it was always performed after white white light cystoscopy (p ϭ 0.0001). The corresponding val- light cystoscopy in this study rather than in random order. ues for T1 lesions were 95% and 86%, respectively. Thus, When designing this study, it was reasoned that the poten- HAL cystoscopy detected an overall higher percentage of Ta tial increased sensitivity of performing cystoscopy with blue and T1 lesions than white light cystoscopy. Although the light first might have increased the rate of detection for difference between the number of lesions detected did not white light above the normal baseline. Furthermore, HAL attain statistical significance, results appear to support the fluorescence cystoscopy has always been intended as a sup- value of HAL cystoscopy as an add-on to standard cystoscopy plement to white light and not a replacement. The use of the for detecting additional Ta and T1 lesions. 2 techniques for diagnosing bladder cancer should enable Of the additional Ta lesions detected by HAL cystoscopy more Ta and T1 papillary tumors to be detected than by and not by white light cystoscopy 68% were grade 1. All white light cystoscopy alone. Early detection and excision of additional T1 lesions detected by HAL cystoscopy were such tumors should lead to improved patient outcomes by grade 3. Of the lesions 47.5% were located in the posterior prolonging the disease-free interval. This is currently the floor or the dome of the bladder. focus of an ongoing randomized trial. The mean false detection rate in this study was 39% for HAL fluorescence cystoscopy and 31% for white light cystos- CONCLUSIONS copy. Although the false detection rate was high for each procedure, this may reflect clinical practice as much as poor HAL fluorescence cystoscopy is an effective, well tolerated technique specificity. The false detection rate, which was procedure for diagnosing Ta and T1 papillary lesions in almost 3 times as high as rates in European HAL stud- patients with bladder cancer. Furthermore, it is able to ies,5,6,9 may indicate in part a more aggressive attitude detect at least 1 more Ta/T1 lesion than white light cystos- toward taking biopsies by some investigators, as evidenced copy in a statistically significant proportion of patients with by a large difference among centers. In many instances all existing Ta/T1 disease. Other studies showed that this may suspicious areas were biopsied. Therefore, false-positive decrease recurrence rates and increase the disease-free in- findings could have arisen from areas judged by the inves- terval. Whether the improved tumor detection in this study tigator to be suspicious but not necessarily a papillary le- would ultimately result in improved patient outcomes has sion. Furthermore, although there was high variability yet to be determined. among the sites in terms of the false detection rate, there was always a slightly higher false detection rate for HAL ACKNOWLEDGMENTS than for white light cystoscopy, which may have been due to false fluorescence from inflamed tissue. Conceivably the David G. Bostwick and Junqi Qian, Bostwick Laboratories, high false detection rate of the 2 procedures could be de- Richmond, Virginia were the 2 central pathologists. H. Barton creased when HAL cystoscopy is used routinely since it Grossman provided the figure. would be possible to change between white and blue light to assess suspicious areas before taking biopsies. APPENDIX HAL fluorescence cystoscopy was well tolerated. Few sys- Other PC B302/01 Study Group members: David Albala, Duke University, temic or local effects occurred but there was a slight de- Durham, North Carolina, Richard Babayan, Boston University, Boston and crease in the levels of red blood cells and hemoglobin, and a William Bihrle, Lahey Clinic, Burlington, Massachusetts, Michael Cook- slight increase in the level of white blood cells. Most adverse son, Vanderbilt University Medical Center, Nashville, Tennessee, Gerhard Fuchs, Cedars Sinai, Los Angeles, California, Seth Lerner, Baylor College events reported after HAL instillation were mild or moder- of Medicine, Houston, Texas, Bruce Malkowicz, University of Pennsylva- ate in severity and resolved spontaneously. Few adverse nia, Philadelphia, Pennsylvania, Raj Pruthi, University of North Carolina, Chapel Hill, North Carolina, Mark Schoenberg, Johns Hopkins, Baltimore, events (2.4%) were related to HAL instillation. Further- Maryland, Craig Zippe, Cleveland Clinic, Cleveland, Ohio, David G. more, none of the serious adverse events, including 1 death, Bostwick, Bostwick Laboratories, Richmond, Virginia, and Norbert Lange, were considered to be related to HAL. University of Geneva, Geneva, Switzerland. The results of previous studies show that HAL fluorescence cystoscopy enables the visualization of more tumors and suspicious areas in the bladder urothelium than can be Abbreviations and Acronyms 4–6,9 seen by white light cystoscopy. In 1 phase II clinical FAS ϭ full analysis set trial 96% of patients with bladder cancer were identified by HAL ϭ hexaminolevulinate HAL fluorescence cystoscopy, while only 73% were identified ITT ϭ intent to treat by white light cystoscopy.5 In this trial HAL cystoscopy detected additional Ta and T1 papillary tumors that were not detected by white light cystoscopy in 11 patients, includ- REFERENCES ing a total of 4 T1 tumors in 3 patients. The results of the current study support those in previous reports. 1. Cancer of the Bladder 1990. National Institutes of Health Publication No. 90-722. Bethesda: National Cancer Insti- Similar findings were also observed in studies with 12–14 tute. 5-aminolevulinic acid fluorescence cystoscopy. In these 2. Ries LAG, Kosary CL, Hankey BF, Miller BA, Harras A and studies longer-term followup showed that improved detec- Edwards BK: SEER Cancer Statistics Review 1973–1994. tion rates translated into clinical benefit in terms of longer National Institutes of Health Publication No. 94-2789. recurrence-free survival and a decreased recurrence rate. Bethesda: National Cancer Institute 1997. FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR PAPILLARY LESION DETECTION 67

3. Herr HW: Natural history of superficial bladder tumors: 10- to 9. Jocham D, Witjes F, Wagner S, Zeylemaker B, van Moorselaar 20-year follow-up of treated patients. World J Urol 1997; J, Grimm MO et al: Improved detection and treatment of 15: 84. bladder cancer using Hexvix imaging: a prospective phase 4. Zaak D, Hungerhuber E, Schneede P, Stepp H, Frimberger D, III multi-center study. J Urol 2005; 174: 862. Corvin S et al: Role of 5-aminolevulinic acid in the detection 10. Sobin LH and Wittekind CH: TNM Classification of Malignant of urothelial premalignant lesions. Cancer 2000; 95: 1234. Tumors, 6th ed. New York: Wiley-Liss 2002. 5. Jichlinski P, Guillou L, Karlsen SJ, Malmstrom PU, Jocham D, 11. Mostofi FK, Sobin LH and Torloni H: Histopathological typing Brennhovd B et al: Hexyl aminolevulinate fluorescence cys- of urinary bladder tumors. In: International Histological toscopy: new diagnostic tool for photodiagnosis of superfi- Classification of Tumours. Geneva: World Health Organi- cial bladder cancer—a multicenter study. J Urol 2003; 170: sation 1973. 226. 12. Filbeck T, Pichlmeier U, Knuechel R, Wieland WF and 6. Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M and Roessler W: Clinically relevant improvement of recurrence- Marberger M: Improved detection of urothelial carcinoma free survival with 5-aminolevulinic acid induced fluores- in situ with hexaminolevulinate fluorescence cystoscopy. cence diagnosis in patients with superficial bladder tumors. J Urol 2004; 171: 135. J Urol 2002; 168: 67. 7. Koenig F, McGovern FJ, Larne R, Enquist H, Schomacker KT 13. Babjuk M, Soukup V, Petrik R, Jirsa M and Dvoracek J: and Deutsch TF: Diagnosis of bladder carcinoma using pro- 5-Aminolaevulinic acid-induced fluorescence cystoscopy toporphyrin IX fluorescence induced by 5-aminolaevulinic during transurethral resection reduces the risk of recur- acid. BJU Int 1999; 83: 129. rence in stage Ta/T1 bladder cancer. BJU Int 2005; 96: 798. 8. Lange N, Jichlinski P, Zellweger M, Forrer M, Marti A, Guillou 14. Daniltchenko DI, Riedl CR, Sachs MD, Koenig F, Daha KL, L et al: Photodetection of early human bladder cancer based Pflueger H et al: Long-term benefit of 5-aminolevulinic acid on the fluorescence of 5-aminolaevulinic acid hexylester- fluorescence assisted transurethral resection of superficial induced protoporphyrin IX: a pilot study. Br J Cancer 1999; bladder cancer: 5-year results of a prospective randomized 80: 185. study. J Urol 2005; 174: 2129. A Comparison of Hexaminolevulinate Fluorescence Cystoscopy and White Light Cystoscopy for the Detection of Carcinoma In Situ in Patients With Bladder Cancer: A Phase III, Multicenter Study Yves Fradet, H. Barton Grossman,* Leonard Gomella,† Seth Lerner,‡ Michael Cookson,§ David Albala¶ and Michael J. Drollerʈ on behalf of the PC B302/01 Study Group From the L’Hotel-Dieu de Québec, Centre Hospitalier Universitaire de Québec (YF), Québec, Province de Québec, Canada, University of Texas M. D. Anderson Cancer Center (HBG) and Baylor College of Medicine (SL), Houston, Texas, Thomas Jefferson Medical Center (LG), Philadelphia, Pennsylvania, Vanderbilt University Medical Center (MC), Nashville, Tennessee, Duke University Medical Center (DA), North Carolina, and Mount Sinai Medical Center (MJD), New York, New York on behalf of the PC B302/01 Study Group

Purpose: We compared hexaminolevulinate (Hexvix®) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. Materials and Methods: In this multicenter study 298 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate for 1 hour. Cystoscopy was then performed, first using standard white light and then hexaminolevulinate fluorescence cystoscopy. Lesions or suspicious areas identified under the 2 illumination conditions were mapped and biopsied for histological examination. In addition, 1 directed biopsy was obtained from an area appearing to be normal. Results: Of 196 evaluable patients 29.6% (58 of 196) had carcinoma in situ, including 18 with carcinoma in situ alone, and 35 with carcinoma in situ and concomitant papillary disease, which was only detected on random biopsy in 5. Of the 18 patients with no concomitant papillary disease carcinoma in situ was detected only by hexaminolevulinate fluorescence in 4 and only by white light in 4. In the group with concomitant papillary disease carcinoma in situ was found only by hexaminolevulinate fluorescence in 5 patients and only by white light in 3. The proportion of patients in whom 1 or more carcinoma in situ lesions were found only by hexaminolevulinate cystoscopy was greater than the hypothesized 5% (p ϭ 0.0022). Overall more carcinoma in situ lesions were found by hexaminolevulinate than by white light cystoscopy in 22 of 58 patients (41.5%), while the converse occurred in 8 of 58 (15.1%). Biopsy results confirmed cystoscopy findings. Of a total of 113 carcinoma in situ lesions in 58 patients 104 (92%) were detected by hexaminolevulinate cystoscopy and 77 (68%) were detected by white light cystoscopy, while 5 were detected only on directed visually normal mucosal biopsy. Hexaminolevulinate instillation was well tolerated with no local or systemic side effects. Conclusions: In patients with bladder cancer hexaminolevulinate fluorescence cystoscopy with blue light can diagnose carcinoma in situ that may be missed with white light cystoscopy. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to aid in the diagnosis of this form of bladder cancer. Key Words: bladder, carcinoma in situ, fluorescence, cystoscopy, 5-aminolevulinic acid hexyl ester

ystoscopy is the major technique for detecting pri- detect endoscopically.1,2 Since CIS in the presence of papil- mary and recurrent transitional cell carcinoma of the lary disease is associated with a high risk of tumor progres- C bladder and it is generally reliable for exophytic sion,3–7 failure to identify CIS may alter treatment or tumors. However, flat CIS may be much more difficult to worsen prognosis. Therefore, improved techniques to detect carcinoma in situ are needed. Porphyrin induced fluorescence cystoscopy uses photoac- Submitted for publication November 8, 2006. Study received approval from the relevant Institutional Review tive porphyrins, such as HAL, that accumulate preferen- Board at each study site. tially in neoplastic tissue and emit red fluorescence under Supported by PhotoCure ASA, Oslo, Norway. 8,9 * Financial interest and/or other relationship with PhotoCure and blue light. Several studies show that HAL fluorescence is GE Healthcare. more sensitive than white light cystoscopy for detecting † Financial interest and/or other relationship with PhotoCure and bladder tumors, particularly flat CIS lesions.10–13 American Urological Association. ‡ Financial interest and/or other relationship with PhotoCure. We tested the hypothesis that HAL fluorescence cystos- § Financial interest and/or other relationship with GlaxoSmith- copy would detect more CIS lesions alone, or in the presence Kline, Ethicon, Sanofi-Aventis, PhotoCure, National Institutes of of papillary Ta or T1 disease compared to white light cys- Health and GTX. ¶ Financial interest and/or other relationship with Sanofi-Aventis, toscopy. Our main objective was to assess the number of GlaxoSmithKline, PhotoCure, Lilly-ICOS and Applied Medical. patients in whom CIS was detected only by HAL fluores- ʈ Correspondence and requests for reprints: Department of cence cystoscopy or by white light cystoscopy. Secondary Urology, Mount Sinai Medical Center, 1 Gustav Levy Pl., Box 1272, New York, New York 10029 (telephone: ϩ1 212-241-8711; FAX: ϩ1 objectives were to compare the false detection rates of the 2 212-876-3246; e-mail: [email protected]). procedures and evaluate the safety of HAL fluorescence For another article on a related topic see page 301. cystoscopy.

0022-5347/07/1781-0068/0 68 Vol. 178, 68-73, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.028 FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR CANCER DETECTION 69

MATERIALS AND METHODS would be recorded in the study. All samples were evaluated and classified as 1) normal urothelium, 2) flat urothelial Study Design hyperplasia, 3) low grade intra-urothelial neoplasia (mild or This was an open label, comparative, controlled (within pa- moderate dysplasia) or 4) high grade intra-urothelial neo- tient), phase III study done at 18 centers in the United plasia (marked dysplasia/CIS). Inflammation in each speci- States and Canada. The study was performed in accordance men was subjectively graded as absent, mild, moderate or with Good Clinical Practice and the Declaration of Helsinki, marked. All concomitant papillary lesions were classified as including the most recent amendment (Edinburgh, Scotland, pTa—papillary urothelial neoplasia without signs of inva- 2000). Written approval was obtained from the relevant Insti- sion, pT1—papillary urothelial neoplasia invading the lam- tutional Review Board at each study site. ina propria or pT2 to pT4—muscle invasive urothelial carcinoma. Patients Staging was performed using the 1997 UICC/American A total of 311 patients with suspected or confirmed bladder Joint Committee on Cancer system.14 Grading of flat lesions cancer (urinary cytology, previous cystoscopy or a history of was performed using the 1998 WHO/International Society of urothelial bladder cancer) were enrolled. All patients pro- Urological Pathology consensus classification of urothelial vided written informed consent. Patients were 18 years or neoplasms of the bladder.15 Grading of papillary lesions, older and fulfilled at least 1 of certain criteria, including when present, was performed using the 1973 WHO sys- prior multiple bladder lesions, a bladder lesion more than tem.16 3 cm in diameter, a bladder tumor at stage T1 or less, or a grade 2 or 3 bladder tumor; positive urine cytology; or re- Efficacy Assessments current bladder cancer at followup examination. (A typo- The primary efficacy end point was the number of patients graphical error in the protocol showed “ՆT1” instead of in whom CIS (alone or in the presence of papillary, Ta or T1 “ՅT1” but this study involved only patients thought to have disease) was detected by only HAL fluorescence cystoscopy superficial disease, ie Ta, T1 and Tis cancer). Exclusion or by white light cystoscopy. The level of significance was criteria were gross hematuria, porphyria, known allergy to considered at p Յ5%, where p is the proportion of patients in HAL or a similar compound, participation in other clinical whom CIS could be detected by HAL cystoscopy but not studies within the last 30 days, pregnancy or lactation and white light. At a power of 90% with this level of significance intravesical bacillus Calmette-Guerin or chemotherapy 40 patients with CIS would be needed to demonstrate a within 3 months before HAL instillation. difference. Using the specified inclusion criteria it was estimated that 20% of the study patients would have CIS. Treatment Therefore, the sample size needed to demonstrate a signifi- HAL hydrochloride (Hexvix) in phosphate buffered saline cant difference would be 200 patients. Five training patients solution, 50 ml of a 2.0 mg/ml (8 mM) solution, was instilled per site were also recruited. into the bladder via a standard catheter 1 to 3.5 hours before Secondary efficacy end points were 1) the calculation of cystoscopy. Patients were then given local or general anes- sensitivity and specificity for detecting CIS with each thesia. The bladder was evacuated and inspected by white method with sensitivity defined as the number of patients light cystoscopy using a D-light system xenon arc lamp light with CIS detected by either method divided by the total source (Karl Storz™). The number and location of lesions or number of patients with CIS and specificity defined as the suspicious areas were determined and categorized as flat or number of patients with no suspected areas divided by the papillary, mapped onto a bladder chart and recorded by total number of patients without any tumor, including those video. A band filter on the lamp was then used to supply blue in whom no biopsy was taken and those who only underwent light (wavelength 380 to 450 nm) for fluorescence cystos- random biopsies that proved to be negative, 2) detection copy. The same investigator noted any lesions or suspicious rates for each method for CIS (the number of lesions de- areas seen by fluorescence, which were again characterized, tected by each procedure divided by the total number of mapped onto the same bladder chart and recorded by video. lesions detected using the 2 methods), 3) false detection No randomization of the sequence was performed because rates for each method (the number of suspected positive the aim of this study was to assess HAL fluorescence cys- lesions but with a negative nontumor histology seen with toscopy as a supplement to white light cystoscopy. each procedure divided by the total number of suspected Biopsies of all flat mapped lesions and suspicious areas positive lesions with negative histology), 4) the number of were taken after the bladder was inspected under white and patients with CIS in whom additional CIS lesions were blue light. One biopsy from normal-appearing urothelium found with HAL fluorescence cystoscopy, 5) the number of based on white and blue light examination was also taken. patients with CIS with concomitant papillary lesions and Papillary lesions detected were resected and collected sepa- with only CIS detected by each method, and 6) the number rately for histological examination. of patients in whom treatment was changed as a result of additional tumor findings on HAL fluorescence cystoscopy. Pathological Findings Urinary cytology was obtained in all patients. Biopsy and Safety Evaluations histology samples were examined by 1 local and 2 reference The safety of HAL instillation was evaluated by performing pathologists (DGB, JQ) blinded to the illumination proce- limited physical examination, measuring vital signs (pulse dure and to patient history. Treatment was based on the rate, and systolic and diastolic blood pressure), and hema- decision of the local pathologist, while the 2 reference pa- tological (hemoglobin, red and white blood cell counts, and thologists jointly reviewed and agreed on the histology that platelet count) and biochemical parameters (aspartate amino- 70 FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR CANCER DETECTION transferase, alanine aminotransferase, creatinine, blood urea TABLE 2. Bladder cancer history in 196 ITT patients nitrogen, ␥-glutamyl transferase, total bilirubin, sodium, potassium, albumin, chloride and calcium) at baseline and 24 History hours after instillation. Adverse events were monitored No. diagnosis (%): throughout a 7-day followup or until they resolved. Primary 62 (32) Recurrent 133 (68) Missing 1 (0.5) Statistical Analysis No. chemotherapy for bladder Ca (%): No 147 (75) All efficacy analyses were performed on the full analysis set Yes 49 (25) of patients (ITT). These 196 patients received HAL instilla- No. bacillus Calmette-Guerin for bladder Ca (%): tion, were evaluated using the 2 methods and had evaluable No 119 (61) Yes 77 (39) data on at least 1 biopsy. Analysis was also performed on the Yrs since first diagnosis:* 2 subgroups of patients with CIS alone and patients who had Mean Ϯ SD 3.3 Ϯ 4.5 CIS concomitant with papillary or sessile lesions. The first 5 Median 2.0 Range 0–24 patients of each investigator who had no previous experience with fluorescence cystoscopy (93) were excluded from ITT * In 185 patients. (training cohort). Safety evaluations were performed in the 298 patients who received HAL instillation and had at least In the ITT group more CIS lesions were found by HAL some safety data available. cystoscopy in 22 patients (41.5%, 95% CI 28–56), while more Tabulation of summary statistics and data analysis were were found by white light cystoscopy in 8 (15.1%, 95% CI performed using SAS®. The exact test for single proportion 7–28). Of the 5 patients with CIS detected only by random was performed on data for the primary efficacy end point and biopsy 3 had negative and 2 had positive cytology. the level of significance was considered at p Ͻ0.05. Since the Detection rates at the biopsy level supported cystoscopy conclusions of the trial were based on the primary objective findings (table 4). Of 113 CIS lesions 104 (92%, 95% CI alone, no adjustment for multiple comparisons was made. 85–96) were detected by HAL cystoscopy and 77 (68%, 95% CI 59–77) were detected by white light cystoscopy. Thus, RESULTS HAL fluorescence cystoscopy detected a higher percent of Study Population lesions overall and a higher percent of CIS lesions than A total of 311 patients were enrolled, of whom 13 did not white light cystoscopy. receive HAL due to technical failure (2), ineligibility (1) and Number of patients. In the 18 patients with no concomi- withdrawal by the patient or investigator (10), leaving 298 tant disease CIS was only detected by HAL fluorescence in 4 who received HAL (safety data set). Of these patients 102 and CIS was detected only by white light cystoscopy in 4. In were excluded from the ITT population, including 93 train- the group with concomitant disease CIS lesions were found ing patients, 3 in whom no cystoscopy was performed, 2 in only with HAL fluorescence in 5 patients and only by white whom blue light analysis was not performed and 4 with no light cystoscopy in 3. valid histology result. Therefore, the ITT consisted of 196 Therefore, CIS lesions were found only by HAL fluorescence patients. cystoscopy in 9 patients (16% 95% CI 7–27), whereas CIS Table 1 lists patient demographics. Table 2 shows the lesions were found only by white light cystoscopy in 7. The history of bladder cancer in the ITT population. proportion of patients in whom 1 or more histologically confirmed CIS lesions were found only by HAL fluorescence cys- Detection toscopy was greater than the hypothesized 5% (p ϭ 0.0022). CIS. CIS lesions were found in 58 patients (29.6%), al- At the patient level the sensitivity of HAL fluorescence though in 5 the CIS lesion was not detected by either cysto- cystoscopy was 87% and for white light it was 83% (p ϭ 0.4). scopic method, only by biopsy from areas that appeared At the lesion level the sensitivity of HAL fluorescence cys- normal. A total of 18 patients (34%) had CIS alone and 35 toscopy was 92% and it was 68% for white light cystoscopy. (66%) had coexisting papillary disease. Table 3 lists the locations of the CIS lesions.

TABLE 3. CIS sites No. CIS ϩ Concomitant TABLE 1. Patient demographics Site No. CIS Alone Papillary Disease

Safety ITT Trigone 1 10 Ureteral oriﬁce: No. pts 298 196 Rt 2 2 Mean Ϯ SD age 67 Ϯ 11 67 Ϯ 11 Lt 2 3 No. sex (%): Posterior ﬂoor 5 17 M 223 (75) 148 (76) Cranial wall 8 10 F 75 (25) 48 (24) Lat wall: Mean Ϯ SD ht (cm) 173 Ϯ 9.9 173 Ϯ 9.7 Rt 2 9 Mean Ϯ SD wt (kg) 83 Ϯ 18 82 Ϯ 17 Lt 5 7 No. ethnic group (%): Dome 4 9 White 274 (92) 187 (95) Anterior bladder wall 3 7 Black 15 (5.0) 5 (2.6) Bladder neck: Asian (Indian) 1 (0.3) 1 (0.5) Anterior 1 1 Asian (Oriental) 1 (0.3) — Posterior 0 5 American Hispanic 4 (1.3) 2 (1.0) Other 3 (1.0) 1 (0.5) Totals (No. pts) 33 (18) 80 (35) FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR CANCER DETECTION 71

The most common adverse event was hematuria, which TABLE 4. CIS detection at biopsy level in 196 ITT patients developed in 43.3% of patients (table 6). Most adverse events No. Detected % Detected (95% CI) were mild or moderate in intensity, resolved spontaneously White Total White and were unrelated to HAL instillation. Of 38 adverse Lesion Type HAL LightNo. HAL Light events rated severe in intensity 11 (29%) were considered to Hyperplasia 3 2 3 100 (29–100) 67 (9–99) be related to HAL instillation, including penile infection, Dysplasia 3 4 5 60 (15–95) 80 (28–99) penile pain, blood in the urine, bladder pain, bladder spasm CIS 104 77 113 92 (85–96) 68 (59–77) and urinary frequency. Totals 110 83 121 93 (90–95) 79 (75–83) No changes in hematological parameters were observed other than those expected following cystoscopy, including a slight decrease in hemoglobin and red blood cell levels, and Specificity by patient was 82% for HAL fluorescence cystos- an increase in the white blood cell count. No significant copy and 72% for white light cystoscopy (p ϭ 0.2). The changes in biochemistry variables, vital signs or physical differences were not significant. examination occurred.

False-Positive Rates DISCUSSION The false-positive detection rate at the biopsy level was 39% This study confirms findings of an earlier study using 5- (95% CI 35–43) for HAL fluorescence cystoscopy and 31% (95% aminolevulinic acid fluorescence, in which 34.2% of tumors CI 27–36) for white light cystoscopy. There were 223 false- (38.7% high risk) were overlooked by white light endoscopy.17 positive biopsies with HAL and the main source (89%) was The rate of additionally detected CIS was increased to 56.8% areas of inflammation. Of the biopsies 25 had no inflammation, compared with white light endoscopy. In a phase II clinical 142 had slight inflammation, 49 had moderate and 7 had trial HAL fluorescence cystoscopy identified 96% of the pa- marked inflammation. For white light the false-positive num- tients with bladder cancer compared to 73% for white bers were 137 biopsies, of which 13 had no inflammation, 86 light.11 It was particularly useful for detecting CIS lesions. had slight inflammation, 33 had moderate inflammation and 5 HAL fluorescence cystoscopy in our study detected CIS had marked inflammation (91% inflammatory). lesions that were not found by white light cystoscopy in 15.5% of patients and it detected more CIS lesions in 42% of Changes in Proposed Treatment Strategy patients. Also, 4 patients with no coexisting disease had CIS Additional information was provided by the use of HAL identified only by HAL fluorescence cystoscopy. In contrast, cystoscopy in 107 patients (55%), as judged by the investi- white light cystoscopy detected more CIS lesions than HAL gators. The proposed treatment strategy was changed in 15 fluorescence cystoscopy in 12% of patients. of these patients (14%) and confirmed in 87 (81.3%). HAL At the biopsy level the mean detection rate for CIS lesions fluorescence cystoscopy was considered to be useful as an was 92% with HAL fluorescence cystoscopy compared with add-on to white light cystoscopy to diagnose bladder tumors only 68% for white light cystoscopy. The difference is not in 66% of patients and for choosing further management large, which partly reflects a high rate of detection at these options in 51% of cases. Of the 9 patients with CIS detected centers using white light, but it suggests that HAL fluores- by only Hexvix 4 had no other tumors in the bladder, and 1 cence cystoscopy might be useful as an add-on because CIS and 4 had grade 2 and grade 3 papillary tumors, respec- lesions can progress to invasive disease if not treated tively, indicating a change in treatment as a result of finding promptly and appropriately. CIS in 5 of the 9 patients.

Safety Results TABLE 6. Adverse events reported by more than 2% HAL was well tolerated. A total of 800 adverse events were of 298 safety set patients reported by 240 of the 298 patients (80.5%) in the safety set (table 5). Of the events only 19 (2.4%) were considered to be Adverse Event No. Pts (%) related to HAL instillation. Of the patients 20 (7%) experi- Hematuria 129 (43.3) enced a total of 23 serious adverse events, including 1 death Dysuria 53 (17.8) Bladder spasm 43 (14.4) due to an aortic aneurysm. The death was unrelated to HAL Nausea 42 (14.1) instillation. Furthermore, none of the other serious adverse Unspeciﬁed pain 30 (10.1) Bladder pain 29 (9.7) events were deﬁnitely related to HAL instillation. Headache 25 (8.4) Urinary retention 25 (8.4) Pubic pain 21 (7.0) Urinary frequency 21 (7.0) Post-procedural pain 19 (6.4) TABLE 5. Adverse events in 298 safety set patients Abdominal pain 17 (5.7) Adverse Event No. (%) Blood in urine 15 (5.0) Pelvic pain 13 (4.4) Pts with at least 1 adverse event 240 (80.5) Vomiting 12 (4.0) Adverse events 800 Insomnia 11 (3.7) Pts with serious adverse event 20 (6.7) Penile pain 11 (3.7) Serious adverse events 23 Urinary urgency 10 (3.4) Pts with adverse event leading to withdrawal 1 (0.3) Hypotension 9 (3.0) Pts with at least 1 adverse drug reaction 55 (18.5) Pharyngolaryngeal pain 7 (2.3) Adverse drug reactions: 122 Back pain 7 (2.3) Treatment related 19 Lower abdominal pain 7 (2.3) Uncertain whether treatment related 103 Constipation 7 (2.3) 72 FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR CANCER DETECTION

In this study 20 of the 53 patients (37.7%) with CIS lesions unexpectedly had negative cytology. It is not clear Abbreviations and Acronyms why cytology was not as sensitive for detecting CIS lesions CIS ϭ carcinoma in situ as previously reported. HAL ϭ hexaminolevulinate The mean false-positive detection rate for HAL fluores- ITT ϭ intent to treat cence cystoscopy was higher than that for white light cystoscopy (39% vs 31%), which was mainly attributable to the fluorescence of inflamed tissue. Hyperplasia has occasion- REFERENCES ally been found to show genetic changes identical to those of 18 papillary tumors in the same patient. At least some false- 1. Soloway MS, Murphy W, Rao MK and Cox C: Serial multiple- positive lesions may represent tumor precursors that are not site biopsies in patients with bladder cancer. J Urol 1978; detectable by traditional histological criteria. Zaak et al 120: 57. frequently derived false-positive responses from lesions with 2. Wiener HG, Vooijs GP and van’t Hof-Grootenboer B: Accuracy inflammation or scarring after prior transurethral resec- of urinary cytology in the diagnosis of primary and recur- tion.17 The rate of false-positive lesions under white light rent bladder cancer. Acta Cytol 1993; 37: 163. examination can also be high and rates of 90.5% have been 3. Althausen AF, Pout GR and Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. reported.19 J Urol 1976; 116: 575. Under white light areas of the mucosa that had a flat- 4. Lamm DL: Preventing progression and improving survival tened and reddened appearance with a splotchy or irregular with BCG maintenance. Eur Urol 2000; 37: S9. contour and those that were slightly raised with a reddened, 5. Solsona E, Iborra I, Ricos JV, Monros JL, Rubio J and Almenar more velvety and smoothly contoured appearance were con- S: Clinical panurothelial disease in patients with superfi- sidered for biopsy. 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Koenig F, McGovern FJ, Larne R, Enquist H, Schomacker KT around 80% for the 2 procedures. Thus, approximately 80% and Deutsch TF: Diagnosis of bladder carcinoma using proof patients with lesions seen by either method actually had toporphyrin IX fluorescence induced by 5-aminolaevulinic cancer. The positive predictive value at the biopsy level was acid. BJU Int 1999; 83: 129. 60% to 70% for the 2 procedures. 9. Lange N, Jichlinski P, Zellweger M, Forrer M, Marti A, Guillou HAL fluorescence cystoscopy was well tolerated. Most L et al: Photodetection of early human bladder cancer based adverse events were mild or moderate in severity and they on the fluorescence of 5-aminolaevulinic acid hexylester- induced protoporphyrin IX: a pilot study. Br J Cancer 1999; resolved spontaneously. 80: 185. 10. Zaak D, Hungerhuber E, Schneede P, Stepp H, Frimberger D, CONCLUSIONS Corvin S et al: Role of 5-aminolevulinic acid in the detection of urothelial premalignant lesions. Cancer 2002; 95: 1234. HAL fluorescence cystoscopy is an effective, well tolerated 11. Jichlinski P, Guillou L, Karlsen SJ, Malmström PU, Jocham D, procedure for diagnosing bladder cancer. Compared with Brennhovd B et al: Hexyl aminolevulinate fluorescence cys- white light cystoscopy it may offer superior overall detection toscopy: a new diagnostic tool for photodiagnosis of super- of bladder lesions and it may improve the diagnosis of CIS ficial bladder cancer—a multicenter study. J Urol 2003; lesions. HAL cystoscopy is easy to perform in conjunction 170: 226. with white light cystoscopy and it can be used to improve the 12. Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M and Marberger M: Improved detection of urothelial carcinoma diagnosis of bladder cancer. in situ with hexaminolevulinate (HAL) fluorescence cystoscopy. J Urol 2004; 171: 135. ACKNOWLEDGMENTS 13. Jocham D, Witjes F, Wagner S, Zeylemaker B, van Moorselaar J, Grimm MO et al: Improved detection and treatment of Statistical analysis was done at Clinical Datacare, Sweden. bladder cancer using Hexvix imaging: a prospective phase III multi-center study. J Urol 2005; 174: 862. APPENDIX 14. Sobin LH and Wittekind CH: TNM Classification of Malignant Tumours, 6th ed. New York: Wiley-Liss 2002. Other PC B302/01 Study Group members: Richard Babayan, Boston Uni- 15. Epstein JI, Amin MB, Reuter MD and Mostofi FK: The World versity, Boston and William Bihrle, Lahey Clinic, Burlington, Massachu- Health Organisation/International Society of Urological setts; Gerhard Fuchs, Cedars Sinai, Los Angeles and Joseph Presti, Stan- ford Cancer Center, Palo Alto, California; Bruce Malkowicz, University of Pathology consensus classification of urothelial (transi- Pennsylvania, Philadelphia, Pennsylvania; Unyime Nseyo, McGuire Vet- tional cell) neoplasms of the urinary bladder. Bladder Con- erans Affairs Medical Center and David Bostwick, Bostwick Laboratories, sensus Conference Committee. Am J Surg Pathol 1998; 22: Richmond, Virginia; Raj Pruthi, University of North Carolina, Chapel Hill, 1435. North Carolina; Chad Ritenour, Emory Clinic, Atlanta, Georgia; Mark Schoenberg, Johns Hopkins, Baltimore, Maryland; Craig Zippe, Cleveland 16. Mostofi FK, Sobin LH and Torloni H: Histopathological typing Clinic, Cleveland, Ohio; Alvaro Morales, Kingston General Hospital, Kings- of urinary bladder tumours. In: International Histological ton, Ontario, Canada; and Norbert Lange, University of Geneva, Geneva, Classification of Tumours. Geneva: World Health Organi- Switzerland. sation 1973. FLUORESCENCE AND WHITE LIGHT CYSTOSCOPY FOR CANCER DETECTION 73

17. Zaak D, Kriegmair M, Stepp H, Stepp H, Baumgartner R, time, expense and morbidity added to transurethral resec- Oberneder R et al: Endoscopic detection of transitional cell tion? The authors rightly point out that, as an add-on pro- carcinoma with 5-aminolevulinic acid: results of 1012 fluo- cedure to conventional cystoscopy, more CIS found by fluorescence endoscopies. Urology 2001; 57: 690. rescence cystoscopy may benefit even a few patients if it 18. Hartmann A, Moser K, Kriegmair M, Hofstetter A, Hofstaedter leads to more effective therapy. Since no outcomes were F, Knüchel R et al: Frequent genetic alterations in simple reported other than changed treatment for some patients, urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol 1999; 154: this assumption awaits further study. 721. Furthermore, technology is rapidly evolving. Video as- 19. van der Meijden A, Oosterlinck W, Brausi M, Kurth KH, sisted digital cystoscopy provides suburb visualization of the Sylvester R and de Balincourt C: Significance of bladder bladder mucosa, super magnifying endoscopy now enables biopsies in Ta, T1 bladder tumors: a report from the microscopic imaging of live bladder cancer cells in situ and EORTC Genito-Urinary Tract Cancer Cooperative group. cystoscopes integrating white and blue light without the Eur Urol 1999; 35: 267. need for a dye are being developed. Also, a diagnosis of CIS can be elusive for pathologists. Moderate to severe dysplasia EDITORIAL COMMENT and denuded mucosa associated with positive urine cytology and red lesions in the bladder also indicate CIS. If such Better detection of visually elusive CIS of the bladder is a lesions were included, would that have changed the results? worthwhile goal. Pooled data on 196 patients in this study None of this detracts from the larger issue of searching for done by experienced urologists at multiple centers show that improved methods to diagnose and treat serious bladder fluorescence cystoscopy detected more CIS than conven- cancers. The authors are on the right tract and it appears tional cystoscopy. However, in real terms the differences that fluorescence cystoscopy in some form is here to stay. were not great. In fact, CIS lesions were found only by fluorescence cystoscopy in 9 patients and by white light Harry W. Herr cystoscopy in 7. At the patient level the sensitivity was 87% Department of Urology for fluorescence cystoscopy and 83% for white light. Is the Memorial Sloan-Kettering Cancer Center current method of fluorescence cystoscopy worth the extra New York, New York Urachal Carcinoma: Contemporary Surgical Outcomes

Harry W. Herr,* Bernard H. Bochner, David Sharp, Guido Dalbagni and Victor E. Reuter From the Departments of Urology and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York

Purpose: We determined surgical outcomes in a contemporary series of patients who underwent surgery for urachal carcinoma. Materials and Methods: A cohort of 50 patients with clinically staged localized urachal carcinoma underwent extended partial cystectomy, including the urachal tumor mass and entire urachus. The patients were followed a median of 5ϩ years for cancer-free survival. Results: Of the 50 patients 93% (26 of 28) with tumor conﬁned to the urachus and bladder survived compared to 69% (9 of 13) with extravesical or peri-urachal tumor invasion and none (9 patients) with tumor invasion into the peritoneal cavity. Local recurrence was noted in 9 patients (18%) and 2 had salvage therapy. The most signiﬁcant predictors of survival were pathological tumor stage and negative surgical margins. Conclusions: Wide resection of the tumor mass and entire urachus resulting in negative soft tissue and bladder margins cures the majority of nonmetastatic urachal cancers. Key Words: urachus, carcinoma, salvage therapy

rachal carcinoma is rare, accounting for less than 1% were diagnosed with transurethral biopsy of a solitary tu- of bladder neoplasms. Urachal remnants persist in mor located at or near the dome of the bladder. Cases were U and above the bladder, and urachal carcinoma may staged as nonmetastatic cancer on radiographic scans of the arise from any of these segments. Most are adenocarcinomas chest, abdomen and pelvis. Because adenocarcinoma of the but other histological subtypes are described. The recom- dome cannot be distinguished clinically from urachal carci- mended treatment is primarily surgical, with extended par- noma, the cases were treated as urachal cancer. Each pa- tial cystectomy, en bloc excision of the urachal mass, urachal tient underwent extended partial cystectomy with en bloc tract and umbilicus, and pelvic lymph node dissection. While resection of the entire urachus including the umbilicus, the some have advocated radical cystectomy as definitive ther- posterior rectus fascia, and a generous portion of overlying apy, this procedure can usually be reserved for larger tu- peritoneum and perivesical soft tissue extending out to the mors that involve more than the upper hemisphere of the lateral pelvic sidewalls. The superior vesical arteries were bladder. Radiation and chemotherapy are ineffective against sacrificed and the upper half of the bladder above this level urachal carcinoma. was removed. Wide margins of bladder were incorporated in Although most urachal cancer invades the bladder, it is the surgical specimen to ensure removal of tumor in the associated with a poor prognosis due to advanced stage at bladder wall and microscopic tumor involving perivesical diagnosis, and extravesical tumor growth favoring local re- fat. Resection of involved adjacent organs was done when currence and distant metastases. Unfavorable tumor fea- needed to remove all disease. A bilateral pelvic lymph node tures coupled with a lack of effective chemotherapy for re- dissection was performed, removing at a minimum all distal current disease emphasize the importance of surgery as common iliac, external iliac, obturator and hypogastric crucial for the survival of patients with nonmetastatic ura- nodes. Six surgeons performed the operations. Final patho- chal cancer. In this report we focus on surgical outcomes in logical stage was based on the Sheldon staging system for a contemporary cohort of patients with urachal carcinoma the primary urachal tumor. However, node status and dis- who were treated in a consistent fashion with extended tant metastases were considered separate categories.1 partial cystectomy and pelvic lymphadenectomy. The end points of our study were cancer-free survival and local recurrence. Survival was defined as the time from PATIENTS AND METHODS surgery until death from urachal cancer. Patients alive at last followup or who died of other causes were censored at We operated on 50 patients who presented with a presumed that point. Local recurrence was defined as tumor recur- urachal carcinoma between 1984 and 2004. All patients rence within the pelvis or bladder. Associations between patient, tumor and surgical variables were tested for their

Submitted for publication October 24, 2006. Study received Institutional Review Board approval. Nothing to disclose. Editor’s Note: This article is the ﬁrst of 5 published in * Correspondence: Department of Urology, Memorial Sloan- this issue for which category 1 CME credits can be Kettering Cancer Center, 1275 York Ave., New York, New York 10021 (telephone: 646-422-4411; FAX: 212-988-0768; e-mail: herrh@ earned. Instructions for obtaining credits are given mskcc.org). with the questions on pages 358 and 359.

0022-5347/07/1781-0074/0 74 Vol. 178, 74-78, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.022 CONTEMPORARY SURGICAL OUTCOMES OF URACHAL CARCINOMA 75 impact on survival by Pearson’s chi-square test. Kaplan- Meier survival curves were constructed and compared using the log rank test. Cox proportional hazards regression was used in a multivariate analysis for predictors of post-cystectomy survival. Statistical tests were 2-sided and p values less than 0.05 were considered signiﬁcant. The Institutional Review Board approved the study.

RESULTS Clinical characteristics of the 50 patients presenting with urachal carcinoma are shown in table 1.1–13 The male-to- female ratio was 1.8:1. Median patient age was 50 years (range 16 to 87). The majority of urachal tumors (88%) was high grade adenocarcinoma. All but 4 urachal cancers showed local extension (stage III). Half of these were confined to the urachus and bladder (IIIA) and half invaded adjacent fat (IIIB) or extended into the peritoneal cavity (IIIC, D). In addition to extended partial cystectomy, tumor resection involving the colon (2 cases), small bowel (1 case), FIG. 1. Cancer-free survival of patients with urachal carcinoma portion of omentum (2 cases), anterior abdominal wall (1 case) and peritoneal implants (1 case) was also performed. Six patients (12%) had positive soft tissue surgical margins retrieved was 14 (range 4 to 34). Nodal metastases (median 3 (local stage IIIB, C or D tumors). None of the patients had a positive nodes) were found in 8 (16%) patients. In 2 patients positive bladder margin. Bilateral pelvic lymph node dissec- distant metastases were found at surgery in the liver and tion was performed in all patients. Median number of nodes ovary despite clinically negative studies. In both cases the metastases were resected along with the primary urachal tumor. None of the patients received adjuvant chemotherapy. Figure 1 shows cancer-free survival in all 50 patients TABLE 1. Characteristics of patients with urachal carcinoma presenting with urachal cancer. A total of 35 patients (70%) No. (%) survived. Median survival was not reached with a median Sex: followup of 5.1 years (6.8 years for survivors and 2.2 years Male 32 (64) for patients who died of disease). Table 2 shows patient Female 18 (36) outcomes by clinical and tumor features. Gender, age, tumor Age: Younger than 55 28 (56) size, histological pattern and tumor grade did not correlate Older than 55 22 (44) with 5-year survival. Worse survival was associated with Tumor size (cm): advanced pathological stage, presence of nodal metastases Less than 4 23 (46) 4 or Greater 27 (54) and positive surgical margins. Figure 2 shows cancer-free Adenocarcinoma: 44 (88) survival stratified by pathological groups. Of 28 patients Enteric type 38 Signet-ring cell 4 with tumor confined to the urachus and bladder (stage IIIA Lymphoepithelioma-like Ca 2 or less), 26 (93%) survived 5 years compared with 9 of 22 Undifferentiated Ca: 6 (12) (41%) with local invasion of surrounding fat (stage IIIB) or Squamous cell features 2 Transitional cell/adenomatous features 3 peritoneal cavity (median survival 2.3 years, 95% CI 1.8– Clear cell features 1 2.7). Figure 3 shows cancer-free survival by surgical mar- Tumor grade: gins. Surgical margins were positive in soft tissue at the Low 3 (6) High 47 (94) lateral pelvic side walls or overlying peritoneum. Only 1 of 6 Pathological tumor stage (Sheldon): patients (17%) with a positive surgical margin survived (me- I (confined to urachal mucosa) 2 (4) II (invasion confined to urachus) 2 (4) dian survival 1.5 years, 95% CI 0.86–2.1) compared with 34 III (local extension) 46 (92) of 44 (77%) patients who had negative surgical margins. Of IIIA (to bladder) 24 (48) 8 patients with node positive disease 2 (25%) survived com- IIIB (peri-urachal ϩ vesical fat) 13 (26) IIIC (to peritoneum) 6 (12) pared with 33 of 42 (78%) with node negative disease. Of the IIID (to viscera other than bladder) 3 (6) 29 patients having 14 or more nodes removed 21 (72%) IVB (metastasis to other organs)* 2 (4) survived vs 14 of 21 patients (67%) with fewer than 14 nodes Lymph node metastasis: Yes 8 (16) (p ϭ 0.66). Although the number of nodes examined did not No 42 (84) correlate with survival, 6 of the 8 patients found to have Pos surgical margins 6 (12) Local recurrence: 9 (18) nodal metastases had more than 14 nodes resected, includ- Pelvis/bladder 6 ing the 2 who survived. Both patients with node positive Bladder only 3 disease (2 and 3 positive nodes, respectively) did not receive Distant metastases: 16 (32) Liver 8 adjuvant chemotherapy and were disease-free after 4 and 8 Lung 6 years of followup. Bone 5 In 9 cases (18%) local recurrence was noted in the pelvis Peritoneal 2 (6 cases, 3 invading the bladder) and bladder only (3 cases) * Discovered at surgery (1 each in liver and ovary). within the first 2 years of followup. Of the 9 cases 4 had 76 CONTEMPORARY SURGICAL OUTCOMES OF URACHAL CARCINOMA

TABLE 2. 5-Year Survival of urachal carcinoma No. (%) p Value No. Pts Alive Without Urachal Ca Dead of Urachal Ca (Pearson’s chi-square test)

Sex: 0.70 Male 32 23 (72) 9 (28) Female 18 12 (67) 6 (33) Age: 0.83 Younger than 55 28 20 (71) 8 (29) Older than 55 22 15 (68) 7 (32) Tumor size (cm): 0.24 Less than 4 23 18 (78) 5 (22) 4 or Greater 27 17 (63) 10 (37) Histological pattern: 0.85 Adenocarcinoma 44 31 (71) 13 (29) Undifferentiated 6 4 (67) 2 (33) Tumor grade: 0.24 Low 3 3 (100) 0 High 47 32 (68) 15 (32) Pathological stage: 0.001 I 2 2 (100) 0 II 2 2 (100) 0 IIIA 24 22 (92) 2 (8) IIIB 13 9 (69) 4 (31) IIIC 6 0 6 (100) IIID 3 0 3 (100) IVB 2 0 2 (100) Lymph node metastasis: 0.02 Yes 8 2 (25) 6 (75) No 42 33 (78) 9 (22) Surgical margins: 0.002 Pos 6 1 (17) 5 (83) Neg 44 34 (77) 10 (23) Local recurrence: 0.008 Yes 9 3 (37) 6 (67) No 41 32 (78) 9 (22) Distant metastases: 0.000 Yes 16 1 (6) 15 (94) No 34 32 (94) 2 (6)

negative and 5 had positive surgical margins (p ϭ 0.007), which was treated successfully with transurethral resection and 4 had stage IIIA or less and 5 had greater than IIIA alone. A third survivor with biopsy proven pelvic recurrence disease (p ϭ 0.06). Of the 9 patients with local recurrence 6 achieved a near complete radiographic response after 6 cy- died, including 5 with pelvic recurrence despite chemoradia- cles of ifosfamide, paclitaxel and cisplatin chemotherapy, tion therapy. One patient had recurrence at the bladder and subsequently underwent resection of a residual pelvic neck after 2 years and had salvage therapy with radical mass. Surgical pathology revealed no viable malignant cells. cystectomy. Invasive poorly differentiated carcinoma devel- This patient is currently alive and disease-free 3 years after oped in another patient in the anterior wall of the bladder, completing chemotherapy.

FIG. 2. Cancer-free survival of urachal carcinoma by pathological FIG. 3. Cancer-free survival of urachal carcinoma by surgical mar- stage. gin status. CONTEMPORARY SURGICAL OUTCOMES OF URACHAL CARCINOMA 77

Distant metastases developed in 16 patients (32%). Me- TABLE 4. Cancer-free survival after surgery for dian time to recurrence after resection of the primary tumor urachal carcinoma was 22 months (range 0.9 to 4 years). Median overall sur- Median Yrs vival from the recognition of metastatic disease was 17 References No. Pts No. Alive (%) Followup months. The most common sites were liver, lung and bone, 1 although peritoneal seeding of tumor was common. Systemic Sheldon et al 5 3 (60) 5 Johnson et al2 14 7 (50) 6 disease was refractory to chemotherapy. Half of the bone Grignon et al3 24 15 (61) 5 metastases involved the spine and required palliative radi- Herr4 12 10 (83) 8 Henly et al5 34 15 (43) 5 ation. A lung metastasis developed in 1 patient identical to Asano et al6 15 9 (60) 7 the urachal tumor after 14 months. This was resected and Santucci et al7 17 15 (88) 6 no chemotherapy was given. He is alive free of recurrence at Dandekar et al8 21 9 (46) 5 Shou et al9 12 4 (33) 5 10 years. Siefker-Radtke et al10 35 16 (46) 5 Table 3 shows a multivariate analysis for survival. Only Wright et al11 71 34 (48) 5 12 pathological stage and surgical margin status predicted can- Pinthus et al 32 20 (61) 6 Ashley et al13 60 29 (49) 5 cer-free survival of urachal carcinoma after surgery. Pa- Current series 50 35 (70) 5 tients reported normal bladder function within 6 months of Totals 402 221 (55) partial cystectomy.

DISCUSSION cause they may have undergone surgery for a presumptive diagnosis of urothelial cancer. However, they observed that The major finding of our study is that en bloc resection of the complete urachectomy and umbilectomy were significant urachal tumor and urachus coupled with extended partial predictors of survival on univariate analysis, and recom- cystectomy cures 70% of patients with clinically localized mended their routine inclusion. We regarded any solitary urachal carcinoma and more than 80% of patients with tumor in the dome of bladder as urachal cancer regardless of tumor confined to the surgical specimen, including some histology, proceeding with aggressive surgical resection. with positive lymph nodes. Patients with tumor confined to None of the series in which specific surgical management the urachus, bladder and peri-urachal fat had a 5-year sur- was detailed showed that radical cystectomy improved survival rate of 88% (36 of 41) compared to none (9 patients) vival compared to extended partial cystectomy. having invasion of the peritoneal cavity. Local recurrence Three different systems have been proposed for staging occurred in 9 patients (18%) but only 1 with pelvic recur- urachal cancer, that is the Sheldon,1 the Mayo13 and the rence had salvage therapy. Tumor stage was the strongest Ontario12 staging systems. None accounts well for the di- predictor of survival. Margin status was also important be- verse local invasion patterns of urachal cancers. The Ontario cause virtually all survivors had negative surgical margins. system provides the most appealing classification in which Although positive margins may reflect local extent of disease the primary tumor is staged as confined to the urachus (T1), or inadequate surgical resection, the fact that many urachal confined to the bladder (T2), invading the surrounding fat cancers invade perivesical and peri-urachal fat emphasizes (T3), or extending into the peritoneum including the abdom- the importance of adequate local resection. In fact, local inal wall and adjacent organs (T4). Regional node and dis- tumor stage and surgical margin status were the 2 most tant metastases are considered separately. T1-3 tumors are important factors predictive of survival. Disease specific potentially curable with appropriate surgery whereas T4 mortality was not evident 4 years after treatment. tumors are less likely to be cured even with an aggressive Collected series of surgically treated urachal cancer in operation. In our series 88% (36 of 41) of patients survived the last 2 decades total 402 patients (including the present after surgery alone (3 with local recurrence had salvage series), showing that nearly half died of disease (table 4). therapy) for disease confined to peri-urachal structures vs However, not all patients had urachectomy. For example, in none of 9 patients in whom tumor breached the peritoneal the M.D. Anderson Cancer Center series only 19 of 35 pa- cavity. Although urachal cancers commonly invade the blad- tients undergoing primary surgical treatment had en bloc der wall, peri-urachal and extravesical soft tissue, the ma- resection of the urachal ligament and umbilicus, including jority can be cured with en bloc excision of the umbilicus, 10 16 long-term survivors. The Mayo Clinic reported a 48% urachus and surrounding soft tissue coupled with extended survival among 60 surgically treated patients. However, partial cystectomy. In contrast, urachal tumors that extend 13 more than half did not undergo urachectomy. The authors into and seed the peritoneal cavity or invade abdominal suggested the urachus was not removed in some cases be- organs are rarely cured even with such aggressive surgery. Thus, staging of primary urachal tumors might better be simply dichotomized as urachal tumor confined to the ura- TABLE 3. Multivariate analysis of cancer-free survival chus, bladder and perivesical tissue (surgical specimen) vs intraperitoneal spread of disease. Hazard Ratio (95% CI)* p Value Grade has been identified as an important predictor of outcome for urachal adenocarcinoma. Although high grade Sex (male vs female) 1.6 (0.47–5.6) 0.43 Age (younger vs older than 55 yrs) 0.8 (0.23–3.1) 0.80 urachal tumors have been strongly associated with poor Histology (adenocarcinoma vs other) 1.5 (0.2–6.5) 0.65 survival, our series demonstrates that most high grade le- Grade (low vs high) 1.0 (0.05–3.2) 0.99 sions can be successfully managed if resection is performed Pathological stage (T3A or less vs 0.08 (0.009–0.49) 0.005 greater than T3A) when the disease is localized to the urachus/bladder. Nodes (pos vs neg) 1.0 (0.28–3.6) 0.95 Although there is no established chemotherapy regimen Surgical margins (pos vs neg) 0.07 (0.02–0.54) 0.01 for urachal carcinoma, some tumors may respond to cispla- 78 CONTEMPORARY SURGICAL OUTCOMES OF URACHAL CARCINOMA tin based chemotherapy.10 The role of post-chemotherapy 11. Wright JL, Porter MP, Li CI, Lange PH and Lin DW: Differ- surgical resection of local recurrence as well as solitary ences in survival among patients with urachal and non- distant metastases should be further explored. Laparoscopic urachal adenocarcinomas of the bladder. Cancer 2006; 107: approaches have recently been advocated for urachal cancer, 721. with claims of simulating the open operation.14,15 We regard 12. Pinthus JH, Haddad R, Trachtenberg J, Holowaty E, Bowler J, Herzenberg AM et al: Population based survival data on any local recurrence as a surgical failure, and it remains to urachal tumors. J Urol 2006; 175: 2042. be seen whether laparoscopic surgery can achieve adequate 13. Ashley RA, Inman BA, Sebo TJ, Leibovich BC, Blute ML, local control of invasive urachal cancers. Kwon ED et al: Urachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy. Cancer 2006; 107: 712. CONCLUSIONS 14. Milhoua PM, Knoll A, Bleustein CB and Ghavamian R: Lapa- roscopic partial cystectomy for treatment of adenocarci- Our results show that adherence to the surgical principles of noma of the urachus. Urology 2006; 67: 423. wide pelvic dissection to encompass the umbilicus, tumor 15. Wadhwa P, Kolla SB and Hemal AK: Laparoscopic en bloc and entire urachus, achieving negative soft tissue and blad- partial cystectomy with bilateral pelvic lymphadenectomy der margins, cures the majority of patients with urachal for urachal adenocarcinoma. Urology 2006; 67: 837. carcinoma. Pelvic lymph node dissection appears to have prognostic and very likely therapeutic value, at least in some EDITORIAL COMMENT patients. Node status will become more important as more effective chemotherapy against adenocarcinoma is gener- Carcinoma of the urachus is a rare and devastating disease. ated. The possibility of local recurrence and distant metas- Because of its low incidence, properly conducted trials to tases warrants further investigation into multimodality determine treatment impact on outcome are essentially im- treatment strategies for urachal cancer. possible. Thus, we are left with cohort-type date to gain insight into optimal management. These data from Memo- rial Sloan-Kettering nicely complement our recent popula- REFERENCES tion based report on outcomes in this disease (reference 12 in article). Although many patients present with incurable dis- 1. Sheldon CA, Clayman RV, Gonzalez R, Williams RD and ease, these data suggest that cure is possible, using impor- Fraley EE: Malignant urachal lesions. J Urol 1984; 131: 1. tant surgical principles, in patients with localized and even 2. Johnson DE, Hodge GB and Abdul-Karim FW: Urachal carci- nodal disease. These data justify an aggressive approach for noma. Urology 1985; 26: 218. 3. Grignon DJ, Ro JY, Ayala AG, Johnson DE and Ordonez NG: patients who present with early stage disease. Primary adenocarcinoma of the urinary bladder. Cancer Unfortunately many patients present with minimally 1991; 67: 2165. symptomatic but metastatic disease (usually to the perito- 4. Herr HW: Urachal carcinoma: the case for extended partial neum). The outcomes are not as well detailed in this report cystectomy. J Urol 1994; 151: 365. because many never make it to tertiary surgical centers of 5. Henly DR, Farrow GM and Zincke H: Urachal cancer: role of excellence. Nonetheless, these cases are essentially fatal in conservative surgery. Urology 1993; 42: 635. outcome. Therefore, effective systemic therapy represents 6. Asano K, Miki J and Yamada H: Carcinoma of the urachus. the only reasonable route to improve outcomes for patients Nippon Hinyokika Gakkai Zasshi 1994; 94: 487. with this disease. However, its rarity usually leads to a futile 7. Santucci RA, True LD and Lange PH: Is partial cystectomy the approach by many medical oncologists who have little inter- treatment of choice for mucinous adenocarcinoma of the urachus? Urology 1997; 49: 536. est in treating this disease. Empirical trials of a variety of 8. Dandekar NP, Dalal AV and Kamat MR: Adenocarcinoma of systemic agents are to be encouraged including newer ty- the bladder. Eur J Surg Oncol 1997; 23: 157. rosine kinase inhibitors. 9. Shou J, Ma J and Xu B: Adenocarcinoma of the urinary blad- Neil Fleshner der: a report of 27 cases. Zhonghua Zhong Liu Za Zhi 1999; 21: 461. Division of Urology 10. Siefker-Radtke AO, Gee J, Shen Y, Wen S, Daliani D, Millikan University Health Network RE et al: Multimodality management of urachal carcinoma: Genitourinary Site Group the M.D. Anderson Cancer Center experience. J Urol 2003; Princess Margaret Hospital 169: 1295. Toronto, Canada Urological Survey

UROLOGICAL ONCOLOGY: RENAL, URETERAL AND RETROPERITONEAL TUMORS

Nucleolar Grade But Not Fuhrman Grade is Applicable to Papillary Renal Cell Carcinoma D. Sika-Paotonu, P. B. Bethwaite, M. R. McCredie, T. William Jordan and B. Delahunt, Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, Wellington, New Zealand Am J Surg Pathol 2006; 30: 1091–1096. This study was undertaken to determine the validity of Fuhrman grading in a series of papillary renal cell carcinomas (PRCCs), to examine the interrelationship and prognostic significance of the individual components of the grading system, and further to determine whether any observed predictive value was independent of other prognostic indicators. Ninety cases of PRCC were studied. Fifty-nine tumors were of type 1 and 31 were of type 2. There were 33 TNM stage 1, 26 stage 2, 18 stage 3, and 12 stage 4 tumors, whereas division of cases according to pT category showed 14 pT1a, 20 pT1b, 25 pT2, 15 pT3a, 4 pT3b, and 11 pT4 tumors. Ten tumors were grade 1, 58 grade 2, and 22 grade 3 when predominant Fuhrman grade was assigned, whereas grading according to the high-power field containing the highest grade (focal grade) showed 40 grade 2, 49 grade 3, and 1 grade 4 tumors. Measurements of nuclear size (area, major axis, perimeter) and shape (shape factor, compactness) were undertaken using image analysis. Nuclear area ranged from 27.63 to 116.39 microM, major axis length 6.70 to 14.06 microM, and nuclear perimeter 20.05 to 41.77 microM. Shape factor ranged from 0.805 to 0.878 and compactness from 14.33 to 15.66. Predomi- nant nucleolar grade using the criteria of the Fuhrman classification was nucleolar grade 1 for 13 tumors, nucleolar grade 2 for 56 tumors, and nucleolar grade 3 for 21 tumors. Focal nucleolar grade based on the high-power field showing the greatest degree of nuclear pleomorphism, was grade 2 for 38 tumors and grade 3 for 52 tumors. pT category, TNM stage, focal Fuhrman grade, and PRCC type were significantly associated with survival. Of the various measures of the components of the Fuhrman classification, only focal nucleolar grade was associated with survival, on univariate analysis. On multivariate analysis, focal nucleolar grade and tumor diameter were independently associated with survival, whereas TNM stage retained significance independent of other parameters. It is concluded that assessment of nucleolar prominence rather than Fuhrman grade is applicable for stratification of tumors within TNM stage or pT category for PRCC and that this should be based upon the high-power field showing the greatest degree of nuclear pleomorphism. Editorial Comment: The authors make some observations on nucleolar grade and its importance as opposed to Fuhrman grade in papillary renal cell carcinoma. Although Fuhrman nuclear grade has been classically used as a prognostic marker for renal cell carcinoma, the authors indicate that only focal nucleolar grade was associated with survival, not measurements on variances in nuclear size or shape. It is possible that more detailed mathematical analysis of the nucleus might change those observations. Fray F. Marshall, M.D.

Laparoscopic and Retroperitoneoscopic Treatment of Pheochromocytomas and Retroperitoneal Paragangliomas: Results of 161 Tumors in 126 Patients M. K. Walz, P. F. Alesina, F. A. Wenger, J. A. Koch, H. P. Neumann, S. Petersenn, K. W. Schmid and K. Mann, Klinik fur Chirurgie und Zentrum fur Minimal Invasive Chirurgie, Kliniken Essen-Mitte, Akademisches Lehrkrankenhaus der Universitat Duisburg-Essen, Essen, Germany World J Surg 2006; 30: 899–908. Background: Laparoscopic and retroperitoneoscopic excisions of pheochromocytomas and retroperitoneal paragangliomas are challenging surgical procedures because of extensive intraoperative catecholamine

0022-5347/07/1781-0079/0 79 Vol. 178, 79-81, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.081 80 UROLITHIASIS, ENDOUROLOGY AND LAPAROSCOPY

release, extreme vascularization, and demanding localization. Materials: In a prospective clinical study 161 chromaffine neoplasias (134 pheochromocytomas, 27 paragangliomas) were removed endoscopically in 126 patients (67 males, 59 females, age 41.7 ϩ/Ϫ 16.4 years; 130 operations). Six patients showed multiple (2–5) tumors. Tumor size ranged from 0.5 to 12 cm (mean 3.5 ϩ/Ϫ 1.9 cm). Forty-two patients suffered from hereditary diseases. Twenty-four patients had bilateral adrenal diseases; in 14 patients pheochromocytomas were removed on both sides synchroneously. Ten neoplasias were local or loco-regional recurrences (7 pheochromocytomas, 3 paragangliomas). The laparoscopic route was chosen in 16 operations; the retroperitoneoscopic technique was performed in 128 others. Partial adrenalectomies were performed in 57 operations (in all but one of the patients with bilateral disease). High-dosage alpha-blockade with phenoxybenzamine was routinely used. Results and Discussion: Conversion to open surgery occurred once. Perioperative complications were minor (17%); mortality was zero. Operating time for unilateral retroperi- toneoscopically removed primary pheochromocytomas (n ϭ 113) was 82 ϩ/Ϫ 49 minutes (range: 20–300 minutes) and depended on tumor size (Ͻ 3cmvsϾ or ϭ 3 cm; P Ͻ 0.05) and gender (P Ͻ 0.001), but not on extent of resection (partial vs total, P ϭ 0.266). Operating time for paragangliomas ranged from 55 to 600 minutes. Median blood loss was 20 ml. Median duration of postoperative hospitalization was 4 days. In 22 of 24 patients with bilateral disease, complete preservation of cortical function was achieved. Locoregional and/or distant metastatic recurrence were found in 5 patients. Conclusions: Endoscopic removal of solitary, bilateral, multiple, and recurrent pheochromocytomas and retroperitoneal paragangliomas is feasible and safe, but surgeons need extensive experience in minimally invasive techniques, as well as in endocrine surgery. Editorial Comment: The authors describe an extensive experience with 161 chromaffin neoplasias, including 134 pheochromocytomas. Most of these tumors were removed from the retroperitoneum but a few were removed intraperitoneally. Interestingly, 57 partial adrenalectomies were performed, chiefly in patients with bilateral disease. All patients received high dose ␣-blockade with phenoxybenzamine. Only 1 patient required an open operation out of the entire group, and there was no mortality. No cortisol replacement therapy was necessary in 21 of 23 patients undergoing partial adrenalectomy, although the main adrenal vein was not preserved in most patients. Use of the ultrasound probe aided partial adrenalectomy in identifying the tumor. It appears that about a third of a normal adrenal gland is necessary to maintain sufficient cortisol function. Fray F. Marshall, M.D.

UROLITHIASIS, ENDOUROLOGY AND LAPAROSCOPY

Laparoscopic Management of Advanced Renal Cell Carcinoma With Level I Renal Vein Thrombus A. Kapoor, C. Nguan, T. F. Al-Shaiji, A. Hussain, L. Fazio, M. Al Omar and P. P. Luke, Division of Urology, Department of Surgery, McMaster University, Hamilton, Ontario, Canada Urology 2006; 68: 514–517.

Objectives: To present our series of laparoscopic radical nephrectomy in patients with level I tumor thrombus. The existence of renal vein tumor thrombus presents a technical challenge in securing hilar control during the resection of a renal mass. To our knowledge, this experience represents one of the largest series of laparoscopic nephrectomy for renal cell carcinoma associated with a macroscopic renal vein thrombus. Methods: From April 2002 to June 2004, 12 patients (8 men and 4 women) were diagnosed with renal masses. In addition to computed tomography, cavography and magnetic resonance imaging were used to determine the levels of tumor thrombi preoperatively in those who had suspicious involvement of the renal vein on computed tomography. Results: Laparoscopic nephrectomy was performed in a standard fashion. Hand-assisted laparoscopic nephrectomy was used in 6 cases involving large tumors with bulky hilar adenopathy. All renal veins were stapled using an endoscopic vascular stapler. Intraoperative laparoscopic ultrasonography was used to delineate the extent of the vein thrombus in 4 cases to enable proper stapler positioning. No intraoperative complications occurred, and 2 cases were electively converted to open nephrectomy. The postoperative narcotic requirements and hospitalization times were low. Pathologic examination of the tumor specimens demonstrated negative resection margins in all patients. Conclusions: In carefully selected patients, laparoscopic resection of renal masses with level I renal vein thrombi is feasible. Because of technical considerations that may be identiﬁed intraoperatively, early conversion to open nephrectomy should be anticipated. Long-term results regarding oncologic control continue to be assessed. UROLITHIASIS, ENDOUROLOGY AND LAPAROSCOPY 81

Editorial Comment: Level I renal vein thrombus is not a contraindication to laparoscopic standard or hand assisted radical nephrectomy at centers with expertise in laparoscopic renal surgery. Success in performing this procedure laparoscopically was initially reported in 1996.1 However, subsequent reports have been few. In this, the largest series of laparoscopic nephrectomies with a level I tumor thrombus, 10 of 12 cases were successfully completed, all using a stapler to secure the thrombus bearing renal vein. The 2 conversions were due to bulky hilar lymphadenopathy and a level II thrombus. It is noteworthy that all diagnoses of renal vein thrombus were made on preoperative imaging. Also, in 4 patients intraoperative ultrasonography was most helpful in identifying the extent of the thrombus and guiding the placement of the endoscopic vascular stapler. Ralph Clayman, M.D.

1. McDougall E, Clayman RV and Elashry OM: Laparoscopic radical nephrectomy for renal tumor: the Washington University experience. J Urol 1996; 155: 1180.

Minimizing Knot Tying During Reconstructive Laparoscopic Urology A. L. Shalhav, M. A. Orvieto, G. W. Chien, A. A. Mikhail, G. P. Zagaja and K. C. Zorn, Section of Urology, University of Chicago Pritzker School of Medicine, Chicago, Illinois Urology 2006; 68: 508–513. Objectives: Intracorporeal knot tying during urologic reconstructive surgery is one of the most technically challenging skills of laparoscopic surgery. We describe our experience using the Lapra-Ty clip to substitute for knot tying. Methods: Our technique for minimizing knot tying entails the use of the Lapra-Ty clip during closure of the collecting system and renal parenchyma for laparoscopic partial nephrectomy, the vesicourethral anastomosis during robotic laparoscopic radical prostatectomy, and the collecting system during laparoscopic pyeloplasty. From October 2002 to July 2005 at our institution, 75 patients underwent laparoscopic partial nephrectomy, 300 underwent robotic laparoscopic radical prostatectomy, and 14 underwent laparoscopic pyeloplasty. We reviewed the charts retrospectively for intraoperative and postoperative parameters related to the use of these clips. Results: In the laparoscopic partial nephrectomy group, the mean tumor size, warm ischemia time, and estimated blood loss was 2.53 cm, 30.1 minutes, and 189 mL, respectively. Two postoperative urine leaks (2.7%) developed, and 3 patients experienced postoperative bleeding (4%). In the robotic laparoscopic radical prostatectomy group, the mean operative time was 295 minutes and the mean estimated blood loss was 303.6 mL. Only 3 patients had a urine leak (1%), and 4 patients had bladder neck contracture (1.3%). With regard to the laparoscopic pyeloplasty group, the mean operative time and estimated blood loss was 224 minutes and 36 mL, respectively. No intraoperative complications or urinary leaks occurred. Conclusions: Using the Lapra-Ty clip, we have safely and efficiently supplemented knot tying in patients undergoing reconstructive laparoscopic surgery. Editorial Comment: Implantable clips are touted in this article as a substitute for knot tying when performing a vesicourethral anastomosis during radical prostatectomy, or renal repair during a wedge/partial nephrectomy or pyeloplasty. These absorbable polydioxanone clips can be used on a single strand of 1-zero to 4-zero suture. They maintain their tensile strength for 2 weeks and are absorbed during a period of 3 months. Does this development mean that one should not learn how to tie knots laparoscopically? The traditionalist in me says, “No,” since I believe that the practice of knot tying makes one a better laparoscopic surgeon. However, this is a belief that I cannot scientifically substantiate. Indeed, the ease of deployment of this clip is such that a relatively inexperienced laparoscopic surgeon can secure a suture faster than an expert laparoscopic surgeon could ever tie a knot. To some extent, this comparison is similar to the hand done bowel anastomosis versus the bowel stapler—traditionalists were horrified, while surgeons in training immediately saw the benefit and rapidly adopted the technology. Ralph Clayman, M.D. Oncology: Prostate/Testis/Penis/Urethra

Decrease in Racial Disparities in the Staging Evaluation for Prostate Cancer After Publication of Staging Guidelines

Nitya Abraham,* Fei Wan, Chantal Montagnet, Yu-Ning Wong and Katrina Armstrong From the New York University School of Medicine (NA), New York, New York, and Center for Clinical Epidemiology and Biostatistics (FW, CM, KA), Department of Medicine (KM) and Abramson Cancer Center (KA), School of Medicine and Leonard Davis Institute of Health Economics (CM, KA), University of Pennsylvania and Fox Chase Cancer Center (YNW), Philadelphia, Pennsylvania

Purpose: We compared how men with incident prostate cancer were staged before and after the 1995 publication of National Comprehensive Cancer Network, American Urological Association and American College of Radiology staging guidelines, and determined whether there were racial differences in the staging evaluation. Materials and Methods: We performed a retrospective cohort study of the use of bone scan and pelvic imaging (pelvic computerized tomography or magnetic resonance imaging) in 96,986 men with incident prostate cancer from 1991 to 1994 compared to 1995 to 1999 from Surveillance, Epidemiology and End Results-Medicare linked data ﬁles. Results: During 1991 to 1994 bone scan was done in 83.1% and 73.7% of men who would and would not have met guideline criteria for staging, respectively. From 1995 to 1999 bone scan use decreased slightly in men who met guideline criteria (74.4%) but it decreased substantially in men who did not meet guideline criteria (55.2%). Between 1991 to 1994 and 1995 to 1999 rates of pelvic imaging increased for men who did and decreased for men who did not meet guideline criteria for staging (45.5% to 57.2% and 48.4% to 41.5%, respectively). On multivariate analysis in men who did not meet guideline criteria there was no change in the association between the use of staging tests and race from 1991 to 1994, to 1995 to 1999. However, of men who met guideline criteria for staging black men were less likely to undergo bone scan and less likely to undergo pelvic imaging than white men diagnosed in 1991 to 1994 but this racial difference was not seen during 1995 to 1999. Conclusions: Using a population based cohort this study reveals a decrease in racial disparity and an increase in evidence based use of staging tests in men with incident prostate cancer in the period after the publication of National Comprehensive Cancer Network, American Urological Association and American College of Radiology guidelines. Key Words: prostate, prostatic neoplasms, neoplasm staging, African Americans, practice guidelines

rostate cancer is the most common cancer in American toms.3–5 By targeting the staging evaluation to men at risk men with an estimated 234,460 new cases in 2006.1 for advanced disease these guidelines served to minimize P Black men are disproportionately affected. The age the excess cost, morbidity and anxiety caused by low yield adjusted incidence rate is 272.0/100,000 black men com- imaging in patients with low risk disease, while maximizing pared to 169.0/100,000 white men, while the age adjusted the identiﬁcation of advanced disease in patients with high death rate due to prostate cancer is more than double in risk disease. Furthermore, by decreasing the risk of false- 2 black men (68.1/100,000 vs 27.7/100,000). positive tests in patients at low risk, this approach lessened Options for prostate cancer management depend on dis- the chance that patients with localized disease would be ease extent. Men with disease limited to the prostate or incorrectly up-staged and not offered appropriate therapy. locally spread may be eligible for radical prostatectomy or Adherence to guidelines is important because an inappro- radiation therapy. Men with distant disease are not candi- priate staging evaluation can lead to inappropriate treat- dates for curative treatment. NCCN, AUA and ACR each ment, which can potentially affect survival. published guidelines in 1995 for managing incident prostate Although many investigators have examined patterns of cancer, recommending staging with bone scan and pelvic prostate cancer treatment and differences in these patterns imaging based on tumor characteristics and clinical symp- by race, to our knowledge there are few published studies of patterns of prostate cancer staging and none that explore how this staging process may differ between black and white Submitted for publication November 13, 2006. men. Racial differences in staging are important because Study received Institutional Review Board approval. Supported by National Cancer Institute Division of Cancer Con- they may contribute to differences in outcomes. Further- trol and Population Sciences P50-CA105641, a Doris Duke Clinical more, although anecdotal evidence suggests that clinical Research Fellowship, and the Center for Population Health and guidelines may decrease racial disparities, empirical evi- Health Disparities at University of Pennsylvania under Public 6 Health Services Grant P50-CA105641. dence examining this association is limited. Thus, we Presented at annual meeting of American Urological Association, compared how men with incident prostate cancer were Atlanta, Georgia, May 21–26, 2006. staged before and after the 1995 publication of NCCN, * Correspondence: New York University School of Medicine, 545 1st Ave., New York, New York 10016 (telephone: 203-561-7615; AUA and ACR guidelines, and determined whether there FAX: 215-573-8778; e-mail: [email protected]). were racial differences in the staging evaluation and

0022-5347/07/1781-0082/0 82 Vol. 178, 82-87, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.035 DECREASED RACIAL DISPARITIES IN PROSTATE CANCER STAGING 83 whether these differences were ameliorated after guide- periods 1991 to 1994 (the period before the availability of line publication. staging guidelines) and 1995 to 1999 (the period after guideline publication). MATERIALS AND METHODS Disease characteristics. The SEER database provides tu- Study Design and Data Source mor grade and disease extent. Based on SEER information We performed a retrospective cohort study of the use of bone about tumor grade coding, poorly differentiated corre- scan and pelvic imaging in men with incident prostate cancer sponded to GS 8 or greater, moderately differentiated corre- using the SEER-Medicare database. The National Cancer In- sponded to GS 5–7 and well differentiated corresponded to stitute SEER program compiles data on incident cancers in GS 2–4. Clinical disease extent was used to determine clin- approximately 14% of the population in the United States. The ical stage according to the 1992 American Joint Committee database includes information on demographic characteris- on Cancer staging system. tics, tumor site, grade and stage, and survival. Medicare files contain claims data for medical and surgical care. Treatment. The mode of treatment used was determined SEER-Medicare data files are created by linking the SEER based on identification of the ICD-9 and Health Care Fi- files of men who have cancer and are eligible for Medicare to nancing Administration Common Procedure Coding System their respective Medicare Part A and B claims data, thus, codes for radical prostatectomy, external beam radiation providing a comprehensive data file containing cancer data and brachytherapy in Medicare files. and related claims data. Comorbidity. ICD-9 and Health Care Financing Adminis- tration Common Procedure Coding System codes for com- Study Subjects mon comorbidities were identified in the 2 years before the The study population included 113,837 men from the SEER- diagnosis date. This method of comorbidity analysis was Medicare linked data files who were age 65 or older and developed and described by Silber.9 diagnosed with prostate cancer between 1991 and 1999. Participants were from 11 different SEER registries (Appen- Sociodemographic characteristics. Age at diagnosis, dix 1). Men were excluded if they were enrolled in a health census tract per capita income, the census tract percent of maintenance organization during the window of claims anal- adults 25 years or older with a college degree, marital status ysis, did not have continuous Medicare A and B coverage, and SEER site were obtained from the SEER Patient Enti- were diagnosed at autopsy or by death certificate, were tlement and Diagnosis Summary File. entitled to Medicare due to end stage renal disease, did not have race information in the Medicare files, had prostatic intraepithelial neoplasia at diagnosis or were older than 85 Statistical Analysis years since their life expectancy was less than 5 years ac- Participant characteristics, including sociodemographic cording to 1995 United States Census Life Tables. This provided a final study cohort of 96,986 men. characteristics, comorbidity, disease characteristics and treatment mode, were compared between black and white men. The frequency of bone scan and pelvic imaging in the Variables overall cohort, and between black and white men was as- Indication for staging tests. The 1995 NCCN, AUA and sessed for patients diagnosed before (1991 to 1994) and after ACR guidelines identify 4 clinical indications for staging (1995 to 1999) guideline publication. Cases were also strat- bone scan, including 1) T3–T4 disease, 2) GS 8 or greater, 3) ified and compared by the presence of an indication for a T1–T2 disease and PSA more than 10 ng/ml, and 4) symp- staging test. Categorical variables were compared using the toms such as bone pain. Since only tumor stage and grade chi-square test and continuous variables were compared are available through SEER-Medicare, we used these 2 pa- using the t test. rameters to create an indication for the bone scan variable. 5 Multivariate logistic regression models were constructed The indication for pelvic imaging is T3–T4 disease. A stag- for cases diagnosed in 1991 to 1994 and 1995 to 1999. Be- ing evaluation is warranted regardless of these indications if cause the indication for staging is based on stage and grade the patient is symptomatic and contraindicated if patient for bone scan, and stage for pelvic imaging, we included only life expectancy is less than 5 years (Appendix 2). the indication variable in the bone scan model, and the Use of staging tests. To determine whether men under- indication variable and grade in the pelvic imaging model. went staging with bone scan or pelvic imaging (computer- We tested the interaction between race and staging indica- ized tomography or magnetic resonance imaging) the corre- tion using the likelihood ratio test. Models were adjusted for sponding Current Procedural Terminology and ICD-9 codes sociodemographic characteristics, comorbidity, treatment were identified in Medicare claims from 3 months before to mode and SEER site. The adjusted OR and 95% CI were 6 months after the date of diagnosis. Several studies show calculated for each variable. Analyses were performed using ␣ that for most patients the interval between diagnosis and Stata® 8.2. All hypotheses were 2-tailed and the critical treatment is 6 months or less.7,8 level was considered at 0.05.

Race. Race was measured as black or white according to the Medicare race deﬁnition. RESULTS

Period. NCCN, AUA and ACR guidelines were ﬁrst pub- Table 1 lists the characteristics of the 96,986 study subjects. lished in 1995. Thus, the cohort was separated into the 2 Of the men 87,300 were white and 9,686 were black. Com- 84 DECREASED RACIAL DISPARITIES IN PROSTATE CANCER STAGING

TABLE 1. Participant characteristics % White % Black

No. men 87,300 9,686 Mean age (95% CI) 73.0 (72.9–73.0) 72.5 (72.4–72.6) Census tract adults 25 or older with 4 yrs college (less than 25%) 38.4 73.5 Census tract per capita income less than $20,000 25.9 69.0 Marital status (single/divorced/widowed) 18.2 35.7 Comorbidity (1 or more) 74.0 82.9 Clinical stage: Localized 84.2 76.9 Metastatic 5.8 9.7 Grade: Well differentiated (GS 2–4) 14.1 11.7 Moderately differentiated (GS 5–7) 57.9 53.1 Poorly differentiated (GS 8–10) 20.3 24.1 Treatment: None/hormone therapy 43.1 54.1 Prostatectomy 22.4 13.5 External beam radiation 22.9 19.1 Brachytherapy 11.6 13.3 The t test was used for comparison of mean age at diagnosis and for all other variables the chi-square test was used for white vs black men with all p values signiﬁcant (p Ͻ0.001). pared to white men, black men were more likely to live in white men during 1991 to 1994 but this racial disparity was low income, less educated census tracts, not be married and no longer seen between 1995 and 1999. Of men who did not have 1 or more comorbidities. A higher percent of black men meet staging guidelines black men were more likely to un- had metastatic disease and poorly differentiated tumors. dergo bone scan in 1995 to 1999 but not in 1991 to 1994. The Black men were less likely to have undergone treatment use of pelvic imaging did not differ by race for men who met compared to white men. Black men who were treated were staging guidelines in either period but of men who did not more likely to have received hormone therapy and less likely meet staging guidelines black men were more likely to un- to have undergone prostatectomy. dergo pelvic imaging in each period. Table 2 shows staging test use by race for men diagnosed Tables 3 and 4 show multivariate regression models pre- in 1991 to 1994 and 1995 to 1999. Overall staging test use dicting the use of bone scan and pelvic imaging in 1991 to decreased with time with 76.0% of men undergoing bone 1994 vs 1995 to 1999. The association between race and bone scan during 1991 to 1994 compared to 59.8% during 1995 to scan or pelvic imaging differed by the presence of an indica- 1999 and 46.7% undergoing pelvic imaging during 1991 to tion for undergoing the test (each model p Ͻ0.001). After 1994 compared to 41.7% during 1995 to 1999. However, the adjustment for multiple potential confounders black men change in staging test use differed by whether the patient who would have met guideline criteria for bone scan were met staging guidelines. From 1991 to 1994, to 1995 to 1999 less likely to undergo this test compared to white men with bone scan use decreased slightly in men who met guideline similar disease during 1991 to 1994. This disparity de- criteria for staging (83.1% to 74.4%) but it decreased sub- creased in 1995 to 1999. There was no racial disparity be- stantially in men who did not meet guideline criteria (73.7% tween men without an indication for bone scan in either to 52.2%). Between 1991 to 1994 and 1995 to 1999 rates of time. pelvic imaging increased in men who met guideline criteria For pelvic imaging black men were less likely to undergo for staging (45.5% to 57.2%) and decreased in men who did imaging compared to white men during 1991 to 1994. This not meet guideline criteria for staging (48.4% to 41.5%). disparity persisted during 1995 to 1999 between black and Racial differences in staging test use varied by whether white men who did not meet guideline criteria for pelvic the patient met guideline criteria. Black men who met stag- imaging but it signiﬁcantly decreased between black and ing guidelines were less likely to undergo bone scan than white men who met guideline criteria.

TABLE 2. Unadjusted racial differences in staging test use by race and indication % Bone Scan % Pelvic Imaging p Value p Value Totals White Black (chi-square test) Totals White Black (chi-square test)

1991–1994: Overall 76.0 76.2 74.1 0.001 46.7 46.3 50.5 Ͻ0.001 Test indicated (T3/T4 stage or poorly differentiated 83.1 83.7 78.1 Ͻ0.001 45.5 45.4 45.8 0.790 tumor, GS 8 or greater) Test not indicated (T1/T2 stage, or moderately or 73.7 73.9 72.4 0.140 48.4 48.1 52.1 Ͻ0.001 well differentiated tumor, GS less than 8) 1995–1999: Overall 59.8 59.5 62.5 Ͻ0.001 41.7 41.5 43.1 0.036 Test indicated (T3/T4 stage or poorly differentiated 74.4 74.5 73.8 0.613 57.2 57.1 57.8 0.847 tumor, GS 8 or greater) Test not indicated (T1/T2 stage, or moderately or 55.2 54.8 58.9 Ͻ0.001 41.5 41.3 43.3 0.019 well differentiated, GS less than 8) DECREASED RACIAL DISPARITIES IN PROSTATE CANCER STAGING 85

Instead of focusing on improving care for black vs white TABLE 3. Bone scan adjusted associations men, standardizing care for all men based on clinical 1991–1994 1995–1999 parameters offers a potentially effective strategy for ame- OR (95% CI) OR (95% CI) liorating racial disparities. This strategy was supported Race ϩ clinical indication: by a study of differences in outcomes in patients with White, no bone scan indication 1.00 1.00 Black, no bone scan indication 0.91 (0.81–1.02) 1.10 (1.00–1.20) acute myocardial infarction and another study of hemodi- Black, bone scan indication 1.53 (1.34–1.74) 2.47 (2.15–2.85) alysis in patients with end stage renal disease, which White, bone scan indication 2.20 (2.08–2.33) 2.60 (2.46–2.75) showed a decrease in racial disparities in management and Age vs 65–69:* 17,18 70–74 1.28 (1.21–1.36) 1.19 (1.13–1.26) outcomes after guideline implementation. 75–79 1.41 (1.32–1.51) 1.24 (1.17–1.31) Despite the advantages of clinical guidelines a significant 80–84 1.16 (1.08–1.25) 1.10 (1.02–1.18) number of men in this cohort were not staged appropriately. Treatment vs no treatment/ hormone therapy: From 1995 to 1999 a fourth of the men who had an indica- Prostatectomy 4.18 (3.92–4.46) 1.82 (1.71–1.93) tion for bone scan and more than a third who had an indi- External beam radiation 8.34 (7.76–8.97) 3.61 (3.40–3.84) Brachytherapy 7.45 (6.63–8.37) 2.95 (2.77–3.14) cation for pelvic imaging did not receive these tests. On the other hand, more than half of the men who did not have an * Sociodemographic factors also adjusted for per capita income, education level, SEER site, comorbidity, marital status and diagnosis year. indication for these tests received them. Prior studies using different data sources also showed a significant proportion of men (15%) with an indication for bone scan and an even greater proportion (62%) with an indication for pelvic imag- 8 DISCUSSION ing who failed to undergo these tests. This evidence emphasizes that inappropriate and inadequate staging is an im- In the early 1990s the use of routine imaging tests for portant and generally overlooked issue in the care of men staging prostate cancer was challenged since multiple obser- with prostate cancer. vational studies demonstrated a significantly low rate of This study has several strengths and limitations. A major positive tests in men with low risk cancer.10–12 These stud- strength of the study is the prospective followup of a large ies prompted the publication of staging recommendations in patient population. The SEER population includes residents 1995 by NCCN, AUA and ACR.3–5 Using a population based from throughout the country and it is representative of the cohort this study reveals a decrease in racial disparity and population in the United States with respect to education an increase in evidence based use of staging tests in men and income. Medicare data provide information on the stag- with incident prostate cancer in the period after the publi- ing practices of a wide spectrum of physicians involved in cation of the NCCN, AUA and ACR guidelines. Prior studies caring for patients with prostate cancer, including primary showed improvements in disease management after the imple- care physicians, urologists, and radiation and medical on- mentation of clinical guidelines.6 Together these data empha- cologists. A major limitation of this study is the lack of PSA size the importance of evidence based clinical guidelines for data. PSA more than 10 ng/ml was an indication for bone streamlining care, especially for prostate cancer, for which scan in 1995. Some men whom we categorized as lacking racial disparities in incidence and mortality are so prominent. bone scan indication would have had PSA more than 10 The implications of our findings are 2-fold. 1) These re- ng/ml, making the 74% (1991 to 1994) and 55% (1995 to sults provide evidence that clinical guidelines can decrease 1999) who received an unnecessary bone scan an inflated unnecessary medical intervention and health care expendi- estimate. One group reported that 37% of men with T1–T2 ture. For prostate cancer staging men with metastatic dis- disease who underwent treatment had PSA more than 10 ease who are not identified by a proper staging evaluation ng/ml.19 After accounting for this percent a fifth of men may undergo treatment for localized disease. On the other hand, men with low risk, localized disease who unnecessarily undergo a staging evaluation may falsely test positive for metastases and subsequently receive treatment for ad- TABLE 4. Pelvic imaging adjusted associations vanced disease. Not only does this misclassification result in 1991–1994 1995–1999 inappropriate treatment with potentially worse survival OR (95% CI) OR (95% CI) outcomes, it can also influence the apparent success rate of Race ϩ clinical indication: the treatment, with localized cancer treatments appearing White, no pelvic imaging 1.00 1.00 less effective and advanced cancer treatments appearing indication Black, no pelvic imaging indication 0.79 (0.72–0.87) 0.77 (0.71–0.84) more effective. Furthermore, at $600 per bone scan and Black, pelvic imaging indication 0.80 (0.69–0.92) 1.59 (1.14–2.22) $1,800 per computerized tomography the economic benefit of White, pelvic imaging indication 1.16 (1.10–1.23) 1.79 (1.59–2.01) guideline based staging test use is dramatic. National an- Age vs 65–69:* 70–74 1.02 (0.97–1.08) 1.03 (0.98–1.09) nual savings for the appropriate use of staging tests in 75–79 0.89 (0.84–0.95) 0.83 (0.78–0.89) prostate cancer cases was estimated to be $80 million (1995 80–84 0.61 (0.57–0.66) 0.59 (0.54–0.64) 13 Grade vs well differentiated GS 2–4: values). Besides the economic burden of unnecessary tests, Moderately differentiated (GS 5–7) 1.24 (1.17–1.32) 1.27 (1.17–1.37) there are additional burdens of needless radiation exposure, Poorly differentiated (GS 8–10) 1.47 (1.37–1.58) 1.85 (1.70–2.03) patient anxiety, and loss of wages and productivity from Treatment vs no treatment/hormone therapy: extra hospital visits. Prostatectomy 1.81 (1.70–1.91) 1.10 (1.03–1.17) 2) In this setting racial disparities in health care de- External beam radiation 8.90 (8.42–9.40) 6.29 (5.91–6.69) creased after the publication of clinical guidelines. The dis- Brachytherapy 8.68 (7.96–9.47) 8.06 (7.53–8.62) parity in cancer treatment and outcomes in black and white * Sociodemographic factors also adjusted for per capita income, education men is well established,14 especially for prostate cancer.15,16 level, SEER site, comorbidity, marital status and diagnosis year. 86 DECREASED RACIAL DISPARITIES IN PROSTATE CANCER STAGING would still have undergone unnecessary bone scan during 1995 to 1999. A second limitation arises from the lack of data Abbreviations and Acronyms on clinical symptoms such as bone pain, which are addi- ACR ϭ American College of Radiology tional indications for bone scan. This may have minimally AUA ϭ American Urological Association ϭ inflated the percent of unnecessary bone scans that we GS Gleason score ICD-9 ϭ International Classification of Diseases, found. Only 8% of white and 14% of black males present with 9th Revision bone metastasis, of whom only a portion present with clini- NCCN ϭ National Comprehensive Cancer Network 20 cal symptoms. Lack of PSA and clinical symptom data do PSA ϭ prostate specific antigen not affect our pelvic imaging use results. A third limitation SEER ϭ Surveillance, Epidemiology and End is that the impact of clinical guidelines should not be over- Results estimated. Since this study is retrospective, an association between appropriate staging test use and the period when guidelines were available does not necessary imply a causal relationship. REFERENCES

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al: Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106. CONCLUSIONS 2. Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L et al: SEER Cancer Statistics Review, 1975–2002. Bethesda: Na- This study stands to impact the staging practices of physi- tional Cancer Institute 2005. cians caring for patients with prostate cancer by increasing 3. Roach MI, Tempany C, Choyke P, Anscher M, Bluth E, awareness of the usefulness of staging guidelines for elimi- Kawashima A et al: Expert Panel on Radiation Oncology— nating racial disparities and improving care for all men. Prostate Work Group (ROP) and Urologic Imaging. Pre- Staging guidelines are updated annually by the NCCN and treatment Staging Prostate Cancer. Reston: American Col- they should be referred to when treating patients with pros- lege of Radiology 1995; p 11. 4. Middleton R, Thompson I and Austenfeld M: AUA Clinical tate cancer. Practice Guidelines: Report on the Management of Clini- cally Localized Prostate Cancer. Baltimore: American Uro- logical Association 1995. 5. Baker L, Hanks G, Gershenson D, Kantoff P, Lange P, Logo- ACKNOWLEDGMENTS thetis C et al: NCCN prostate cancer practice guidelines. This study used the SEER-Medicare database. Interpreta- Oncology 1996; 10: 265. tion and reporting of these data are the sole responsibility of 6. Grimshaw JM and Russell IT: Effect of clinical guidelines on medical practice: a systematic review of rigorous evalua- the authors. tions. Lancet 1993; 342: 1317. 7. Cooperberg M, Lubeck D, Grossfeld G, Mehta S and Carroll P: APPENDIX A Contemporary trends in imaging test utilization for pros- SEER Sites tate cancer staging: data from the Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 2002; 168: Whites Blacks Total 491. (nϭ87,300) (nϭ9,686) (nϭ96,986) 8. Kindrick AV, Grossfeld GD, Stier DM, Flanders SC, Henning San Francisco 6,127 856 6,983 JM and Carroll PR: Use of imaging tests for staging newly Connecticut 11,972 693 12,665 diagnosed prostate cancer: trends from the CaPSURE da- Detroit 15,119 4,842 19,961 Hawaii 756 11 767 tabase. J Urol 1998; 160: 2102. Iowa 12,831 127 12,958 9. Silber J: Multivariate matching and bias reduction in the sur- New Mexico 4,862 68 4,930 gical outcomes study. Med Care 2001; 39: 1048. Seattle 10,663 276 10,939 Utah 6,094 26 6,120 10. Oesterling JE, Martin SK, Bergstralh EJ and Lowe FC: The Atlanta 4,791 1,445 6,236 use of prostate-specific antigen in staging patients with San Jose 3,616 84 3,700 newly diagnosed prostate cancer. JAMA 1993; 269: 57. Los Angeles 10,469 1,258 11,727 11. Levran Z, Gonzalez JA, Diokno AC, Jafri SZ and Steinert BW: Are pelvic computed tomography, bone scan and pelvic lymphadenectomy necessary in the staging of prostatic can- APPENDIX B cer? Br J Urol 1995; 75: 778. 12. Chybowski FM, Keller JJ, Bergstralh EJ and Oesterling JE: 1995 NCCN, AUA and ACR Guidelines Predicting radionuclide bone scan findings in patients with for Staging Tests newly diagnosed, untreated prostate cancer: prostate spe- Bone Scan Pelvic Imaging cific antigen is superior to all other clinical parameters. J Urol 1991; 145: 313. T3 or T4 tumor stage Yes Yes GS 8 or greater Yes * 13. Saigal CS: The economic costs of early stage prostate cancer. Bone Pain Yes Pharmacoeconomics 2002; 20: 869. PSA greater than 10 ng/ml* Yes * 14. Shavers VL and Brown ML: Racial and ethnic disparities in * The 2007 NCCN guidelines recommend bone scan if PSA is greater than the receipt of cancer treatment. J Natl Cancer Inst 2002; 20 ng/ml and pelvic imaging if there is a greater than 20% probability of 94: 334. lymph node involvement based on nomogram using preoperative clinical 15. Shavers V, Brown M, Potosky A, Klabunde C, Davis W, Moul stage, biopsy Gleason score and serum PSA in ng/ml. J et al: Race/ethnicity and the receipt of watchful waiting DECREASED RACIAL DISPARITIES IN PROSTATE CANCER STAGING 87

for the initial management of prostate cancer. J Gen Intern When staging bone scan was not indicated, there was a Med 2004; 19: 146. decrease in the number of bone scans ordered by 13.5% and 16. Underwood W 3rd, Demonner S, Ubel P, Fagerlin A, Sanda M 19.1% in black and white patients, respectively, after the and Wei J: Racial/ethnic disparities in the treatment of guidelines were published. When staging bone scan was localized/regional prostate cancer. J Urol 2004; 171: 1504. indicated, the test was ordered more commonly in white 17. Williams ML, Hill G and Jackson M: The impact of an acute than in black patients (83.7% vs 74.5%) before guideline myocardial infarction guideline and pathway on racial outcomes at a university hospital. Ethn Dis 2006; 16: 653. publication but no statistically significant difference was 18. Owen WF Jr, Szczech LA and Frankenfield DL: Healthcare noted after the guidelines were published (74.5% vs 73.8%). system interventions for inequality in quality: corrective Interestingly this decrease in racial disparities in staging action through evidence-based medicine. J Natl Med Assoc test use is not because more bone scans were ordered for 2002; 94: 83S. black patients, but because fewer were ordered for white 19. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank patients. These authors suggest that the difference in pros- K, Broderick GA et al: Biochemical outcome after radical tate cancer survival outcomes is not due to disparities in prostatectomy, external beam radiation therapy, or inter- staging test use. stitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969. Tracy M. Downs 20. Carlin B and Andriole G: The natural history, skeletal compli- Department of Surgery (Urology) cations and management of bone metastases in patients University of California, San Diego with prostate carcinoma. Cancer 2000; 88: 2989. Veterans Affairs San Diego Healthcare System San Diego, California EDITORIAL COMMENT 1. Underwood W III, Jackson J, Wei JT, Dunn R, Baker B, 1 Similar to other published data using the SEER registry, DeMonner S and Wood DP: Racial treatment trends in during this era (1991 to 1999) fewer black patients under- localized/regional prostate carcinoma: 1992–1999. Cancer went definitive therapy than their white counterparts. 2005; 103: 538. Under Diagnosis and Over Diagnosis of Prostate Cancer

Theresa Graif, Stacy Loeb, Kimberly A. Roehl, Sara N. Gashti, Christopher Grifﬁn, Xiaoying Yu and William J. Catalona* From the Department of Urology, Northwestern Feinberg School of Medicine (TG, SNG, CG, XY, WJC), Chicago, Illinois, Department of Urology, Georgetown University School of Medicine (SL), Washington, D. C., and Department of Psychiatry, Washington University School of Medicine (KAR), St. Louis, Missouri

Purpose: We quantified the rates of over and under diagnosis of prostate cancer in 2 large patient cohorts during the last 15 years. Materials and Methods: A total of 2,126 men with clinical stage T1c prostate cancer were treated with radical prostatectomy during 1 of the 3 periods 1989 to 1995, 1995 to 2001 and 2001 to 2005. The respective proportions of men with a tumor that met our criteria for over diagnosis (0.5 cm3 or less, confined to the prostate with clear surgical margins and no Gleason pattern 4 or 5) and under diagnosis (nonorgan confined, pathological stage T3 or greater, or positive surgical margins) were examined. Results: The proportion of men with an over diagnosed tumor was 1.3% to 7.1%. The proportion with prostate cancer that was under diagnosed was 25% to 30%. An ancillary finding was that decreasing the prostate specific antigen threshold for biopsy from 4.0 to 2.5 ng/ml in the screened population resulted in a lower rate of under diagnosis from 30% to 26%, a higher rate of over diagnosis from 1.3% to 7.1% and an increase in the 5-year progression-free survival rate from 85% to 92%. Men who were 55 years or younger were significantly more likely to meet our criteria for over diagnosed cancer. Conclusions: Under diagnosis of prostate cancer continues to occur more frequently than over diagnosis. Lowering the prostate specific antigen threshold for recommending biopsy to 2.5 ng/ml resulted in a lower rate of under diagnosis and a higher progression-free survival rate. Key Words: prostate, prostatic neoplasms, diagnosis, mass screening, prostate-specific antigen

rostate cancer is the most prevalent noncutaneous MATERIALS AND METHODS cancer and the second leading cause of cancer death in P American men.1 Approximately 18% of men are diag- The study population consisted of 2,126 men with clinical nosed with PCa during their lifetime and 3% die of it. stage T1c PCa treated with RRP from 1989 to 2005. We Although there is no evidence from a randomized, con- divided the study period into the 3 intervals 1989 to April 30, trolled trial to prove that PCa screening decreases mortality 1995 (era 1), May 1, 1995 to 2001 (era 2) and 2001 to 2005 rates, there has been a dramatic favorable stage migration (era 3). Men from eras 1 and 2 were participants in a longi- concurrent with the widespread use of PSA testing. Data tudinal screening study that enrolled 35,661 men from 1989 6 from the Surveillance, Epidemiology and End Results pro- to 2001, as previously described. During this study 3,568 gram show a 32.5% decrease in the PCa mortality rate men were diagnosed with PCa and 2,279 underwent RRP. In during the PSA era.2 era 1 PSA 4.0 ng/ml was used as the threshold for recom- Nevertheless, the incidence of PCa has increased consid- mending prostate needle biopsy. Until 1991 DRE and trans- erably, raising concern about the possibility of over diagno- rectal ultrasonography were performed for any PSA greater sis and overtreatment.3 These concerns have triggered than 4.0 ng/ml and quadrant biopsy was then performed broader questions about the justiﬁcation for PCa screen- only if DRE or transrectal ultrasonography was abnormal. ing.4,5 From 1991 to 1995 DRE and PSA were performed at all We evaluated the frequency of over and under diagnosis screenings and any palpable abnormality or PSA greater in 2 large cohorts of patients with PCa treated with radical than 4.0 ng/ml prompted a recommendation for biopsy. In prostatectomy. Speciﬁcally we examined the pathological era 2 we lowered the PSA threshold to 2.5 ng/ml and the features of PSA detected PCa in men from a formal screen- number of biopsy cores obtained was increased to at least 6 ing study from 1989 to 2001 and a cohort of referred patients (sextant biopsies). Data on the extent of cancer in biopsy treated from 2001 to 2005. cores were not recorded in our database for eras 1 and 2. Five-year cancer PFS probabilities were calculated for eras 1 and 2. We had postoperative followup on 1,304 men, Submitted for publication October 25, 2006. Supported by Beckman Coulter, Inc., Fullerton, California, North- of whom 848 (65%) had at least 5 years of followup. We western University Prostate Cancer SPORE GCRC MO1 RR00036 censored patients without progression at the most recent and the Urological Research Foundation. followup. * Correspondence: 675 North St. Clair, 20-150, Chicago, Illinois 60611 (telephone: 312-695-4471; FAX: 312-695-1482; e-mail: Wcatalona@ Era 3 included 740 men with clinical stage T1c PCa who nmff.org). were referred for RRP from 2001 to 2005. There was no

0022-5347/07/1781-0088/0 88 Vol. 178, 88-92, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.017 UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER 89 standard biopsy strategy in this era. Clinical and patholog- The 5-year PFS rate for men who were over diagnosed was ical tumor features were evaluated for men in all 3 eras. 100% under each definition. We defined possible over diagnosis using the Ohori crite- Table 3 shows the over diagnosis, under diagnosis and ria of tumor volume less than 0.5 cm3, Gleason less than 7 5-year PFS rates as a function of age. Over diagnosis was and organ confined disease in the RRP specimen,7 which we significantly more common in men 55 years or younger than modified by also requiring clear surgical margins. We dein men 56 to 65 or older than 65 years (6.5% vs 4.9% and fined under diagnosis as nonorgan confined disease, includ- 3.2%, respectively, p ϭ 0.02). ing extracapsular tumor extension, positive (cancerous) surgical margins (R1), seminal vesicle invasion or lymph node metastases. We also calculated the rate of under diagnosis Early vs Later Screened Cohort using an alternate classification of margin status, in which The proportion of men with seminal vesicle invasion, posi- men with positive surgical margins in the absence of other tive lymph nodes and extracapsular tumor extension was adverse pathological features were excluded from the under similar in the early (era 1) and later (era 2) screened popu- diagnosis category. Similarly we calculated rates of over lations. However, mean PSA and tumor volume were signif- diagnosis using an alternate definition, in which men with icantly lower in later screened patients. In addition, there positive surgical margins who met all Ohori criteria were was a significant decrease in the proportion with positive included in the over diagnosis category. surgical margins in later screened men. Mean pathological The percent of cancer in the prostate gland was assessed Gleason score was significantly higher in the later years of by visual estimation in the majority of cases, although the the study, perhaps reflecting changes in pathological grad- grid morphometric method was used in a small proportion. ing practices. Tumor volume was calculated by multiplying the estimated Lowering the PSA threshold from 4.0 to 2.5 ng/ml re- percent of cancer by prostate volume in the RRP specimen. A sulted in a 4% decrease in the rate of under diagnosis by our stated percent of less than 1% in the pathology report was definition and a corresponding 7% increase in 5-year PFS. It considered 1%, less than 5% was considered 5%, etc. also increased the overall rate of potential over diagnosis by All statistical calculations were performed using SAS®, 5.8% (p Ͻ0.0001). version 8.2. We used 1-way ANOVA to compare the means of Table 4 shows the over diagnosis, under diagnosis and continuous variables, the Kruskal-Wallis test to compare 5-year PFS rates during ERA 2 stratified by PSA at diagno- medians and the Armitage chi-square or Fisher exact test to sis. Of men with PSA between 2.5 and 4.0 ng/ml at biopsy compare categorical variables between groups. We used 19% had under diagnosed cancer compared to 33% of those Kaplan-Meier product limit estimates to calculate 5-year who underwent biopsy at PSA higher than 4.0 ng/ml PFS probabilities, stratified by era and age. Finally, we (p Ͻ0.0001). Using the alternate definition that excluded censored patients without progression at the most recent positive margins only for under diagnosis the under diagno- followup and used the log rank test to compare the strata. sis rates were 9% and 17%, respectively (p ϭ 0.0006).

RESULTS Later Screened vs Referred Cohort The study population included 2,126 men with clinical stage The proportion of men with seminal vesicle invasion and T1c PCa. Table 1 shows their clinical and pathological fea- lymph node metastases was similar in the later screened tures. and referred populations. Referred men had significantly From 1989 to 2005, 27% of men treated with RRP met our more adverse pathological findings (extracapsular extension criteria for under diagnosis, while 5% met our criteria for and high Gleason) than the screened population, except possibly over diagnosed disease. Table 2 shows the rates of positive surgical margins. over and under diagnosis stratified by era. The 5-year PFS Over diagnosis rates were significantly lower for the re- rate for men meeting our criteria for under diagnosis was ferred population than for the later screened cohort (3.4% vs 79% (95% CI 75–84). After excluding under diagnosed men 7.1%). Under diagnosis rates were similar in the 2 eras using with T2 disease and positive surgical margins from the our definition. However, after excluding men with positive under diagnosis category the 5-year PFS rate was 74% (95% surgical margins alone as being under diagnosed under di- CI 67–80). The 5-year PFS rate for men who did not meet agnosis was significantly more common in the referred co- our criteria for under diagnosis was 92% (95% CI 90–94). hort (18% vs 13%, p ϭ 0.007).

TABLE 1. Study population clinical and pathological features Era 1 Era 2 Era 3 p Value

No. pts 554 832 740 Mean age 65 64 60 Ͻ0.0001 Median PSA (ng/ml) 5.9 4.0 5.2 Ͻ0.0001 Median tumor vol (cc) 4.2 2.3 4.1 Ͻ0.0001 Median followup (mos) 114 62 13 Ͻ0.0001 Mean pathological Gleason score 5.6 6.1 6.5 Ͻ0.0001 No. organ conﬁned excluding R1 (%) 384 (69) 615 (74) 552 (75) 0.08 No. organ conﬁned including R1 (%) 476 (86) 720 (87) 607 (82) 0.01 No. extracapsular (%) 60 (11) 92 (11) 127 (17) 0.0009 No. seminal vesicle invasion (%) 16 (3) 20 (2) 28 (4) 0.33 No. lymph nodes (%) 2 (0.4) 2 (0.3) 7 (1) 0.13 No. R1 (%) 138 (25) 167 (20) 112 (15) Ͻ0.0001 90 UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER

TABLE 2. Over diagnosis, under diagnosis and 5-year PFS stratiﬁed by era Era 1 Era 2 Era 3 p Value

No. over diagnosed/total No. (%) 5/379 (1.3) 53/742 (7.1) 23/679 (3.4) Ͻ0.0001 No. over diagnosed including R1/total No. (%) 6/379 (1.6) 56/742 (7.5) 23/679 (3.4) Ͻ0.0001 No. under diagnosed/total No. (%) 163/547 (30) 213/828 (26) 186/738 (25) 0.08 No. under diagnosed excluding R1/total No. (%) 69/547 (13) 108/828 (13) 131/738 (18) 0.007 % 5-Yr PFS 85 92 — Ͻ0.0001

DISCUSSION agnosis similar to those in the current study, Ohori et al reported a 17% rate of unimportant cancer7 and Epstein Since the introduction of widespread PSA testing in the et al calculated a 26% rate of insignificant or minimal can- early 1990s, there has been a 75% decrease in the proportion cer.11 More recently Postma et al reported rates of 32% and of patients presenting with metastatic disease and PCa spe- 43% of minimal cancer in the first and second rounds, re- cific mortality rates have decreased dramatically.2 Never- spectively, of a screening study.12 theless, there is currently concern about the possible over Our results show much lower rates of over diagnosis. diagnosis of PCa. The potential morbidity associated with Fewer than 8% of men in our series underwent treatment for overtreatment has led some to call for a limitation on PCa possibly over diagnosed cancer at any point in our study and screening and/or delayed definitive therapy in patients at the overall rate was 5%. The disparity between our results low risk until there is clinical evidence of progressive dis- and those in other published series may relate to differences ease.4,5 in the method of tumor volume calculation, patient selection Using epidemiological studies groups have attempted to and exclusion criteria. calculate the frequency of over diagnosis by comparing ob- Although considerable attention has been given to the served vs expected cancer incidence rates in population subject of over diagnosis, less has been given to the persis- based cancer registries. These estimations range from 27% to 84%.8–10 The wide variability in these results may relate tent prevalence of under diagnosis. To our knowledge no to differences in the methods used by the investigators. group has simultaneously examined the prevalence of over In a screening study Draisma and De Koning performed and under diagnosis in a large population of men undergoing a simulation analysis to estimate lead times and over detec- RRP. Our study shows that, although under diagnosis rates tion.8 In their model at age 55 years the estimated lead time have decreased in the PSA era, PCa is still more likely to be and over detection rates were 12.3 years and 27%, respec- under diagnosed than over diagnosed. tively. In contrast, at age 75 years the corresponding rates It has been argued that cases of a low grade, apparently were 6 years and 56%, respectively. These results highlight organ confined tumor might be better managed if left un- the difficulty in extrapolating over diagnosis rates calcu- treated, including some found to have positive surgical mar- lated in older men to young men. gins at prostatectomy, since margin status may reflect sur- Similarly Etzioni et al reported over diagnosis rates of gical technique as well as tumor biology. However, to our 29% for white men and 44% for black men with estimated knowledge there is currently no reliable means to accurately lead times of 5 and 7 years, respectively.9 They estimated predict pathological tumor features preoperatively. More- that current PSA based screening practices would have de- over, it is impossible to prove that any PCa is over diagnosed tected a maximum of 15% and 37% in white and black men, in a young man because even small, low grade lesions can respectively, of the latent PCa that was found at autopsy acquire mutations and aggressive features with time. before the PSA era. Conversely it was suggested that under diagnosis may In contrast, in an epidemiological study McGregor et al not be a relevant issue in older men. However, Wong et al reported an over detection rate of 84% in a population of recently noted that even in men who are 65 to 80 years old Quebec men 50 to 70 years old,10 demonstrating the vari- active treatment has a survival advantage over watchful ance that results when different end point definitions are waiting.13 Nevertheless, since all men in our study under- used. Unlike Etzioni et al, who used clinical diagnosis as an went RRP, it is unknown what the outcome would have been end point,9 McGregor et al used cancer specific mortality as in the absence of treatment. the end point.10 An ancillary finding of our study is that decreasing the In prior clinical studies investigators also attempted to PSA threshold for recommending biopsy from 4.0 to 2.5 characterize the prevalence of over diagnosis based on ng/ml resulted in a lower rate of under diagnosis and an pathological criteria, ie low volume, low grade, organ con- increase in the 5-year PFS rate. Under the alternate defini- fined tumors in RRP specimens. Using criteria for over dition of under diagnosis that excludes men with positive

TABLE 3. Over diagnosis, under diagnosis and 5-year PFS stratiﬁed by patient age 1989 to 2005 No. Pts/Total No. (%) 55 or Younger 56–65 Older Than 65 p Value

Over diagnosed 18/279 (6.5) 41/837 (4.9) 22/684 (3.2) 0.02 Over diagnosed including R1 19/279 (6.8) 43/837 (5.1) 23/684 (3.4) 0.02 Under diagnosed 70/307 (23) 255/980 (26) 237/826 (29) 0.04 Under diagnosed excluding R1 40/307 (13) 146/980 (15) 122/826 (15) 0.57 % 5-Yr PFS 87 87 89 0.78 UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER 91

ing our criteria. Decreasing the PSA threshold for biopsy TABLE 4. Over diagnosis, under diagnosis and 5-year PFS during era 2 stratified by PSA at diagnosis from 4.0 to 2.5 ng/ml results in a lower rate of under diagnosis and increased 5-year PFS. These results suggest that No. Pts/Total No. (%) PCa screening does more good than harm. Further research PSA Greater PSA 4 ng/ is needed to determine the optimal screening protocol to Than 4 ng/ml ml or Less p Value simultaneously minimize the over and under diagnosis of Over diagnosed 17/372 (4.6) 36/370 (9.7) 0.007 PCa. Over diagnosed including R1 19/372 (5.1) 37/370 (10) 0.01 Under diagnosed 135/409 (33) 78/419 (19) Ͻ0.0001 Under diagnosed excluding R1 70/409 (17) 38/419 (9) 0.0006 % 5-Yr PFS 90 93 0.17 Abbreviations and Acronyms DRE ϭ digital rectal examination PCa ϭ prostate cancer surgical margins alone a similar decrease in the under di- PFS ϭ progression-free survival agnosis rate was not observed. Thus, it might be argued that PSA ϭ prostate specific antigen the decrease in under diagnosis may be the result of im- R1 ϭ positive surgical margins proved surgical technique rather than more favorable bio- RRP ϭ radical retropubic prostatectomy logical tumor characteristics. Our decision to include positive margin status in our definition of under diagnosis was REFERENCES based on an overwhelming body of evidence suggesting that positive surgical margins are strongly associated with 1. American Cancer Society. Cancer Facts and Figures 2007. poorer prognosis and more aggressive tumor biology.14–16 Available at http://www.cancer.org/downloads/STT/CAFF Furthermore, although lowering the PSA threshold for 2007PWSecured.pdf. Accessed January 28, 2007. biopsy increased the rates of possible over diagnosis, it re- 2. Surveillance, Epidemiology and End Results (SEER) Program. mained less than 10% throughout the study interval. Strat- SEER*Stat Database: Mortality-All COD, Public-Use With ified data on era 2 show that rates of under diagnosis and State, Total U. S. (1969–2003). National Cancer Institute, Division of Cancer Control and Population Sciences, Sur- PFS are intimately linked to PSA at biopsy, providing fur- veillance Research Program, Cancer Statistics Branch, re- ther support for the suggestion that waiting until PSA is 4.0 leased April 2006. Available at www.seer.cancer.gov. Un- ng/ml may be too late for some patients. derlying mortality data provided by National Center for Several limitations of our study deserve mention. Al- Health Statistics. Available at www.cdc.gov/nchs. Accessed though our data were collected prospectively, we performed October 18, 2006. a retrospective analysis in patient populations that are not 3. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis strictly comparable. For example, the men from era 1 un- RAM, Schroder FH et al: Lead times and overdetection due derwent a limited biopsy protocol that is no longer used and to prostate-specific antigen screening: estimates from the it is unknown how the rates of over diagnosis and under European Randomized Study of Screening for Prostate diagnosis may have been affected by a more extensive biopsy Cancer. JNCI 2003; 95: 868. 4. Talcott JA: What patients should be told before agreeing to a regimen. Also, as reported previously, we found higher tu- blood test that could change their lives. Urology 2003; 61: 7. mor volumes in the referred population than in the screened 17,18 5. Hoffman RM: Viewpoint: limiting prostate cancer screening. population. Nevertheless, the inclusion of these men in Ann Intern Med 2006; 144: 438. the study provides a useful comparison. Furthermore, the 6. Smith DS and Catalona WJ: The nature of prostate cancer definitions that we used for over and under diagnosis are detected through prostate specific antigen based screening. subject to debate, particularly concerning the role of positive J Urol 1994; 152: 1732. margin status. In addition, although the current analysis 7. Ohori M, Wheeler TM, Dunn JK, Stamey TA and Scardino PT: only included men with clinical stage T1c PCa, some palpa- The pathological features and prognosis of prostate cancer ble tumors may still meet the pathological criteria for insig- detectable with current diagnostic tests. J Urol 1994; 152: nificant cancer. 1714. 8. Draisma G and De Koning HJ: MISCAN: estimating lead-time Another limitation to this study is that the pathological and over-detection by simulation. BJU Int, suppl., 2003; 92: examination was not standardized. While studies have 106. shown that assessment of the cancer percent via visual 9. Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann estimation yields results similar to those of the grid mor- PH et al: Overdiagnosis due to prostate-specific antigen 19 phometric method, it was not possible to differentiate or screening: lessons from U S prostate cancer incidence compare the methods in this study and it is possible that trends. JNCI 2002; 94: 981. visual estimation may be less precise when describing small 10. McGregor M, Hanley JA, Boivin JF and McLean RG: Screen- tumor volumes. Such differences in pathological reporting ing for prostate cancer: estimating the magnitude of over- practices may have affected the reported rates of over diag- detection. CMAJ 1998; 159: 1368. nosis. Future studies are warranted to provide additional 11. Epstein JI, Walsh PC, Carmichael M and Brendler CB: Patho- logic and clinical findings to predict tumor extent of non- insight into the true prevalence of PCa over and under palpable (stage T1c) prostate cancer. JAMA 1994; 271: 368. diagnosis. 12. Postma R: Population Based Screening for Prostate Cancer: Prognostic Findings of Two Subsequent Screening Rounds. CONCLUSIONS Rotterdam: Erasmus University 2006. 13. Wong YN, Mitra N, Hudes G, Localio R, Schwartz JS, Wan F Despite the stage migration in PCa that has occurred since et al: Survival associated with treatment vs observation of the advent of widespread PSA screening, under diagnosis localized prostate cancer in elderly men. JAMA 2006; 296: continues to occur more frequently than over diagnosis us- 2683. 92 UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER

14. Karakiewicz PI, Eastham JA, Graefen M, Cagiannos I, 17. Roehl KA, Eggener SE, Loeb S, Smith ND, Antenor JA and Stricker PD, Klein E et al: Prognostic impact of positive Catalona WJ: Survival results in patients with screen- surgical margins in surgically treated prostate cancer: detected prostate cancer versus physician-referred patients multi-institutional assessment of 5831 patients. Urology treated with radical prostatectomy: early results. Urol 2005; 66: 1245. Oncol 2006; 24: 465. 15. Han M, Partin AW, Chan DY and Walsh PC: An evaluation 18. van der Cruijsen-Koeter IW, Vis AN, Roobol MJ, Wildhagen of the decreasing incidence of positive surgical margins MF, de Koning HJ, van der Kwast TH et al: Comparison of in a large retropubic prostatectomy series. J Urol 2004; screen detected and clinically diagnosed prostate cancer in 171: 23. the European Randomized Study of Screening for Prostate 16. Wieder JA and Soloway MS: Incidence, etiology, location, pre- Cancer, Section Rotterdam. J Urol 2005; 174: 121. vention and treatment of positive surgical margins after 19. Humphrey PA and Vollmer RT: Percentage carcinoma as a radical prostatectomy for prostate cancer. J Urol 1998; 160: measure of prostatic tumor size in radical prostatectomy 299. tissues. Mod Pathol 1997; 10: 326. Under Diagnosis and Over Diagnosis of Prostate Cancer in a Screening Population With Serum PSA 2 to 10 ng/ml

Alexandre E. Pelzer,* Jasmin Bektic, Thomas Akkad, Stefano Ongarello, Georg Schaefer, Christian Schwentner, Ferdinand Frauscher, Georg Bartsch and Wolfgang Horninger From the Departments of Urology (AEP, JB, TA, CS, GB, WH), Pathology (GS) and Radiology (FF), Medical University Innsbruck and Institute of Analytical Chemistry and Radiochemistry, University of Innsbruck (SO), Innsbruck, Austria, and Department of Information Engineering, University of Padova (SO), Padova, Italy

Purpose: Since the implementation of widespread serum total prostate specific antigen based screening, the risk of prostate cancer over diagnosis has become a concern. We evaluated the amount of possible over and under diagnosis of prostate cancer in an asymptomatic screening population with a total prostate specific antigen of 2.0 to 3.9 (lower range) and 4.0 to 10.0 ng/ml (higher range). Materials and Methods: A total of 680 patients with prostate cancer were included. Possible over diagnosis was defined as Gleason score less than 7, pathological stage pT2a and negative surgical margins. Under diagnosis was defined as pathological stage pT3 or greater, or positive surgical margins. Furthermore, insignificant tumors according to the Epstein criteria were evaluated in a small subset of patients for whom cancer volume information was available. Results: In the lower and higher total prostate specific antigen ranges there was an over diagnosis rate of 19.7% and 16.5%, and an under diagnosis rate of 18.9%* and 36.7%, respectively (p Ͻ0.05). In the prostate specific antigen range of 2.0 to 10.0 ng/ml combined the rates of over and under diagnosis were 17.6% and 30.3%, respectively. In addition, 8.7% of tumors with total prostate specific antigen 2.0 to 10.0 ng/ml met the Epstein criteria for insignificance. Conclusions: These data show that the reported estimates of over diagnosis in the low total prostate specific antigen group are exaggerated in a screening population. Using our criteria prostate cancer under diagnosis occurs more frequently than over diagnosis in the total prostate specific antigen range of 4.0 to 10 ng/ml. Key Words: prostate, prostatic neoplasms, diagnosis, mass screening, prostate-specific antigen

n 2006 PCa affected an estimated 232,090 men in the METHODS United States and 30,350 were expected to die of the I disease. This incidence is the highest of all noncutane- From 1996 to 2005 after obtaining informed consent 680 ous malignancies and its mortality in men is third only to consecutive patients with PCa (T1c) and tPSA 2.0 to 10.0 that of lung and colorectal cancer. Since the implementation ng/ml who underwent prostate biopsy and consecutive RRP of widespread tPSA based screening, the risk of over diag- were included in our study population. All patients from the nosis has become a concern. However, proponents of screen- Tyrol screening study were white. Pathological stage and GS ing point to the fact that screening detected cancers tend to were assessed. Possible over diagnosis was defined as GS have favorable stage distribution, ie they are localized and less than 7, pathological stage pT2a and negative surgical curable with low morbidity, compared with clinically diag- margins. Under diagnosis was defined as pathological stage nosed cancers and a certain percent of over diagnosis is pT3 or greater, or positive surgical margins. Insignificant acceptable if it is weighed against treatment morbidity and tumors were assessed according to the Epstein criteria as 3 a decrease in mortality.1 Opponents of screening suggest less than 0.2 cm , confined to the prostate and Gleason sum 5 that the observed decrease in PCa mortality might be due to less than 7. better treatment or to misclassification of the cause of death The study population was recruited from the Tyrol 6 and they stress that some men are treated unnecessarily screening project. Digital rectal examination was not part because they would not have been diagnosed with PCa with- of the screening protocol, although it was performed at pros- out screening.2–4 We evaluated the amount of possible PCa tate biopsy. From 1996 to 2000, 10 systematic gray-scale over and under diagnosis in an asymptomatic screening ultrasound guided prostate biopsy cores in a standard spa- population with tPSA 2.0 to 3.9 (low tPSA group) and 4.0 to tial distribution were taken, while from 2000 to 2005 an 10.0 ng/ml (high tPSA group). additional 5 color Doppler enhanced targeted biopsy cores were taken based on age specific tPSA reference ranges. These reference ranges were defined as half the age referenced tPSA reported by Oesterling et al7 in combination Submitted for publication October 24, 2006. with percent free PSA less than 18%. Gray-scale ultrasonog- * Correspondence: Department of Urology, Medical University raphy was done using a Combison™ 530MT unit fitted with Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria (telephone: ϩ43 512 504 81130; FAX: ϩ43 512 504 24863; e-mail: alexandre. a biplane probe operating at a gray-scale frequency of 10 [email protected]). MHz and as previously described.8 Each biopsy core was

0022-5347/07/1781-0093/0 93 Vol. 178, 93-97, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.021 94 UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER

TABLE 1. Study population characteristics TABLE 3. Pathological stage and GS for tPSA 2.0 to 3.9 ng/ml Mean Ϯ SD tPSA (ng/ml) % tPSA 2.0–3.9 ng/ml (No. pts) 2.0–3.9 4.0–10.0 GS Less GS7or Totals Than 6 GS 6 Greater No. pts 244 436 Age (range) 58.3 (40–75) 63.2 (40–75)* pT2a 25.0 (61) 5.3 (13) 14.8 (36) 4.9 (12) tPSA (ng/ml) 2.9 6.3 pT2b 38.5 (94) 5.7 (14) 18.0 (44) 14.8 (36) % Free PSA (range) 13.3 (3.0–58) 12.7 (2.9–50) pT2c 25.8 (63) 6.6 (16) 9.8 (24) 9.4 (23) cm3 PV (range) 28.3 (10–61) 33.8 (11–130) pT3a 8.6 (21) 1.2 (3) 2.0 (5) 5.3 (13) pT3b 1.6 (4) 0 0.4 (1) 1.2 (3) *pՅ0.05. pT4 0.4 (1) 0 0 0.4 (1) Totals 100 (244) 18.9 (46) 45.1 (110) 36.1 (88) reviewed by a single pathologist and assessed as cancerous with an assigned GS. In a subset of 69 patients with PCa CVol was measured. CVol was calculated as the sum of Over diagnosis was found in 19.7% of the low tPSA group tumor areas at different levels multiplied by section thick- (2.0 to 3.9 ng/ml) and 16.5% of the high tPSA group (4.0 to ness and a shrinkage factor of 1.33. Assuming a Gaussian 10.0 ng/ml). Under diagnosis was found in 18.9% of the low distribution minimal sample size (n) was calculated with the tPSA group and 36.7% of the high tPSA group. The amount -formula, n ϭ [z_␣/2 ϫ ␴/E]ٙ2, where for each parameter ␴ of under diagnosis was statistically significant different be represents the population SD, E represents the margin of tween the low and high tPSA groups (p Յ0.05). In the 2 tPSA error that defines the difference between population and ranges combined (2.0 to 10.0 ng/ml) the over and under subgroup averages, and z_␣/2 represents the corresponding diagnosis rates were 17.6% and 30.3%, respectively. Table 2 critical value in the Gaussian distribution for the chosen lists data on over and under diagnosis. level of significance, ␣. The margin of error was 10% of the Tables 3 and 4 list data on the distribution of pathological average of the specific value of the entire population. Thus, stage and GS in the tPSA 2.0 to 3.9 and 4.0 to 10.0 ng/ml we could ensure that for the specific values of tPSA, GS, PV groups, respectively. In the low and high tPSA groups we and pathological stage these 69 patients were similar and found pathological stage pT2, pT3 and pT4 in 89.3%, 10.2% representative of the larger cohort (␣ Յ0.05). and 0.4% (pT2 vs pT4 p Ͻ0.05) and in 74.1%, 21.8% and Blood serum samples were obtained before any prostatic 4.1% of cases (p Ͻ0.05). Pathological stages pT2b and pT2c manipulation and they were evaluated at our laboratory on (TNM 2002) were found in 64.3% and 55.3% of all PCa cases, the same day. PSA was assessed with the IMx® Immunoas- respectively. say. After PCa diagnosis RRP was performed 2 months later In a subset of 69 patients with PCa Cvol was measured. using an open retropubic approach. All statistical calcula- These patients had a mean tPSA of 5.4 ng/ml (range 2.1 to tions were performed using SPSS®, version 10.0 with 9.8) and a mean percent free PSA of 12.3% (range 3.4% to p Ͻ0.05 considered statistically significant. 49.9%). Mean PV in this subset was 31.2 cm3 (range 13.2 to 76.3). Concerning the criteria of Epstein et al (less than 3 RESULTS 0.2 cm , confined to the prostate and Gleason sum less than 7)5 there were insignificant tumors in 8.7% of the A total of 680 consecutive screening volunteers with tPSA whole tPSA group of 2.0 to 10.0 ng/ml. 2.0 to 10.0 ng/ml were assessed. Table 1 lists the study population characteristics of the different tPSA subgroups. DISCUSSION Mean patient age was 60.8 years (range 40 to 75), mean tPSA was 4.6 ng/ml, the mean free PSA-to-tPSA ratio was There is general agreement among clinicians that tPSA 13.0% (range 2.9% to 58%) and mean PV was 30.9 cm3 screening can detect early stage PCa and most PCa de- (range 10 to 130). Mean age in patients with tPSA 2.0 to 3.9 tected by tPSA screening appears to be clinically impor- ng/ml was 58.3 years, mean tPSA was 2.9 ng/ml and mean tant when pathological characteristics are used as a sur- PV was 28.3 cm3. Mean age in patients with tPSA 4.0 to 10 rogate for biological potential.9 Since the implementation ng/ml was 63.2 years, mean tPSA was 6.3 ng/ml and mean of widespread tPSA based screening, the risk of over di- PV was 33.8 cm3. Statistically significant differences were agnosis has become a concern. The rate of over diagnosis found in age and PV between these 2 groups with patients in can be expressed in several ways. Etzioni et al calculated the lower tPSA group being younger and having a smaller the amount of over diagnosis in the current tPSA testing mean PV (p Յ0.05). practice in the United States as a percent of total detec-

TABLE 2. Under and over diagnosis using different deﬁnitions % ng/ml tPSA (No. pts) 2.0–10 2.0–3.9 4.0–10.0

No. pts 680 244 436 Under diagnosis (pT3 or greater, or pos surgical margins) 30.3 (206) 18.9 (46) 36.7 (160)* Over diagnosis (pT2a ϩ GS less than 7 ϩ neg surgical margins) 17.6 (120) 19.7 (48) 16.5 (72)* % Insigniﬁcant Ca (Epstein deﬁnition) 8.7 (69)† *pՅ0.05. † ␣ Յ0.05. UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER 95

that many tumors follow an indolent course for the first 10 TABLE 4. Pathological stage and GS for tPSA 4.0 to 10 ng/ml to 15 years after diagnosis but beyond 15 years the PCa % tPSA 4.0–10 ng/ml (No. pts) specific mortality rate triples.15 In this series cause spe- GS Less GS 7 cific survival decreased from 79% at 15 years to 54% at 20 Totals Than 6 GS 6 or Greater years. The 20-year results were also reported by Albertsen pT2a 18.8 (82) 6.7 (29) 9.9 (43) 2.3 (10) et al in an observational cohort followed in the Connecti- pT2b 31.0 (135) 6.7 (29) 15.6 (68) 8.7 (38) cut Tumor Registry.16 This study stratified outcomes by pT2c 24.3 (106) 10.6 (46) 9.6 (42) 4.1 (18) pT3a 19.0 (83) 5.3 (23) 5.0 (22) 8.7 (38) GS and showed that mortality rates ranged dramatically pT3b 2.8 (12) 0.5 (2) 0.9 (4) 1.4 (6) from 6/1,000 person-years for tumors with a GS of 2 to 4 to pT4 4.1 (18) 1.8 (8) 0.9 (4) 1.4 (6) 121/1,000 person-years for tumors with a GS of 8 to 10 Totals 100 (436) 31.4 (137) 42.0 (183) 26.6 (116) with progressive increases in cancer specific mortality through GS 5 to 7. A second Scandinavian study, which is to our knowledge the only randomized trial reported to date of initial surveillance vs radical prostatectomy or any tion by considering the probability of over detection to be active treatment for that matter, showed that after 5 equal to the probability of dying of other causes during the years of followup overall survival diverged between the 2 10 lead time. McGregor et al defined over diagnosis as the 17 11 treatment arms. At a median of 8 years of followup RR detection of nonlethal cancer. In our study over diagno- in the surgery arm compared with that in the watchful sis was based on the pathological features Gleason score waiting arm was 0.74 (95% CI 0.56 to 0.99) for all cause and pathological stage after RRP. PCa pathological stage mortality, 0.56 (95% CI 0.36 to 0.88) for cause specific and Gleason grade are established and important mortality and 0.60 (95% CI 0.42 to 0.86) for distant me- predictors of biochemical failure after radical prostatec- tastases. Furthermore, patients diagnosed at younger tomy.12,13 A statistically significant correlation was noted than 65 years were at 19% risk of cause specific mortality between disease-free survival after RRP, and preoperative on observation, a rate almost twice that in the radical tPSA and final pathological GS in most series. Patients prostatectomy arm. A possible limitation is that this study with a pathological GS of 6 have an excellent progression- enrolled patients with relatively high stage disease. Pa- free survival rate of up to 90%. However, men with PCa tients in the observational study were diagnosed before with GS 7 are at 29% to 43% risk for death from PCa the advent of widespread tPSA screening, as in our study within 20 years.14 population in Tyrol, Austria. Although accrual in the ran- To our knowledge the perception of under diagnosis has domized trial continued until 1999, only 5% of PCas were not been carefully evaluated in patients with prostate screen detected, more than three-quarters were palpable cancer. We evaluated patients with PCa in the low tPSA stage T2 tumors and about half were diagnosed with tPSA group (2.0 to 3.9 ng/ml) in whom disease would not have 10 ng/ml. However, it should be emphasized that studies been detected if the threshold for prostate biopsy was tPSA greater than 4.0 ng/ml. We compared this to the were performed in nonscreened population and lead time amount of so-called over diagnosis. In our study popula- could have biased the results. tion at the low and high tPSA values there was an over Although on balance our results and these articles diagnosis rate of 19.7% and 16.5%, respectively. Thus, the support a role for early PCa diagnosis and treatment, we amount of over diagnosis was not appreciably higher in believe that patients should be carefully selected for ag- the low tPSA group. On the other hand, the incidence of gressive therapy. However, it must be pointed out that our under diagnosed patients was 18.9% and 36.7% in the low results are only based on a screening population in Aus- and high tPSA groups, respectively. Thus, in the higher tria and to our knowledge no data on the value of over and tPSA range there was a 2.5-fold higher proportion of pa- under diagnosis in patients who participated in a tPSA tients with extracapsular disease or positive margins with screening program are yet available. Our data highlight almost the same amount of over diagnosis. concerns regarding the prevalence of PCa over diagnosis. Epstein et al identified a subset of patients with poten- Estimates of the rate of over diagnosis vary considerably tially biological insignificant tumor who might not be fol- from 15% to 84% in recent studies depending on the def- lowed without immediate treatment.5 They defined an insig- inition of over diagnosis used as well as on such factors as nificant tumor as a tumor with a volume of less than 0.2 cm3 the pattern and method of screening, average lead time that is confined to the prostate with a GS of less than 7. They between detection and expected clinical presentation, and 10,11,18 concluded that 16% of nonpalpable (pT1c) PCas diagnosed secular trends in the cancer incidence. However, of by screening techniques are insignificant. In our study the our study population 19.7% and 16.5% met the criteria for incidence of insignificant tumor according to the criteria of over diagnosis for the lower and higher PSA ranges, re- Epstein et al in patients with PCa who had tPSA 2.0 to 10.0 spectively. Our data show that the reported estimates of ng/ml was 8.7%. over diagnosis in the low tPSA group were exaggerated in Patients with PCa who have tPSA 2.0 to 4.0 ng/ml our screening population and there was still a large profit from tPSA screening because they are younger amount of under diagnosis in the tPSA range of 4.0 to 10 (mean age 58 years) and have a life expectancy of more ng/ml. than 20 years. Recent updates to long established obser- There are several implications of our study. It is im- vational studies shed important light on the natural pro- possible to say with certainty in a young man that his gression of PCa and the impact of local therapy on ulti- tumor has been over diagnosed. Currently we cannot es- mate survival. A Scandinavian observational study of PCa timate tumor volume or localization accurately before natural history reported by Johansson et al confirmed treatment with RRP even with computerized tomography, 96 UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER magnetic resonance imaging or ultrasound. On the other hand, little has been said or written about under diagno- Abbreviations and Acronyms sis and at least using our criteria under diagnosis is still Cvol ϭ prostate cancer volume more common than over diagnosis. To avoid under diag- DRE ϭ digital rectal examination ϭ nosis early screening with a low tPSA approach to identify GS Gleason score PCa ϭ prostate cancer aggressive PCa by rapidly increasing tPSA (tPSA veloc- PSA ϭ prostate specific antigen ity), volume of cancer in biopsies or PSA density should be PV ϭ prostate volume used. RRP ϭ radical retropubic prostatectomy Possible consequences of over diagnosis can be mini- tPSA ϭ total PSA mized by a high quality treatment, eg continence preservation and potency by nerve sparing surgery for organ confined tumors. It is apparent that there is a pressing REFERENCES need for biomarkers of PCa that go beyond PSA. Tumors 1. Catalona WJ, Smith DS, Ratliff TL and Basler JW: Detection of associated with a high risk for mortality that occur in the organ-confined prostate cancer is increased through prostate- low tPSA range must be identified sufficiently early to specific antigen-based screening. JAMA 1993; 270: 948. allow the opportunity to provide individually curative 2. Feuer EJ, Merrill RM and Hankey BF: Cancer surveillance se- treatment. It is be necessary to initiate prospective stud- ries: interpreting trends in prostate cancer—part II: cause of ies that allow the validation of new prognostic markers. death misclassification and the recent rise and fall in prostate Prospective analyses of markers require assessment not cancer mortality. J Natl Cancer Inst 1999; 91: 1025. only of their performance characteristics, but also of their 3. Etzioni R, Legler JM, Feuer EJ, Merrill RM, Cronin KA and interaction with constitutional variables. The ultimate Hankey BF: Cancer surveillance series: interpreting trends in prostate cancer—part III: quantifying the link between pop- goal should be the detection of biologically consequential ulation prostate-specific antigen testing and recent declines in disease sufficiently early to allow treatment for cure. prostate cancer mortality. J Natl Cancer Inst 1999; 91: 1033. There are several possible limitations of our study. 4. Newschaffer CJ, Otani K, McDonald MK and Penberthy LT: Since it is known that estimates of under and over diag- Causes of death in elderly prostate cancer patients and in a nosis depend highly on the definition used and these def- comparison nonprostate cancer cohort. J Natl Cancer Inst initions are subject to debate, the current results are valid 2000; 92: 613. in a screening population with the current definitions. 5. Epstein JI, Walsh PC, Carmichael M and Brendler CB: Patho- Concerning margin status, the higher incidence of biologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994; 271: 368. chemical failure in margin positive cases may depend 6. Bartsch G, Horninger W, Klocker H, Reissigl A, Oberaigner W, more on biological factors that, while not directly measur- Schonitzer D et al: Prostate cancer mortality after introduc- able, are better represented by higher stage, grade and tion of prostate-specific antigen mass screening in the Fed- PSA than by margin status. Nevertheless, we included eral State of Tyrol, Austria. Urology 2001; 58: 417. margin status in our definitions of over and under diag- 7. Oesterling JE, Kumamoto Y, Tsukamoto T, Girman CJ, Guess nosis. HA, Masumori N et al: Serum prostate-specific antigen in a Even if it is not possible to be certain whether a posi- community-based population of healthy Japanese men: lower values than for similarly aged white men. Br J Urol tive surgical margin occurred as a result of aggressive 1995; 75: 347. tumor biology and/or an error in surgical technique, mar- 8. Pelzer A, Bektic J, Berger AP, Pallwein L, Halpern EJ, gin status is important, especially in the patients with Horninger W et al: Prostate cancer detection in men with 19 pT3 disease in our study population. Another possible prostate specific antigen 4 to 10 ng/ml using a combined limitation is that the whole study population is of white approach of contrast enhanced color Doppler targeted and European ancestry in Austria. Thus, results may not ap- systematic biopsy. J Urol 2005; 173: 1926. ply to other patient groups. A third possible limitation is 9. Horninger W, Berger AP, Rogatsch H, Gschwendtner A, that there were 2 biopsy techniques from 1996 to 2000 and Steiner H, Niescher M et al: Characteristics of prostate cancers detected at low PSA levels. Prostate 2004; 58: 232. 2000 to 2005. In our study of the influences of the different 10. Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann prostate biopsy techniques at our department there were PH et al: Overdiagnosis due to prostate-specific antigen no differences in the biological behavior of the PCa de- screening: lessons from U.S. prostate cancer incidence tected or of pathological stage.8 Differences were noted in trends J Natl Cancer Inst 2002; 94: 981. detection rates by core. 11. McGregor M, Hanley JA, Boivin JF and McLean RG: Screen- ing for prostate cancer: estimating the magnitude of overdetection. CMAJ 1998; 159: 1368. 12. Han M, Partin AW, Pound CR, Epstein JI and Walsh PC: CONCLUSIONS Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. We evaluated the amount of the possible over and under The 15-year Johns Hopkins experience. Urol Clin North diagnosis of PCa in an asymptomatic screening population Am 2001; 28: 555. with tPSA 2.0 to 3.9 (lower range) and 4.0 to 10.0 ng/ml 13. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD and Walsh PC: Natural history of progression after PSA elevation (higher range). Our data show that the reported estimates of following radical prostatectomy. JAMA 1999; 281: 1591. over diagnosis in the low tPSA group are exaggerated in a 14. Sweat SD, Bergstralh EJ, Slezak J, Blute ML and Zincke H: screening population. Using our criteria prostate cancer un- Competing risk analysis after radical prostatectomy for clin- der diagnosis occurs more frequently than over diagnosis in ically nonmetastatic prostate adenocarcinoma according to the tPSA range of 4.0 to 10 ng/ml. clinical Gleason score and patient age. J Urol 2002; 168: 525. UNDER AND OVER DIAGNOSIS OF PROSTATE CANCER 97

15. Johansson JE, Andren O, Andersson SO, Dickman PW, H. Ballentine Carter Holmberg L, Magnuson A et al: Natural history of early, The James Buchanan Brady Urological Institute localized prostate cancer. JAMA 2004; 291: 2713. Johns Hopkins School of Medicine 16. Albertsen PC, Hanley JA and Fine J: 20-year outcomes follow- Baltimore, Maryland ing conservative management of clinically localized prostate cancer. JAMA 2005; 293: 2095. 1. Holmberg L, Bill-Axelson A, Garmo H, Palmgren J, Norlén BJ, 17. Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson SO, Adami HO et al: Prognostic markers under watchful waiting Bratell S et al: Radical prostatectomy versus watchful waiting in and radical prostatectomy. Hematol Oncol Clin North Am early prostate cancer. N Engl J Med 2005; 352: 1977. 2006; 20: 845. 18. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis 2. Wong YN, Mitra N, Hudes G, Localio R, Schwartz SJ, Wan F RA, Schroder FH et al: Lead times and overdetection due to et al: Survival associated with treatment vs observation of local- prostate-specific antigen screening: estimates from the ized prostate cancer in elderly men. JAMA 2006; 296: 2683. European Randomized Study of Screening for Prostate 3. Cooperberg MR, Moul JW and Carroll PR: The changing face of prostate cancer. J Clin Oncol 2005; 23: 8146. Cancer. J Natl Cancer Inst 2003; 95: 868. 19. Pettus JA, Weight CJ, Thompson CJ, Middleton RG and REPLY BY AUTHORS Stephenson RA: Biochemical failure in men following radical retropubic prostatectomy: impact of surgical margin The “more rigorous outcome of death from prostate cancer to status and location. J Urol, 2004; 172: 129. define life threatening disease” is tantamount to saying that if a man does not die of prostate cancer, he did not have life EDITORIAL COMMENT threatening disease. However, many men do not die of prostate cancer because the life threatening tumor was diagnosed early These authors present data suggesting that prostate cancer and cured. Therefore, this “rigorous” definition is imperfect at under diagnosis occurs more frequently than over diagnosis best, and the claim that “over diagnosis and over treatment of in a screened population using definitions based on cancer nonlife threatening cancer are far more common than suggested” stage and grade. Using the more rigorous outcome of death is not fully supported by facts. The same argument could apply from prostate cancer to define life threatening disease the in regard to the Scandinavian study (reference 1 in comment). over diagnosis and over treatment of nonlife threatening Since the patients in that study had more advanced disease, cancer are far more common than suggested by the current probably fewer were cured of life threatening disease than if study. they had been screened, diagnosed earlier and cured. Thus, the Consider that in men older than 65 years randomized to difference in prostate cancer specific mortality and overall mor- surgery versus no treatment in the Scandinavian Prostate tality between surgery and watchful waiting could have been Cancer Group-4 study (a cohort in which 3 of 4 men had greater in a screen detected population. Therefore, estimates of palpable cancer, of which 95% were not screening detected, the number of patients who would need to undergo treatment and more than half had PSA above 10 ng/ml) 333 would need to prevent a prostate cancer death also may be inaccurate. to undergo surgery to prevent 1 prostate cancer death in 10 In regard to “treatment provides no gain in years of life,” it years.1 These data are consistent with those on the 200 men is noteworthy that a 32.5% decrease in the prostate cancer older than 65 years who would need to undergo treatment to mortality rate has been observed in the SEER (Surveillance, prevent 1 prostate cancer death during 12 years reported in Epidemiology, and End Results) statistics since the beginning an observational study of treatment vs observation.2 of the PSA era. In the Tyrol early detection program, in which Most men in the United States today (more than 85%) 86.6% of men were tested at least once during the 18-year have low to intermediate risk prostate cancer diagnosed at a study period, the number of cancer deaths in 2003, 2004 and median age of 68 years and more than 90% of them undergo 2005 was reduced by 48%, 55% and 54%, respectively (refer- active treatments.3 Thus, I would conclude that for most ence 6 in article). In that study population over diagnosis men diagnosed and treated for prostate cancer in the United (17.6% of patients) was offset not only by the decrease in mortality, but also by treatment morbidity (anatomical radical States today treatment received provides no gain in years of prostatectomy). One year after surgery 95.1% of men had re- life. This may not be the case for younger men, in whom covered urinary continence (no pads), and erectile potency was competing causes of death are much lower. preserved in 78.9% of men younger than 65 years. One could argue, as the authors do, that over diagnosis Finally, clinicians have available many markers of poten- can be balanced by high quality treatment that minimally tially lethal prostate cancer, such as GS, PSa doubling time, impacts quality of life. However, most men with newly di- PSA velocity, PSA based artificial neural networks and family agnosed prostate cancer do not have access to the high history. In the future over diagnosis will be characterized by quality treatment that was delivered by the authors of this computational system biology. Using this approach individu- report. alized prostate cancer diagnosis will identify markers for pa- I believe that prostate cancer mortality decreases in the tients who do not need curative intent and markers of risk of United States represent progress made in large part due to progression after treatment. earlier diagnosis and treatment of disease. However, the Until these new markers for insignificant or aggressive trade-off has been over diagnosis and over treatment of disease are found, early diagnosis through screening combined prostate cancer. Whether this tradeoff is acceptable varies with application of known prognostic parameters, patient age, greatly depending on the individual perspective. Until there medical comorbidity, good clinical judgement and thoughtful is a marker(s) of lethal prostate cancer our current ap- use of the best available treatment options will continue to proach(es) to diagnosis will continue to uncover a greater reduce prostate cancer morbidity and mortality rates. We proportion of cancers that pose no threat to life compared to agree with the critical importance of high quality treatment, as those that do, especially in older men. shown in our study. Clinical Judgment Analysis of the Parameters Used by Consultant Urologists in the Management of Prostate Cancer

Michael G. Clarke,* James R. M. Wilson, Katherine P. Kennedy and Ruaraidh P. MacDonagh From the Department of Urology, Taunton and Somerset Hospital, Taunton, United Kingdom

Purpose: We assessed which clinical parameters consultant urologists use to recommend treatment for early prostate cancer. Materials and Methods: A total of 30 consultant urologists reviewed 70 paper representations of patients with prostate cancer. Each contained 7 commonly available cues, including prostate specific antigen, Gleason grade, rectal examination, magnetic resonance imaging/laparoscopic stage, medical history, patient choice and age, in addition to 2 cues not yet routinely available, that is predicted life expectancy and 10-year survival probability, as calculated using actuarial formulas based on noncancer comorbidity. Consultants indicated how strongly they would recommend radical prostatectomy, radiotherapy with or without hormones, or active surveillance/hormones. Judgment analysis was performed using multiple regression analysis with significance considered at p Յ0.01 to identify which cues consultants had used. Results: Consultants varied in the treatments that they recommended. An average of only 3 of the possible 9 cues was used to formulate decisions. Prostate specific antigen and predicted 10-year survival probability were most commonly used for recommending all 3 treatment options. Patient choice, predicted life expectancy, rectal examination and age were all used infrequently. Consultants were inconsistent in an average of 31.4% of judgments when repeat cases were analyzed with the greatest inconsistency observed when recommending radiotherapy with or without hormones and the least inconsistency when recommending radical prostatectomy. Conclusions: Consultants were inconsistent in their decisions regarding the management of early prostate cancer and they used only a small number of available clinical parameters. Ensuring that all relevant information is available and providing clinicians with further education and training would ensure that treatment decisions become more reliable, appropriate and targeted toward patient choice. Key Words: prostate, prostatic neoplasms, decision making, therapy

he incidence of prostate cancer has increased signifi- probabilistic functionalism, social judgment theory and cog- cantly in recent years following the introduction of nitive continuum theory,2–5 can be used. Real patient or T PSA testing in the 1990s. Earlier detection of the paper patient cases are presented to judges, following which disease has also resulted in a greater number of subclinical the factors or cues used to produce a specific judgment can be cases being identified.1 Several treatment modalities exist, determined through statistical analysis. Therefore, we as- of which the commonest are radical prostatectomy, external sessed which clinical factors are used by consultant urolo- beam radiotherapy, active surveillance/watchful waiting gists to formulate decisions regarding early prostate cancer and hormone therapy, with newer technologies now emerg- and their degree of consistency in decision making. ing. However, each is associated with potential risks and benefits that may significantly impact the quantity and MATERIALS AND METHODS quality of life. The process by which urologists formulate their decisions The design of this study involved 2 key stages, namely in the context of prostate cancer remains unclear. In general questionnaire design and questionnaire completion by con- such decisions are based on a number of objective (eg PSA sultant urologists. and Gleason grade) and subjective (eg predicted life expectancy and patient choice) factors. However, to our knowledge the manner in which these individual factors are used to Questionnaire Design influence final treatment decisions is currently unknown. In The questionnaire was constructed using clinical JA tech- addition, inconsistency may exist among individual clini- niques. A list of only 9 factors (cues) thought to be important cians, whereby similar patients are offered different treat- for making decisions regarding early prostate cancer were ments. To examine these judgments clinical JA, a technique compiled since research suggests that the human short-term Ϯ taking its origins from the psychological methodology of memory can only deal with 7 2 pieces of information at a time.6 These cues included age, PSA, Gleason grade, PR stage, MRI/laparoscopy stage, patient choice and medical history as well as 2 cues not yet routinely available in Submitted for publication November 8, 2006. Supported by AstraZeneca. clinical practice. They were used to predict 10-year survival * Correspondence: (e-mail: [email protected]). probability (the percent chance of surviving 10 years) and

0022-5347/07/1781-0098/0 98 Vol. 178, 98-102, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.029 CLINICAL JUDGMENT ANALYSIS OF PARAMETERS FOR MANAGING PROSTATE CANCER 99 life expectancy (the average number of years that an indi- Questionnaire Completion vidual of a given age is expected to live if current mortality In general the number of judges included in JA studies is rates apply) based on medical history alone. This informa- less important than the number of cases when defining tion was generated in collaboration with a professional ac- statistical power. However, clusters of judgment policies tuary using actuarial tables in association with the numer- may exist, typically 3 to 6 in standard studies and, thus, it is ical rating system of mortality ratios. These evidence based recommended that at least 10 judges per cluster should be actuarial mortality ratios, which are used by the insurance included. Based on these criteria 30 consultant urologists at industry and are continually updated in line with the avail- district general and teaching hospitals across several re- 9 able medical literature, are calculated based on patient age, gions in the United Kingdom completed the questionnaire. smoking habits and comorbidity. Therefore, they can pro- Using SPSS®, version 10.0 multiple stepwise linear regression analysis was performed to ascertain which cues vide an accurate method of life expectancy assessment in were used by consultants to formulate their decisions. patients with several comorbid factors. ANOVA was performed to examine consultant consistency To accurately reflect clinical practice the judgment mea- in decision making. For all analyses p Ͻ0.01 was considered sure incorporated accurate units of measurement with data statistically significant. shown in a similar tabulated format at a multidisciplinary team meeting (fig. 1). Treatment options available were limited to 1) radical prostatectomy, 2) radical radiotherapy RESULTS with or without hormones and 3) active surveillance or hormones. The latter encompassed active surveillance with the Overall consultants varied substantially in the treatments option for later selective radical therapy and watchful wait- that they recommended, more commonly recommending ra- ing with the option for later selective palliative treatment. diotherapy with or without hormones, or active surveillance/ hormones rather than radical prostatectomy. There was also Although other treatments exist, these 3 remain the most variation in the cues used to formulate these decisions with commonly used. Each treatment modality was shown in the most consultants using PSA, MRI stage, Gleason and pre- form of a 10 cm visual analog scale, which was previously dicted 10-year survival probability (fig. 2). Patient choice, used successfully by Kirwan et al to measure physician predicted life expectancy, PR stage and age were used less assessments of patient change in function following treat- 7 frequently. Consultants were an average of 31.4% inconsis- ment. Therefore, for each case a raw score of 0 to 10 cm tent in their judgments when repeat cases were analyzed could be measured to the nearest mm, providing an indica- with the greatest inconsistency when recommending radio- tion of how strongly that particular treatment was advised. therapy with or without hormones and the least inconsis- In addition, a fractional score calculated using the formula, tency when recommending radical prostatectomy. raw score in cm/total of all 3 raw scores in cm, could be measured to assess the strength of conviction when recommending 1 treatment option over another as well as stan- Consultant Treatment Preferences dardize results for comparison among consultants. Using the 10 cm visual analog scale radiotherapy with or A total of 57 cases were constructed using mixed combi- without hormones received the highest mean Ϯ SD raw nations of the 9 available cues. A ratio of 5 cases to 1 cue was score of 6.1 Ϯ 2.5 cm and fractional mean score of 0.4 Ϯ 0.2 required (ie a minimum of 45 cases) to support accurate cm across the 70 cases. Active surveillance or hormone treat- Ϯ multiple regression analysis.8 In addition, 13 replicated ment received a lower mean raw score of only 5.6 2.7 cm Ϯ cases interspersed randomly were included to enable consis- but it accounted for a fractional mean of 0.4 0.2 cm, which tency to be measured. Therefore, the final questionnaire was comparable. Radical prostatectomy received a mean raw score of 2.2 Ϯ 2.7 cm and a fractional mean of 0.1 Ϯ 0.2 cm. contained 70 cases.

Cues Used by Consultants Two main types of correlation were observed between clinical factors or cues (eg PSA) and fractional scores (eg 0.4 cm). They included a linear correlation (direct linear relationship between clinical factor and fractional score) and a quadratic correlation (nonlinear relationship).

Radical Prostatectomy Consultants most commonly used PSA, predicted 10-year survival probability and MRI/laparoscopic stage when recommending this treatment, as indicated by a signiﬁcant correlation with a fractional score in 27, 20 and 19 consultants, respectively (p Ͻ0.01). Consultants more strongly recommended radical prostatectomy when PSA or MRI/laparoscopy stage was low (negative correlation) or the predicted 10-year survival probability was high (positive correlation) (p Ͻ0.01). The mean R2 of these signiﬁcant correlations was FIG. 1. Example of case presented in questionnaire 0.50 (range 0.25 to 0.65). 100 CLINICAL JUDGMENT ANALYSIS OF PARAMETERS FOR MANAGING PROSTATE CANCER

ants were generally most consistent when recommending radical prostatectomy and least consistent when recommending radiotherapy with or without hormones with a mean consistency of 79% (range 44.2% to 98.9%) and 55.5% (range 0% to 89.8%), respectively. Mean consistency for active surveillance or hormones was 68% (range 19.6% to 94.4%) (ﬁg. 3).

DISCUSSION This study provides insight into how consultant urologists use clinical parameters to formulate treatment decisions regarding early prostate cancer and whether their use of these parameters is consistent. The large number of cases FIG. 2. Cues used to advise about 3 treatment options enabled accurate analyses of individual judgment processes and the inclusion of consultants from several United King- dom regions, including district general and teaching hospi- Radiotherapy With or Without Hormones tals, ensured a broad representation of opinion. Consultants most commonly used predicted 10-year survival In recent years the management of early prostate cancer probability, PSA and Gleason grade when recommending has become increasingly complex due to the earlier detection this treatment, as indicated by a significant correlation with of low grade tumors and the introduction of newer treatment the fractional score in 12, 12 and 13, respectively (p Ͻ0.01). techniques. Therefore, it is essential that management de- While most consultants recommended this treatment when cisions be based on a number of objective (eg PSA and predicted 10-year survival probability was high (positive Gleason grade) and subjective parameters (eg predicted life correlation), a subgroup of 4 recommended this treatment expectancy, operative fitness and patient choice). However, when the survival probability was less than 40% to 60% although many such parameters are available, it would ap- (p Ͻ0.01). PSA and Gleason demonstrated positive and neg- pear that only a small number influence consultant deci- 2 ative correlations with consultant decisions. Mean R of sions. In the current study PSA, Gleason grade and these significant correlations was 0.33 (range 0 to 0.61). MRI/laparoscopy stage were the most commonly used parameters. Age was used infrequently with more than two- Active Surveillance or Hormones thirds of consultants using survival probability instead for Consultants most commonly used predicted 10-year survival formulating treatment decisions regarding radical prosta- probability, MRI/laparoscopy stage and PSA when recom- tectomy and active surveillance/hormones. This is surpris- mending this treatment, as indicated by a significant corre- ing since in routine clinical practice age is always available, lation with fractional score in 23, 16 and 10, respectively while survival probability is not. However, in a recent study (p Ͻ0.01). Consultants more strongly recommended active assessing urologist and oncologist predictions of patient 10- surveillance or hormones when MRI/laparoscopy stage and year survival based on age and comorbidity it was noted that PSA were high (positive correlation) or the predicted 10-year clinicians were inaccurate and inconsistent in their estima- survival probability was low (negative correlation). One con- tions with a tendency toward underestimation.10 As such, sultant more strongly recommended this treatment when this has led to a reported age bias among clinicians in the predicted 10-year survival probability was high. Mean advising more radical treatments.11 Therefore, it would R2 of these significant correlations was 0.48 (range 0.06 to seem logical to assess ways of more accurately determining 0.77). survival probability and life expectancy, such that these Patient choice, age and PR stage were used by 7, 9 and 10 data are routinely available to clinicians and patients when consultants, respectively, to recommend treatment. In gen- decisions are being made. eral consultants more strongly recommended radical prostatectomy/radiotherapy with or without hormones as PR stage decreased or patient choice toward radical therapy increased, and they recommended active surveillance/hormones as PR stage or patient choice toward conservative treatment increased. Four consultants used patient choice to recommend more than 1 treatment option. With respect to age, consultants more strongly recommended radiotherapy in patients younger than 65 years and active surveillance/ hormones in those older than 65 to 70 years.

Consultant Consistency Based on the 13 repeat cases consultants demonstrated substantial inconsistency in the treatments that they recommended, although identical cues were presented. Overall mean consistency was 68.6% (range 30.9% to 91.6%), mean- FIG. 3. Mean percent consistency with which consultants advised ing that consultants would make the same treatment deci- treatments based on repeat cases. Horizontal line indicates overall sion 68.6% of the time if faced with identical cases. Consult- mean. CLINICAL JUDGMENT ANALYSIS OF PARAMETERS FOR MANAGING PROSTATE CANCER 101

Patient choice is clearly fundamental to any clinical de- management can have a major part in deciding treatment, a cision and it remains an essential component of patient good correlation was previously shown between real and centered care. Likewise patient choices are often influenced paper cases as a means of assessing clinical decision mak- by clinician treatment recommendations. Therefore, it is ing.7 2) The list of treatment options available did not in- worrying that only 7 consultants appeared to use this cue clude all those currently available in clinical practice. In- when determining treatment options. Such information re- deed, certain patients may have been eligible for multicenter garding patient choice must be obtained from patients and trials or perhaps newer techniques, such as brachytherapy. made available to clinicians. Indeed, it is essential that However, the 3 options provided are those with which con- patient treatment decisions are arrived at using all avail- sultants in the United Kingdom are most familiar, which able information, including subjective and objective clinical was explained before completing the patient case scenarios. parameters. Thus, sufficient information must be provided 3) This study assumed that clinicians would recommend a by clinicians and nurse specialists, and patients must be particular treatment option, while in practice the role of the given time to assimilate this information before making clinician is often to exclude inappropriate treatments, and so treatment choices. offer a range of modalities to patients. 4) Only 9 cues were While the use of clinical parameters appeared to vary provided for consultants to make decisions. In reality there among the consultants in this study, the treatments that may be more cues available, although the limited use of the 9 they recommended also varied. For example, we found that cues in this study would suggest that, even if more were avail- for some individual scenarios 3 consultants recommended able, consultants may still not make use of them. different treatment options. Discussion in a multidisciplinary team setting should aim to address this issue by CONCLUSIONS ensuring a consensus among clinicians. Despite these differences there was an overall trend toward recommending ra- Greater education and training are required to ensure that diotherapy or active surveillance for the 70 cases studied consultants are consistent and use all available parameters with radical prostatectomy the least commonly recom- when formulating treatment decisions. The development of mended therapy. Such differences in treatment preference a tool to more accurately assess life expectancy would facil- have been previously reported and they appear to relate to itate this process. In addition, sufficient information must be patient age, comorbidity, clinician specialty, experience with given to patients by their clinical team to ensure that pa- performing specific procedures or the country of prac- tient choices are appropriate. All available objective and tice.12–14 However, until now little has been reported about subjective parameters, particularly patient choice, must be the influence of more objective factors on clinician decisions. available to clinicians to ensure that patient treatment is In the current study findings may be explained by the inclu- more reliable, appropriate and indicative of patient choices. sion of only a small number of cases with low grade, organ confined disease or less consultant involvement with per- ACKNOWLEDGMENTS forming radical prostatectomy due to the centralization of Paul Ewings provided statistical support. cancer services. Alternatively it may reflect a tendency among current consultants in the United Kingdom to avoid surgery, particularly in light of the evidence supporting active surveillance as an effective treatment option in cases Abbreviations and Acronyms of well confined, low grade disease.15 JA ϭ judgment analysis In addition to differences in treatment advice among con- MRI ϭ magnetic resonance imaging sultants, there was also evidence of inconsistency among PR ϭ per rectum ϭ individual consultants. Thus, an individual consultant may PSA prostate specific antigen recommend different treatment options for the same patient on separate occasions. This is concerning because it suggests REFERENCES that consultants use identical available clinical parameters to generate different decisions. While the reasons for this 1. Quinn M and Babb P: Patterns and trends in prostate cancer are unclear, the parameters used in this study only ap- incidence, survival, prevalence and mortality. 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7. Kirwan JR, Chaput de Saintonge DM, Joyce CR and Currey 12. Desch CE, Penberthy L, Newschaffer CJ, Hillner BE, HL: Clinical judgment in rheumatoid arthritis. I. Rheuma- Whittemore M and Mcclish D: Factors that determine the tologists’ opinions and the development of ‘paper patients’. treatment for local and regional prostate cancer. Med Care Ann Rheum Dis 1983; 42: 644. 1996; 34: 152. 8. Hair JF, Anderson RE and Tatham RL: Multivariate Data 13. Fowler FJ Jr, McNaughton Collins M, Albertsen PC, Zietman Analysis With Readings, 3rd ed. New York: Macmillan Pub- A, Elliott DB and Barry MJ: Comparison of recommenda- lishing Co 1992. tions by urologists and radiation oncologists for treatment 9. Cooksey RW, Freebody P and Bennett AJ: The ecology of spell- of clinically localized prostate cancer. JAMA 2000; 283: ing: a lens model analysis of spelling errors and student 3217. judgements of spelling difﬁculty. Read Psychol Int Quart 14. McNaughton Collins M, Barry MJ, Zietman A, Albertsen PC, 1990; 11: 293. Talcott JA and Walker-Corkery E: United States radiation 10. Wilson JR, Clarke MG, Ewings P, Graham JD and Macdonagh oncologists’ and urologists’ opinions about screening and RP: The assessment of patient life expectancy: how accu- treatment of prostate cancer vary by region. Urology 2002; rate are urologists and oncologists? BJU Int 2005; 95: 794. 60: 628. 11. Alibhai SMH, Krahn MD, Cohen MM, Fleshner NE, Tomlinson 15. Parker C: Active surveillance: towards a new paradigm in the GA and Naglie G: Is there age bias in the treatment of management of early prostate cancer. Lancet Oncol 2004; localized prostate carcinoma? Cancer 2004; 100: 72. 5: 101. Does the Intrarectal Instillation of Lidocaine Gel Before Periprostatic Neurovascular Bundle Block During Transrectal Ultrasound Guided Prostate Biopsies Improve Analgesic Efﬁcacy? A Prospective, Randomized Trial

Tae Jin Yun, Hak Jong Lee,* Seung Hyup Kim, Sang Eun Lee, Jeong Yeon Cho and Chang Kyu Seong From the Department of Radiology, Seoul National University College of Medicine (CKS), Seoul National University Hospital (TJY, SHK, JYC), Seoul and Departments of Radiology (HJL) and Urology (SEL), Seoul National University College of Medicine, Seoul National University Bundang Hospital, Institute of Radiation Medicine, Seoul National University Medical Research Center (HJL) and Clinical Research Institute, Seoul National University Hospital (HJL), Gyeonggi-do, Korea

Purpose: We assessed the analgesic effect of additional intrarectal lidocaine gel instillation during transrectal ultrasound guided prostate biopsy and identified the procedural steps that benefit from lidocaine gel instillation. Materials and Methods: A total of 250 consecutive patients scheduled for prostate biopsy were randomized into 2 groups. In the 125 group 1 patients lidocaine gel was instilled intrarectally before periprostatic neurovascular bundle block. The 125 patients in group 2 underwent only periprostatic neurovascular bundle block without lidocaine gel instillation. Of the 250 patients 90 in group 1 and 113 in group 2, in whom 12 systematic cores were obtained, were enrolled for data analysis. Pain was assessed using a visual analog scale during periprostatic neurovascular bundle block (visual analog scale 1), during biopsy (visual analog scale 2) and 20 minutes after biopsy (visual analog scale 3). Differences between the visual analog scale scores of the 2 groups at each procedural step were evaluated using the unpaired t test with p Ͻ0.05 considered significant. Results: In terms of pain experienced during the 3 procedural steps scores were significantly different during biopsy (p Ͻ0.01). Visual analog scale scores of patients in group 1 showed a tendency to be lower than the scores of patients in group 2 during periprostatic neurovascular bundle block and 20 minutes after biopsy (p ϭ 0.11 and 0.20, respectively). Conclusions: Intrarectal lidocaine gel instillation before periprostatic neurovascular bundle block produces a significant additional analgesic effect during biopsy. The procedure is simple, safe and rapid, and it should be considered in all patients undergoing transrectal ultrasound guided prostate biopsy. Key Words: prostate, biopsy, pain, lidocaine, analgesia

he diagnosis of prostate cancer requires obtaining his- sally confirmed,6,7 some groups recently reported that this tologically malignant tissue from the prostate gland method effectively provides satisfactory anesthesia during T and TRUS guided prostate biopsy is the accepted gold TRUS guided prostate biopsies.5,8–10 standard for obtaining such tissues. Although the analgesic However, to our knowledge questions concerning the pro- efficacy of local anesthesia has not been universally con- cedural steps that benefit from lidocaine gel application firmed,1 many investigators have stressed the importance of have not been addressed. We assessed the additional anal- analgesia as an integral part of the biopsy procedure.2–5 gesic effects of intrarectal lidocaine gel instillation before Soloway and Obek reported that only 1 of 50 men who periprostatic neurovascular bundle block during TRUS received periprostatic local anesthesia experienced signifi- guided prostate biopsy and identified the procedural steps cant discomfort and all who underwent previous biopsies that benefit from lidocaine gel instillation. indicated a dramatic difference after receiving a periprostatic neurovascular bundle block.2 Other investigators have investigated pain reduction us- MATERIALS AND METHODS ing the noninvasive analgesic method of intrarectal lido- This prospective study was approved by our institutional caine gel instillation. Although the analgesic efficacy of in- review board. All patients provided written informed con- trarectal lidocaine gel instillation has not been univer- sent before TRUS guided biopsy.

Submitted for publication November 30, 2006. Patients and Selection Criteria Study received institutional review board approval. During the 8-months from March to October 2004, 250 pa- * Correspondence: Department of Radiology, Seoul National tients who satisﬁed certain criteria were enrolled in this University Bundang Hospital, 300 Gumi-dong, Bundang-gu, study, including patients 1) with increased PSA with or Seongnam-si, Gyeonggi-do 463-707, Korea (telephone: ϩ82-31- 787-7605; FAX: ϩ82-31-787-4011; e-mail: [email protected]. without abnormal digital rectal examination, 2) with lesion ac.kr). suspected malignancy on TRUS with or without abnormal

0022-5347/07/1781-0103/0 103 Vol. 178, 103-106, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.047 104 LIDOCAINE BEFORE PERIPROSTATIC NEUROVASCULAR BUNDLE BLOCK digital rectal examination, 3) without a history of warfarin TABLE 2. VAS scores in 2 study groups treatment or bleeding tendency, or allergy to lidocaine and 4) without a history of TRUS guided prostate biopsy. All pa- Mean Ϯ SD Mean Ϯ SD p Value VAS Group 1 Group 2 (unpaired t test) tients were randomized into 2 groups, including 125 in group 1 and 125 in group 2. Of the 250 patients 90 in group 1 and 113 No. pts 90 113 1 (during block) 4.761 Ϯ 1.62 5.133 Ϯ 1.65 0.11 in group 2, in whom 12 systematic cores biopsy were obtained, 2 (during biopsy) 2.994 Ϯ 2.31 3.903 Ϯ 2.05 Ͻ0.01 were enrolled for data analysis. Of the patients 35 in group 1 3 (20 mins after biopsy) 0.998 Ϯ 1.47 1.257 Ϯ 1.60 0.20 and 12 in group 2 were excluded from study because they underwent greater than 12 systemic cores biopsies. ances between the patients in the 2 groups. Differences in Technique age, serum PSA, total prostate volume and VAS scores in Two uroradiologists (HJL and TJY) performed TRUS guided patients in the 2 groups at each procedural step were eval- biopsies. Imaging was performed using an HDI 5000 ultra- uated with the unpaired t test. Fisher’s exact test was used sound scanner (Philips, Bothell, Washington) equipped with to assess the difference in cancer prevalence in the 2 groups a 9.4 MHz broadband curved array endocavitary transducer. with p Ͻ0.05 considered significant. Before biopsy total prostate volume was measured using the prolate ellipse formula, which is the most commonly RESULTS used method of determining prostate volume. In the 125 group 1 patients 10 ml 2% lidocaine gel were instilled in- Mean patient age, serum PSA, total prostate volume and can- trarectally 10 minutes before periprostatic neurovascular cer prevalence were similar between the 2 groups (table 1). bundle block. For the periprostatic neurovascular bundle Eight patients underwent TRUS guided prostate biopsy due block a total of 8 ml 1% lidocaine were administered at to lesion suspected malignancy on TRUS without increased each basolateral aspect of the prostate 5 minutes before PSA and without abnormal digital rectal examination, and prostate biopsies using a 22 gauge Sonoriject needle (TSK no cancer was detected. Of the other 195 patients malignan- Laboratories, Nagoya, Japan). The 125 group 2 patients cies were confirmed in 70. underwent only periprostatic neurovascular bundle block Table 2 and the figure show VAS scores at each of the 3 without additional lidocaine gel instillation. procedural steps. In terms of the 3 steps mean VAS 2 scores In most patients 12 systematic prostatic cores, including at biopsy were significantly different in groups 1 vs 2 (2.994 Ͻ 6 parasagittal and 6 laterally targeted biopsies covering the vs 3.903, p 0.01). VAS scores in patients with lidocaine gel base, mid zones and apexes, were obtained using an 18 instillation (VAS 2) showed a tendency to be lower than gauge spring loaded Acecut biopsy gun (TSK Laboratories). scores in patients who did not receive instillation during Of the 250 patients 35 in group 1 and 12 in group 2, in whom periprostatic neurovascular bundle block (4.761 vs 5.133, ϭ greater than 12 systematic cores (including additional cores p 0.11) and 20 minutes after biopsy (VAS 3) (0.998 vs ϭ at the area of suspected malignancy) were obtained, were 1.257, p 0.20, table 1 and see figure). excluded from data analysis. All patients were observed for at least a day after the procedure. DISCUSSION The pain associated with TRUS guided prostate biopsy is Data Acquisition composed of 2 major components, which are due to needle During the hospital stay before biopsy patients were in- passage through the prostate, and probe insertion and nee- formed about the TRUS guided biopsy procedures. They were counseled about the need to complete a questionnaire that included a VAS of 0 to 10 cm regarding pain/discomfort, scored as 0—no pain, 1 to 3—mild, 4 to 6—moderate, 7 to 9—severe and 10—unbearable pain. The VAS was used to score the pain experienced 1) during periprostatic neurovascular bundle block (VAS 1), 2) during biopsy procedure (VAS 2) and 3) 20 minutes after biopsy (VAS 3). VAS scores were recorded after each of these 3 procedural steps.

Statistical Analysis Statistical analysis was performed using SPSS®, version 11.0. The Levene tests were used to assess equality of vari-

TABLE 1. Age, PSA and total prostate volume results in 203 patients in 2 study groups Mean Ϯ SD Mean Ϯ SD Parameters Group 1 Group 2 p Value

No. pts/No. Ca 90/34 113/36 0.46 (Fisher’s exact test) Age 66.2 Ϯ 8.6 64.8 Ϯ 10.1 0.28 (unpaired t test) Ϯ Ϯ PSA (ng/ml) 9.69 9.16 9.30 9.26 0.77 (unpaired t test) Median and IQR, and mean and 95% CI VAS scores in 203 patients Total prostate 51.0 Ϯ 23.6 46.9 Ϯ 26.7 0.22 (unpaired t test) Ͻ vol (cc) in 2 study groups. Asterisk indicates unpaired t test p 0.05. PNB, periprostatic neurovascular bundle block. LIDOCAINE BEFORE PERIPROSTATIC NEUROVASCULAR BUNDLE BLOCK 105 dle piercing through the rectal wall. Pain associated with periprostatic neurovascular bundle block. However, there prostate biopsy predominantly arises from the prostatic cap- may be different mechanisms for pain sensing between sule or stroma, which is richly innervated with autonomic probe insertion and needle piercing into the rectum and the fibers. Innervation of the prostate is derived from the caudal analgesic effect of lidocaine gel is indeed limited during roots of S2 to S5 and from the sympathetic chain via the periprostatic neurovascular bundle block. Further investi- presacral and hypogastric neural plexus. Nerve fibers from gations are required. these nerve plexus branch out in the prostatic plexus and VAS scores in patients with lidocaine gel instillation then travel with the prostatic vascular pedicles. It is be- showed a tendency to be lower than scores in patients who lieved that these posterolateral nerve fibers provide the did not receive instillation 20 minutes after the procedure main nerve supply to the prostate.4,11,12 Issa et al suggested (p ϭ 0.20). that pain is generated by direct contact between these In the current study periprostatic neurovascular bundle nerves and it passes through the prostate.8 Based on these block was the most painful step. Although the most painful considerations some investigators attempted periprostatic step during TRUS guided prostate biopsy has not been uni- neurovascular bundle block before prostate biopsy and found versally confirmed, recently investigators reported that the that local anesthesia effectively decreases patient discom- step of initial probe insertion and periprostatic lidocaine fort.2–5 instillation is more painful than biopsy when biopsy is per- However, a neurovascular bundle block cannot reduce formed using periprostatic neurovascular bundle block.13,14 pain associated with the rectal wall during probe insertion The current data corroborate the results of these previous and initial rectal wall piercing. Therefore, a noninvasive studies and urge us to investigate adjuvant analgesic meth- analgesic means of decreasing pain associated with the rec- ods that can decrease the pain associated with periprostatic tal wall is required. neurovascular bundle block. Several investigators have addressed the analgesic effect This study has a few limitations. 1) Two uroradiologists of intrarectal lidocaine gel instillation. Issa8 and Saad9 et al performed prostate biopsies. There could have been variabil- reported significantly less pain vs placebo administration for ity in the pain threshold because of differences in procedure intrarectal lidocaine instillation instead of periprostatic expertise. 2) Although the study design was prospective, neurovascular bundle block. However, periprostatic neuro- pain score questionnaires were not completed in a double- vascular bundle block appears to be superior to intrarectal blind manner. The investigator attitude and the environ- lidocaine gel instillation in terms of analgesic efficacy.5 The mental factors could have influenced the score significantly. use of anesthetic gel before periprostatic neurovascular bun- 3) Although the procedural steps that benefit from gel ap- dle block is not original and it was described by Obek et al.10 plication were investigated, the pain associated with probe The rationale was to avoid or decrease the pain induced by insertion was not measured separately. ultrasound probe insertion and pain from the needle punctures that deliver the local lidocaine-indocaine infiltration. The result of the prospective, randomized study showed a CONCLUSIONS significant difference in overall pain between patients ad- In the current study we evaluated the additional analgesic ministered a combination of periprostatic neurovascular effect of intrarectal lidocaine gel instillation on pain associ- bundle block (2% 5 ml) plus gel (2% 10 ml) and those admin- ated with TRUS guided prostate biopsy during periprostatic istered periprostatic neurovascular bundle block alone. neurovascular bundle block, during biopsy procedure and 20 The results of the current prospective, comparative study minutes after biopsy. Intrarectal lidocaine gel instillation reveal that additional instillation of intrarectal lidocaine gel before periprostatic neurovascular bundle block was found before periprostatic lidocaine infiltration for pain relief dur- to produce an additional analgesic effect with a significant ing the TRUS guided prostate biopsy procedure provides reduction in pain during biopsy. The method is simple, safe effective analgesia. The analgesic effect is greatest and sta- and rapid, and it should be considered in all patients under- tistically significant while taking the biopsy (VAS 2). Con- going transrectal ultrasound guided prostate biopsy. sidering that the biopsy procedure is a combination of repetitive needle piercing of the rectal wall and prostate we presume that the additional instillation of intrarectal lidocaine gel is effective for decreasing pain associated with the Abbreviations and Acronyms needle piercing through the rectal wall and prostate. PSA ϭ prostate specific antigen During periprostatic neurovascular bundle block patients TRUS ϭ transrectal ultrasound who received lidocaine gel instillation (VAS 1) experienced VAS ϭ visual analog scale less pain than patients who did not. However, this trend did not attain significance (p ϭ 0.11). Previously Stirling et al reported that patients with lidocaine gel experienced less REFERENCES pain than those with periprostatic neurovascular bundle block during initial probe insertion (10 ml 2% intrarectal 1. Wu CL, Carter HB, Naqibuddin M and Fleisher LA: The effect lidocaine gel vs 5 ml 1% periprostatic lidocaine infiltration).5 of local anesthetic on patient recovery after transrectal biopsy. Urology 2001; 57: 925. It seems that there were factors that may have contributed 2. Soloway MS and Obek C: Periprostatic local anesthesia before to an underestimation of the true correlation between addi- ultrasound guided prostate biopsy. J Urol 2000; 163: 172. tional gel instillation and pain associated with probe inser- 3. Alavi AS, Soloway MS, Vaidya A, Lynne CM and Gheiler EL: tion into the rectum in the current study, such as an in- Local anesthesia for ultrasound guided prostate biopsy a crease in VAS scores due to psychological factors, including prospective randomized trial comparing 2 methods. J Urol the fear of the initial step, or potential malignancy during 2001; 166: 1343. 106 LIDOCAINE BEFORE PERIPROSTATIC NEUROVASCULAR BUNDLE BLOCK

4. Nash PA, Bruce JE, Indudhara R and Shinohara K: Transrec- gel on pain level in patients undergoing transrectal ul- tal ultrasound guided prostatic nerve blockade eases sys- trasound biopsy. Can J Urol 2002; 9: 1592. tematic needle biopsy of the prostate. J Urol 1996; 155: 607. 10. Obek C, Ozkan B, Tunc B, Can G, Yalcin V and Solok V: 5. Stirling BN, Shockley KF, Carothers GG and Maatman TJ: Comparison of 3 different methods of anesthesia before Comparison of local anesthesia techniques during transrec- transrectal prostate biopsy: a prospective randomized trial. tal ultrasound-guided biopsies. Urology 2002; 60: 89. J Urol 2004; 172: 502. 6. Garcia Mediero JM, Martinez-Pineiro Lorenzo L, Nunez Mora 11. Hollabaugh RS, Steiner MS and Dmochowski RR: Neuroanat- C, de Fata Chillon FR, Cruz Jimeno JL, Alonso y Gregorio omy of the male rhabdosphincter. Urology 1997; 49: 426. S et al: Use of intrarectal lidocaine gel in ultrasound-guided 12. Hollabaugh RS Jr, Dmochowski RR, Kneib TG and Steiner transrectal biopsies of the prostate. Actas Urol Esp 2003; MS. Preservation of the continence nerves during radical 27: 793. retropubic prostatectomy leads to more rapid return of uri- 7. Cevik I, Ozveri H, Dillioglugil O and Akdas A: Lack of effect of nary continence Urology 1998; 51: 960. intrarectal lidocaine for pain control during transrectal prostate biopsy: a randomized prospective study. Eur Urol 13. Inal G, Yazici S, Adsan O, Ozturk B, Kosan M and Cetinkaya 2002; 42: 217. M: Effect of periprostatic nerve blockade before transrectal 8. Issa MM, Bux S, Chun T, Petros JA, Labadia AJ, Anastasia K ultrasound-guided prostate biopsy on patient comfort: a et al: A randomized prospective trial of intrarectal lidocaine randomized placebo controlled study. Int J Urol 2004; 11: for pain control during transrectal prostate biopsy the 148. Emory University experience. J Urol 2000; 164: 397. 14. Schostak M, Christoph F, Muller M, Heicappell R, Goessl G, 9. Saad F, Sabbagh R, McCormack M and Peloquin F: A prospec- Staehler M et al: Optimizing local anesthesia during 10- tive randomized trial comparing lidocaine and lubricating core biopsy of the prostate. Urology 2002; 60: 253. Finasteride Decreases the Risk of Prostatic Intraepithelial Neoplasia

Ian M. Thompson,* M. Scott Lucia,† Mary W. Redman, Amy Darke, Francisco G. La Rosa, Howard L. Parnes, Scott M. Lippman and Charles A. Coltman From the Department of Urology, University of Texas Health Science Center at San Antonio and Southwest Oncology Group, San Antonio, Texas, Department of Pathology, University of Colorado Health Science Center, Denver, Colorado, Fred Hutchinson Cancer Research Center, Seattle, Washington, and Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Purpose: High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia. Materials and Methods: The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups. Results: The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73–0.99, p ϭ 0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56–0.85, p ϭ 0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70–0.89, p Ͻ0.001). Conclusions: Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention. Key Words: prostate, prostatic neoplasms, finasteride, risk, prevention and control

rostate cancer is ubiquitous and clinically evident in prostatic adenocarcinoma.3 The lesion was subsequently 18% of men during their lifetime, and it claims the named PIN and it was initially categorized into 3 grades P lives of 27,350 men annually in the United States.1,2 from low to high. This classiﬁcation was later dichotomized The pathogenesis of the disease is complex, involving a com- into low PIN or HGPIN. Only HGPIN is currently thought bination of constitutional and exposure risk factors. Consid- to be associated with increased prostate cancer risk but erable evidence suggests that prostate cancer is the culmi- whether HGPIN is a prostate cancer precursor is subject to nating manifestation of a cumulative progression of genetic serious debate.4 Many observations suggest that HGPIN is and molecular events. premalignant. It is frequently associated with or may pre- In 1986 McNeal and Bostwick described a lesion in which cede a diagnosis of prostate cancer.4,5 HGPIN shares molec- architecturally benign prostatic glands are lined by cells ular features with prostate cancer4,6,7 and it is morphologi- with cytological changes similar to those in invasive prostate cally similar to prostate cancer.4 cancer and which were found more commonly in men with Based on these data the diagnosis of PIN generally leads to a recommendation for repeat prostate biopsy, which reveals prostate cancer in 22% to 58% of cases Submitted for publication September 26, 2006. (median 25%).8–10 An estimated 115,000 new cases of Supported by Public Health Service Cooperative Agreement HGPIN are diagnosed annually.11,12 In recognition of the Grants CA37429, CA35178 and CA45808 awarded by the National Cancer Institute, Department of Health and Human Services. high risk nature of this disease HGPIN is a target for * Correspondence: Department of Urology, University of Texas prostate cancer chemoprevention and a potential surro- Health Science Center at San Antonio, 7703 Floyd Curl Dr., San gate biomarker for prostate cancer chemoprevention tri- Antonio, Texas 78229 (telephone: 210-567-5643; FAX: 210-567- 6868; e-mail: [email protected]). als. Several large-scale chemoprevention trials are ongo- † Financial interest and/or other relationship with GlaxoSmithKline. ing in men with PIN.13,14

0022-5347/07/1781-0107/0 107 Vol. 178, 107-110, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.012 108 FINASTERIDE DECREASES RISK OF PROSTATIC INTRAEPITHELIAL NEOPLASIA

In 2003 we reported the results of the PCPT.15 In this study we found a 24.8% decrease in the risk of prostate cancer in men randomized to receive finasteride. We report the influence of finasteride in the diagnosis of PIN.

METHODS Patients and Clinical Methods The PCPT tested the 5␣-reductase inhibitor finasteride for decreasing the risk of prostate cancer. The study randomized 18,882 men to receive 5 mg finasteride daily or placebo and followed these men for 7 years with annual digital rectal examination and PSA measurement. Because of the effect of finasteride on PSA, annual PSA values in this treatment group were adjusted upward, initially by a factor of 2.0 and after 4 years of therapy by a factor of 2.3, to ensure an opportunity to receive a biopsy recommendation equal to that of the placebo group.14 If digital rectal examination or PSA was abnormal, prostate biopsy was recommended. Af- ter 7 years all cancer-free subjects were asked to undergo end of study prostate biopsy with a minimum of 6 cores. Consolidated standards of reporting trials diagram of study The diagnosis of prostate cancer or HGPIN was established at the PCPT Core Pathology Laboratory and the pa- DISCUSSION thologist at the participating study site. Disagreements between these 2 pathologists were resolved by a consensus The current study demonstrates that finasteride decreased the diagnosis involving an arbiter pathologist. Study patholo- risk of HGPIN by 21% overall (alone or with cancer), a similar gists were blinded to assigned treatment. degree as the overall 24.8% decrease of cancer in the PCPT. These findings have important implications for the scientific/ Statistical Analysis medical debate on whether HGPIN is involved in multistep Men were considered evaluable for HGPIN if they 1) were prostate carcinogenesis. A body of evidence implicates HGPIN diagnosed with HGPIN or prostate cancer on interim or end of as a precursor to at least a subset of carcinomas. Like prostatic study biopsy, or 2) had a negative end of study biopsy at 7 years carcinoma, HGPIN tends to be multifocal, occurs in the periph- on the study. The chi-square test of homogeneity was used to eral zone of the prostate, increases in extent with advancing compare the proportions of men with HGPIN randomized to age and is more prevalent in prostates that harbor carcinomas placebo vs finasteride. All reported p values are 2-sided. The than in those that do not.4,16,17 A number of genetic and mo- 95% CI for RR estimates were calculated by normal approxi- lecular abnormalities in HGPIN are also found in prostate mation of the log RR and exponentiation of the bounds. Anal- cancer.6,7 These findings support the contention that HGPIN is yses were performed using SAS® or S-Plus®. a pre-invasive intermediate step in prostatic carcinogenesis and, therefore, it may be an ideal target for chemoprevention 18,19 RESULTS studies. Therefore, a prostate cancer chemopreventive agent would decrease the risk of HGPIN as well as prostate Of the 9,459 men randomized to the placebo group 4,886 cancer. The similar effects of finasteride on HGPIN and pros- (52%) were evaluable for the diagnosis of HGPIN during the tate cancer in this study further support the view that HGPIN study. In the finasteride group 4,568 of 9,423 randomized is a stage in prostate carcinogenesis. Finasteride appears to individuals (48%) were similarly evaluable for HGPIN diag- have an effect across a broad spectrum of neoplastic stages, nosis. Of 4,886 evaluable men in the placebo group 3,409 ranging from premalignant to invasive disease. The similar (69.8%) had a negative end of study biopsy and were not effects on HGPIN and prostate cancer risk also support the diagnosed with HGPIN or prostate cancer during the study potential role of HGPIN as a surrogate end point for future course compared to 3,500 of 4,568 evaluable men (76.6%) prostate cancer prevention trials. with a negative end of study biopsy in the finasteride group The findings of finasteride in the PCPT are analogous to (RR 0.77, 95% CI 0.72–0.83, p Ͻ0.0001). Of evaluable men those of tamoxifen in the Breast Cancer Prevention Trial and 347 of 4,886 (7.1%) in the placebo group compared to 276 of the Study of Tamoxifen and Raloxifene, although the latter 4,568 (6.0%) in the finasteride group were diagnosed with was not placebo controlled.20,21 Tamoxifen decreased invasive HGPIN alone (RR 0.85, 95% CI ϭ 0.73–0.99, p ϭ 0.04). and pre-invasive (breast) disease to similar degrees. It is inter- HGPIN was diagnosed concurrently with prostate cancer in esting that raloxifene decreased invasive cancer to the same 223 of 4,886 men (4.6%) in the placebo group vs 144 of 4,568 degree as tamoxifen but the rate of pre-invasive breast disease (3.2%) in the finasteride (HR 0.69, 95% CI 0.56–0.85, was substantially higher with raloxifene. Another interesting p ϭ 0.0004). When HGPIN alone and HGPIN diagnosed parallel between finasteride and tamoxifen is that, despite concurrently with prostate cancer were examined jointly, reducing overall cancer, neither decreased disease generally 570 of 4,886 men (11.7%) in the placebo group were diag- associated with a more aggressive phenotype, including high nosed vs 420 of 4,568 (9.2%) in the finasteride group (HR grade tumors in the case of finasteride and estrogen receptor 0.79, 95% CI 0.70–0.89, p Ͻ0.001). The figure lists these negative disease in the case of tamoxifen. The collective find- data. ings of hormonal therapy, whether in the prostate or breast, FINASTERIDE DECREASES RISK OF PROSTATIC INTRAEPITHELIAL NEOPLASIA 109 raise important clinical and biological issues regarding the 8. Park SJ, Miyake H, Hara I and Eto H: Predictors of prostate effects of this class of agents. cancer on repeat transrectal ultrasound-guided systemic The means by which finasteride decreased prostate can- prostate biopsy. Int J Urol 2003; 10: 68. cer risk in the PCPT are not well understood but the current 9. Shepherd D, Keetch DW, Humphrey PA, Smith DS and Stahl D: Repeat biopsy strategy in men with isolated prostatic study suggests 2 possibilities. 1) Finasteride may decrease intraepithelial neoplasia on prostate needle biopsy. J Urol prostate cancer as a direct result of reducing HGPIN. 2) 1996; 156: 460. Finasteride may target HGPIN as well as prostate cancer, 10. Epstein JI and Herawi M: Prostate needle biopsies containing inducing cases of each to regress or undergo apoptosis. Ei- prostatic intraepithelial neoplasia or atypical foci suspi- ther possibility confers potential benefits for men at risk for cious for carcinoma: implications for patient care. J Urol prostate cancer. A diagnosis of prostate cancer or HGPIN 2006; 175: 820. leads to a series of undesirable events. Despite the medically 11. Bostwick DG and Brawer MK: Prostatic intra-epithelial neo- acceptable option of active surveillance after a diagnosis of plasia and early invasion in prostate cancer. Cancer 1987; 59: 788. prostate cancer, most men elect treatment,22 which is asso- 12. Steiner MS, Raghow S and Neubauer BL: Selective estrogen ciated with significant risks of sexual, urinary and bowel receptor modulators for the chemoprevention of prostate 23,24 toxicities. Undesirable consequences of a diagnosis of cancer. Urology 2001; 57: 68. HGPIN include repeat prostate biopsies, which frequently 13. Nelson MA, Reid M, Duffield-Lillico AJ and Marshall JR: Pros- detect prostate cancer, and anxiety regarding prostate can- tate cancer and selenium. Urol Clin North Am 2002; 29: 67. cer risk.11 These data support the consideration of finas- 14. Steiner MS and Pound CR: Phase IIA clinical trial to test the efficacy teride by men who are at risk for prostate cancer, participate and safety of Toremifene in men with high-grade prostatic intra- in regular screening and desire to decrease the cancer risk. epithelial neoplasia. Clin Prostate Cancer 2003; 2: 24. However, men considering finasteride for prostate cancer 15. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG et al: The influence of finasteride on the develop- prevention must also consider the PCPT finding that a small ment of prostate cancer. N Engl J Med 2003; 349: 215. but significant increase in the diagnosis of high grade pros- 16. Qian J, Wollan P and Bostwick DG: The extent and multi- 14 tate cancer was observed in men receiving finasteride. centricity of high-grade prostatic intraepithelial neoplasia Despite this observed increased risk of high grade disease, in clinically localized prostatic adenocarcinoma. Hum the much greater decrease in the frequency of other tumor Pathol 1997; 28: 143. grades was suggested to have an overall population based 17. Sakr WA, Billis A, Ekman P, Wilt T and Bostwick DG: Epide- benefit.25,26 Ongoing analyses are addressing the true na- miology of high-grade prostatic intraepithelial neoplasia. ture of the finasteride associated risk of HG prostate cancer Scand J Urol Nephrol, suppl., 2000; 205: 11. 18. Clark LC and Marshall JR: Randomized, controlled chemo- and they will further elucidate the risk-benefit ratio of this prevention trials in populations at very high risk for prostate agent for prostate cancer prevention. cancer: elevated prostate specific antigen and high-grade prostatic intraepithelial neoplasia. Urology 2001; 57: 185. 19. Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet R and Doody Abbreviations and Acronyms LA: Surrogate endpoint biomarkers for phase II cancer chemoprevention trials. J Cell Biochem, suppl., 1994; 19: 1. ϭ HGPIN high grade PIN 20. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Ka- ϭ PCPT Prostate Cancer Prevention Trial vanah M, Cronin WM et al: Tamoxifen for prevention of ϭ PIN prostatic intraepithelial neoplasia breast cancer: report of the National Surgical Adjuvant ϭ PSA prostate specific antigen Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 16: 1371. 21. Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN et al: Effects of tamoxifen vs ralox- REFERENCES ifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen 1. American Cancer Society. Cancer Facts and Figures 2006. and Raloxifene (STAR) P-2 Trial. JAMA 2006; 295: 2727. Atlanta: American Cancer Society 2006; p 13. 22. Harlan SR, Cooperberg MR, Elkin EP, Lubeck DP, Meng MV, 2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C and Mehta SS et al: Time trends and characteristics of men choos- Thun MJ: Cancer statistics 2006. CA Cancer J Clin 2006; ing watchful waiting for initial treatment of localized prostate 56: 106. cancer: results from CaPSURE. J Urol 2003; 170: 1804. 3. McNeal JE and Bostwick DG: Intraductal dysplasia: a pre- 23. Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson RA, malignant lesion of the prostate. Hum Pathol 1986; 17: 64. Eley JW et al: Urinary and sexual function after radical pros- 4. Bostwick DG and Qian J: High-grade prostatic intraepithelial tatectomy for clinically localized prostate cancer: the Prostate neoplasia. Mod Pathol 2004; 17: 360. Cancer Outcomes Study. JAMA 2000; 283: 354. 5. Davidson D, Bostwick DG, Qian J, Wollan PC, Oesterling JE, 24. Zietman AL, DeSilvio ML, Slater JD, Rossi CJ, Miller DW, Rudders RA et al: Prostatic intraepithelial neoplasia is a Adams JA et al: Comparison of conventional-dose versus risk factor for adenocarcinoma: predictive accuracy in nee- high-dose conformal radiation therapy in clinically local- dle biopsies. J Urol 1995; 154: 1295. ized adenocarcinoma of the prostate: a randomized con- 6. Emmert-Buck MR, Vocke CD, Pozzatti RO, Duray PH, trolled trial. JAMA 2005; 294: 1233. Jennings SB, Florence CD et al: Allelic loss on chromosome 25. Unger JM, Thompson IM Jr, LeBlanc M, Crowley JJ, Goodman PJ, 8p12-21 in microdissected prostatic intraepithelial neopla- Ford LG et al: Estimated impact of the Prostate Cancer Preven- sia. Cancer Res 1995; 55: 2959. tion Trial on population mortality. Cancer 2005; 103: 1375. 7. Qian J, Bostwick DG, Takahashi S, Borell TJ, Herath JF, 26. Lotan Y, Cadeddu JA, Lee JJ, Roehrborn CG and Lippman Lieber MM et al: Chromosomal anomalies in prostatic intra- SM: Implications of the prostate cancer prevention trial: a epithelial neoplasia and carcinoma detected by fluorescence decision analysis model of survival outcomes. J Clin Oncol in situ hybridization. Cancer Res 1995; 55: 540814. 2005; 23: 1911. 110 FINASTERIDE DECREASES RISK OF PROSTATIC INTRAEPITHELIAL NEOPLASIA

EDITORIAL COMMENT cians in patients with HGPIN? Does finasteride have a similar effect on atypical small acinar proliferation? A pro- HGPIN is frequently associated with prostate cancer and it spective trial evaluating the benefits of a 5␣-reductase in- may be a precursor to malignant transformation. There is hibitor would be necessary to determine the role of such considerable interest in preventing prostate cancer develop- medications in preventing cancer progression in patients ment in men with HGPIN and currently there are 2 ongoing with HGPIN and it appears to be justified. placebo controlled, randomized studies evaluating the benefits of selenium and toremifene, a selective estrogen recep- Yair Lotan tor modulator, for such a cause.1,2 PCPT is a landmark study Department of Urology in prostate cancer chemoprevention that has resulted in University of Texas Southwestern multiple important observations (reference 15 in study). Medical Center at Dallas These authors evaluated the impact of finasteride on the Dallas, Texas prevalence of HGPIN as a secondary end point and found a 1. Price D, Stein B, Sieber P, Tutrone R, Bailen J, Goluboff E et al: significant decrease in HGPIN in the finasteride group in for Toremifene for the prevention of prostate cancer in men with cause and end of study biopsies. They speculated that the high grade prostatic intraepithelial neoplasia: results of a decrease in HGPIN may have a role in the overall reduction double-blind, placebo controlled, phase IIB clinical trial. of prostate cancer in PCPT. J Urol 2006; 176: 965. 2. Marshall JR, Sakr W, Wood D, Berry D, Tangen C, Parker F As with many studies, this one raises many interesting et al: Design and progress of a trial of selenium to prevent questions. How long does it take HGPIN to transform into prostate cancer among men with high-grade prostatic intra- prostate cancer? What is the mechanism by which finas- epithelial neoplasia. Cancer Epidemiol Biomarkers Prev teride reduces HGPIN? Should finasteride be used by clini- 2006; 15: 1479. Effect of Prostate Volume on Tumor Grade in Patients Undergoing Radical Prostatectomy in the Era of Extended Prostatic Biopsies

Wassim Kassouf, Hiroyuki Nakanishi, Atsushi Ochiai, Kara N. Babaian, Patricia Troncoso and R. Joseph Babaian* From the Departments of Urology (WK, AO, KNB, HN, RJB) and Pathology (PT), McGill University Health Center, Montreal, Quebec, Canada, and University of Texas M. D. Anderson Cancer Center, Houston, Texas

Purpose: We investigated the influence of prostate volume on biopsy and prostatectomy Gleason score, the incidence of upgrading and total tumor volume. Materials and Methods: From 1997 to 2004, 247 patients were diagnosed with prostate cancer by multisite extended prostatic biopsy (10 or 11 cores) and underwent radical prostatectomy at our institution without neoadjuvant therapy. Medical records were reviewed to determine patient age at diagnosis, preoperative prostate specific antigen, prostate volume, clinical stage, biopsy Gleason score, pathological stage, prostatectomy Gleason score and total tumor volume. The Mann- Whitney and chi-square tests were used to compare variables among groups and multivariate regression analysis was used to determine predictors of Gleason score. Results: Median patient age was 61 years and median preoperative prostate specific antigen was 5.5 ng/ml. Median prostate volume on transrectal ultrasound was 37 cc. Prostatectomy Gleason score was 6 in 31% of cases, 7 in 57% and 8–9 in 12%. Prostate volume greater than 50 cc was significantly associated with a higher incidence of well differentiated tumors (Gleason score 6) at prostatectomy, that is 17.9% in patients with a prostate volume of 25 cc or less, 28.9% in those with a prostate volume of 25 to 50 cc and 45.3% in those with a prostate volume of greater than 50 cc (p Ͻ0.01). In addition, the incidence of tumor upgrading was significantly lower in patients with a large prostate volume (greater than 50 cc) compared to that in those with a smaller prostate volume (20.8% vs 36.1%, p Ͻ0.05), particularly in the subset with biopsy Gleason score 6 (24% vs 54.1%, p Ͻ0.01). Patients with a large prostate volume (greater than 50 cc) had smaller total tumor volume with a trend toward statistical significance (median total tumor volume 0.86 vs 1.1 cc, p ϭ 0.0631). Conclusions: In the era of extended prostatic biopsies patients with a large prostate volume have a significantly higher incidence of well differentiated tumor at prostatectomy and a lower likelihood of tumor upgrading. Key Words: prostate, prostatic neoplasms, biopsy, prostatectomy, Gleason score

tage migration is well documented with PSA screening concomitantly present when cancer is found. Also, cancers and it has resulted in increased concern regarding the detected in this setting are typically well differentiated and S detection of low volume/low grade prostate cancers of low volume. To further evaluate the effect of prostate size and potential overtreatment. In addition, several groups on tumor grade in the era of extended prostatic biopsies we have evaluated various chemoprevention strategies for pros- investigated the relationships among PV, biopsy and prostate cancer. Recently a large, prospective, randomized che- tatectomy GS, the incidence of upgrading and TTV. moprevention trial (PCPT) showed that finasteride decreases the incidence of prostate cancer by 25%.1 In this trial a lower rate of high grade prostate cancer was found in METHODS prostates that were not downsized by finasteride. It is unclear whether these findings were a result of prostate cancer After obtaining Institutional Review Board approval we biology, which demonstrates a predilection for high grade searched our patient database to identify all men who un- cancer in smaller prostates, or the fact that the incidence of derwent extended prostate biopsy at our institution. Be- upgrading is higher in large glands that have vs have not tween 1997 and 2004 we identified 247 men who underwent been hormonally downsized. Alternatively in larger glands multisite extended biopsy, including 10 cores in 100 and 11 increased PSA, which is the driving factor for biopsy, is cores in 147, as well as radical prostatectomy without neo- commonly the result of benign prostatic hyperplasia that is adjuvant therapy. These patients form the basis of this report. All patients underwent digital rectal examination, PSA Submitted for publication September 12, 2006. determination and transrectal ultrasound of the prostate Study received Institutional Review Board approval. using a 7.5 MHz transducer. PV determined by transrectal * Correspondence and requests for reprints: Department of Urol- ogy, Unit 1373, University of Texas M. D. Anderson Cancer Center, ultrasound was calculated using the formula for elliptical 1515 Holcombe Blvd., Houston, Texas 77030 (telephone: 713-792- volume, ␲/6 ϫ height ϫ width ϫ length. Indications for 3250; FAX: 713-794-5293; e-mail: ([email protected]). biopsy were abnormal digital rectal examination and/or in- For another article on a related topic see page 308. creased PSA. The variables assessed were patient age, pre-

0022-5347/07/1781-0111/0 111 Vol. 178, 111-114, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.013 112 PROSTATE VOLUME AND TUMOR GRADE IN EXTENDED PROSTATIC BIOPSY ERA operative PSA, clinical stage, PV, biopsy and prostatectomy TABLE 2. GS at biopsy and at prostatectomy GS, pathological stage and total TTV. Ten-core biopsy consisted of standard sextant cores and 2 cores each from the No. Prostatectomy GS (%) right and left anterior horns of the peripheral zone. The Biopsy GS 6 7 8–10 Total No.

11-core biopsy consisted of standard sextant cores, 1 core 6 65 (52) 57 (46) 3 (2) 125 each from the right and left anterior horns of the peripheral 7 11 (13) 71 (80) 15 (7) 97 zone, 1 core each from the right and left anterior portion of 8–10 — 13 (65) 12 (35) 25 the transition zone, and 1 core from the midline peripheral Totals 76 (31) 141 (57) 30 (12) 247 zone.2 A single pathologist (PT) analyzed prostatectomy specimens according to a serial step-sectioned method, as previously described.3 TTV was determined by adding the lower in patients with a large PV (greater than 50 cc) com- volume of each cancer focus. Each cancer focus volume (me- pared with that in patients with a smaller PV (20.8% vs dian 3.0 cancer foci per case) was calculated using the pre- 36.1%, p Ͻ0.05), particularly in the subset with biopsy GS 6 viously published formula, 0.4 ϫ length ϫ width ϫ cross- (24% vs 54.1%, p Ͻ0.01, table 3). There was no significant section thickness, ie the number of cross-sections ϫ sectional difference in the incidence of tumor upgrading between large thickness.4 and small prostates in patients with biopsy GS 7 or greater The Mann-Whitney test was used to compare variables tumors. among groups. The chi-square test was used to assess for PV greater than 50 cc was associated with a higher inci- trends. Variables were coded as continuous. Cutoff points dence of well differentiated tumors on prostatectomy GS, were used for prostate volume, which is consistent with that is 45% in patients with a PV of greater than 50 cc vs previously published studies by our group.5–7 The cutoffs for 29% in those with a PV of 25 to 50 cc and 18% in those with prostate volume work well clinically and they are broad a PV of 25 cc or less (p Ͻ0.01), and biopsy GS, that is 55% in enough to incorporate errors in measurements. Multiple patients with a PV of greater than 50 cc vs 41% in those with stepwise logistic regression analysis was used to determine a PV of 25 cc or less (p Ͼ0.05, table 3). The incidence of high the significant predictors of biopsy GS and prostatectomy grade cancer decreased in direct relationship to increasing GS. The forward stepwise method was used for the multiva- PV in biopsy and radical prostatectomy specimens. How- riable model. These statistical analyses were performed us- ever, the incidence of high grade disease in prostatectomy ing SPSS®, version 12.0 with p Ͻ0.05 considered statisti- specimens between men with a PV of 50 cc or less and cally significant. greater than 50 cc was statistically significantly different. Tables 4 and 5 list the predictors of high grade tumors RESULTS and tumor upgrading on univariate and multivariate anal- ϭ Table 1 lists patient clinical and pathological characteris- yses. On multivariate analysis clinical stage (p 0.003) and ϭ tics. Table 2 shows the relationship between prostatectomy PSA (p 0.008) were independently associated with high GS and biopsy GS. The overall incidence of upgrading and grade tumors on biopsy. However, at prostatectomy PV was downgrading was 30% and 10%, respectively. The incidence the best independent predictor of high grade disease. Larger of upgrading was significantly associated with biopsy GS at prostates (greater than 50 cc) were also associated with a a rate of 47% of biopsy GS 6 tumors (60 of 125) compared smaller TTV with a trend toward statistical significance with 15.6% of biopsy GS 7 tumors (15 of 97) (p Ͻ0.05). In compared to prostate glands that were 50 cc or less (median ϭ addition, the incidence of tumor upgrading was significantly TTV 0.86 vs 1.1 cc, p 0.063). TTV and the number of positive cores were significantly associated with biopsy GS and prostatectomy GS (each p Ͻ0.01). TTV was significantly

TABLE 1. Patient clinical and pathological characteristics No. race (%): White 197 (80) TABLE 3. Prostatectomy GS, biopsy GS and tumor Black 32 (13) upgrading by PV Hispanic 13 (5) Asian 5 (2) No. PV (%) No. clinical stage (%): Less Than 25 cc 25–50 cc Greater Than 50 cc T1c 166 (67) T2 80 (32) Prostatectomy GS: T3 1 (0.6) 6 7 (18) 44 (29) 24 (45) No. biopsy GS (%): 7 25 (64) 90 (59) 24 (45) 5–6 125 (50) 8–10 7 (18) 18 (12) 5 (10) 7 97 (40) 8–10 25 (10) Totals 39 (100) 152 (100) 53 (100) No. prostatectomy GS (%): Biopsy GS: 6 76 (31) 6 16 (41) 78 (51) 29 (55) 7 141 (57) 7 18 (46) 60 (39) 18 (34) 8–10 30 (12) 8–10 5 (13) 14 (10) 6 (11) No. pathological stage (%): T2 196 (80) Totals 39 (100) 152 (100) 53 (100) T3a 35 (14) Grading: T3b 10 (4) Downgraded 3 (8) 15 (10) 5 (9) TxNϩ 6 (2) Same 21 (54) 83 (54) 37 (70) Median cc TTV (range) 1.0 (0.4–2.4) Upgraded 15 (38) 54 (36) 11 (21) Median age (range) 61 (56–65) Totals 39 (100) 152 (100) 53 (100) Median ng/ml PSA 5.5 (4.3–8.7) Median cc PV 37 (28.5–48) Complete data missing on 3 patients. PROSTATE VOLUME AND TUMOR GRADE IN EXTENDED PROSTATIC BIOPSY ERA 113

strated that PV is an independent predictor of high grade TABLE 4. Multivariate predictors of high grade tumors ϭ at biopsy and prostatectomy tumor on prostatectomy specimens (p 0.001) with a trend on biopsy specimens (p ϭ 0.052). Large glands were also Biopsy Prostatectomy associated with a smaller TTV compared to smaller glands. OR (95% CI) p Value OR (95% CI) p Value Although this comparison was not statistically significant, it Age 1.044 (1.000–1.090) 0.051 1.038 (0.991–1.087) 0.116 showed a trend (p ϭ 0.063), suggesting a relationship among PV 0.984 (0.968–1.000) 0.052 0.970 (0.954–0.987) 0.001 tumor volume, GS and gland volume. PSA 1.080 (1.020–1.143) 0.008 1.100 (1.022–1.183) 0.011 Clinical stage 2.419 (1.361–4.299) 0.003 1.655 (0.873–3.176) 0.122 Whether these findings were due to real biological differences or mostly PSA driven biopsies in larger glands remains unclear. However, we speculate that it is probably the latter. On a theoretical basis large glands are secondary to associated with tumor upgrading (p Ͻ0.01), although the an enlarged transition zone, which has a lower incidence of number of positive cores was not. prostate cancer, and cancers originating at this location are more commonly well differentiated. We believe that prostate DISCUSSION cancer in large glands is mostly detected by PSA driven biopsies, which explains the higher incidence of lower grade In our study patients with large glands (greater than 50 cc) tumors in large prostates. Although the determination of a had a significantly higher incidence of well differentiated biopsy scheme for large glands was not an objective of this tumor at prostatectomy (p Ͻ0.01), a lower likelihood of tu- study, data suggest that a strategy that increases the num- mor upgrading (p Ͻ0.05) and a similar incidence of down- ber of cores based on a gland size of greater than 50 cc has grading compared to men with smaller glands (50 cc or less). the potential to detect a greater proportion of low volume/ Patients with large glands also had a higher likelihood of low grade cancers for which diagnosis and treatment might well differentiated tumor on biopsy compared to men with be unwarranted since the increase in sampling dispropor- smaller glands. However, the difference with respect to this tionately favors biopsy of the transition zone. variable was not statistically significant. How do our findings support or contradict PCPT results? Our study supports the recent findings by Freedland We found that large glands are associated with a higher et al, in which men with a small prostate were found to have incidence of well differentiated prostate cancer. Hence, if the more advanced disease and be at greater risk for progression larger glands are downsized by finasteride, the chance of after radical prostatectomy than men with large glands.8 finding well differentiated cancer should be higher. On this Several other studies also clearly demonstrated that the basis we do not believe that finasteride identified high grade cancer detection rate is lower in men with a large pros- cancers only due to a sampling effect. Another plausible tate.9,10 A possible explanation is that the PSA level, which explanation is a grading issue caused by the hormonal in- drives biopsy recommendations, is commonly influenced by fluence of finasteride affecting tumor biology or the pathol- gland volume and not by cancer.11 The concomitant presence ogist interpretation. of a large volume, benign gland is a confounding factor in the The uniform use of extended biopsies in our study mini- relationship between PSA and prostate cancer.7,11 Another mized sampling error and its potential influence on tumor explanation could be the suboptimal sampling of large upgrading. This strategy rendered the results more clini- glands at biopsy, particularly in the past, when sextant cally applicable to the practicing urologist because the cur- biopsies were in vogue. However, in patients diagnosed with rent standard of care involves extended biopsies rather than prostate cancer by extended biopsy strategies the influence sextant biopsies. Although some physicians performed 10- of PV on biopsy GS, prostatectomy GS and the incidence of core biopsies and others performed 11-core biopsies, compar- tumor upgrading has not been well evaluated in the litera- ative analysis showed no significant differences between ture. In recent studies larger prostates were associated with men who underwent 10 vs 11-core biopsies with regard to fewer high grade cancers diagnosed by sextant biopsies, age, clinical stage, biopsy GS, prostatectomy GS, tumor up- although the distribution of prostatectomy GS was not as- grading, PV, PSA or tumor volume. As such, it was reason- sociated with PV, suggesting a biopsy grade artifact.12 Be- able to combine the 2 groups to increase statistical power. cause previous groups used sextant biopsies, we evaluated Another strength of this report is that all patients under- the influence of prostate volume on GS and tumor volume in went uniform biopsies and the prostatectomy specimens a contemporary series of men undergoing multisite extended were analyzed by a single genitourinary pathologist. In ad- biopsy, followed by radical prostatectomy. dition, median PV was representative of that of the general We found that patients with a large PV (greater than 50 population, as evidenced by comparison with the PV in men cc) had a significantly lower incidence of tumor upgrading in the placebo group of the PCPT trial (37 vs 34 cc).1 than men with a smaller PV (20.8% vs 36.1%, p Ͻ0.05). The difference was more pronounced in patients with a biopsy GS of 6 (24% vs 54.1%, p Ͻ0.01). This finding was based on TABLE 5. Multivariate predictors of tumor upgrading at the observation that larger prostates are significantly asso- radical prostatectomy ciated with a higher incidence of well differentiated tumors at prostatectomy compared to smaller glands (45.3% vs Variable OR (95% CI) p Value 17.9%, p Ͻ0.01). A recently published report also described Age — Not significant a similar finding.8 These results provide valuable informa- Clinical stage — Not significant PSA 1.082 (1.024–1.143) 0.005 tion and they strongly suggest that the finding of low grade PV 0.976 (0.957–0.995) 0.014 cancer on biopsy is not secondary to a sampling phenome- Biopsy GS 6 3.028 (1.102–8.325) 0.032 non. Furthermore, multivariate analysis of our data demon- Biopsy GS 7 0.382 (0.124–1.180) 0.094 114 PROSTATE VOLUME AND TUMOR GRADE IN EXTENDED PROSTATIC BIOPSY ERA

Despite the pitfalls of the retrospective nature of this 2. Babaian RJ, Toi A, Kamoi K, Troncoso P, Sweet J, Evans R study our findings support the conclusion that prostate size et al: A comparative analysis of sextant and an extended is an important factor in the relationship to GS and the 11-core multisite directed biopsy strategy. J Urol 2000; 163: incidence of upgrading. We believe that this finding is di- 152. rectly related to PV as a confounding variable affecting PSA, 3. Babaian RJ, Troncoso P, Bhadkamkar VA and Johnston DA: Analysis of clinicopathologic factors predicting outcome af- which is currently the primary consideration regarding a ter radical prostatectomy. Cancer 2001; 91: 1414. biopsy recommendation. Therefore, the advisability of in- 4. Chen ME, Johnston D, Reyes AO, Soto CP, Babaian RJ and creasing the number of biopsies based on increasing gland Troncoso P: A streamlined three-dimensional volume esti- size remains unclear because it may further increase the mation method accurately classifies prostate tumors by vol- number of newly diagnosed, low volume/low grade cancers. ume. Am J Surg Pathol 2003; 27: 1291. 5. Ochiai A, Troncoso P, Chen ME, Lloreta J and Babaian RJ: The relationship between tumor volume and the number of pos- CONCLUSIONS itive cores in men undergoing multisite extended biopsy: implication for expectant management. J Urol 2005; 174: In the era of extended prostatic biopsies patients with 2164. large glands have a significantly higher incidence of well 6. Babaian RJ, Miyashita H, Evans RB and Ramirez EI: The differentiated tumor at prostatectomy and a lower likeli- distribution of prostate specific antigen in men without hood of tumor upgrading compared to men with small clinical or pathological evidence of prostate cancer: relation- glands. Because PV is significantly associated with GS ship to gland volume and age. J Urol 1992; 147: 837. and the incidence of tumor upgrading, it may prove to be 7. Chen ME, Troncoso P, Johnston D, Tang K and Babaian RJ: a useful variable when counseling patients with newly Prostate cancer detection: relationship to prostate size. Urology 1999; 53: 764. diagnosed prostate cancer. 8. Freedland SJ, Isaacs WB, Platz EA, Terris MK, Aronson WJ, Amling CL et al: Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after Abbreviations and Acronyms radical prostatectomy: a search database study. J Clin Oncol 2005; 23: 7546. ϭ GS Gleason score 9. Karakiewicz PI, Bazinet M, Aprikian AG, Trudel C, Aronson S, ϭ PCPT Prostate Cancer Prevention Trial Nachabe M et al: Outcome of sextant biopsy according to ϭ PSA prostate specific antigen gland volume. Urology 1997; 49: 55. ϭ PV prostate volume 10. Uzzo RG, Wei JT, Waldbaum RS, Perlmutter AP, Byrne JC ϭ TTV total tumor volume and Vaughan ED Jr: The influence of prostate size on cancer detection. Urology 1995; 46: 831. 11. Kojima M, Troncoso P and Babaian RJ: Influence of non- REFERENCES cancerous prostatic tissue volume on prostate-specific antigen. Urology 1998; 51: 293. 1. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller 12. Kulkarni GS, Al-Azab R, Lockwood G, Toi A, Evans A, GJ, Ford LG et al: The influence of finasteride on the Trachtenberg J et al: Evidence for a biopsy derived grade development of prostate cancer. N Engl J Med 2003; 349: artifact among larger prostate glands. J Urol 2006; 175: 215. 505. Is Routine Digital Rectal Examination Required for the Followup of Prostate Cancer?

Katherine S. Warren* and Jonathan P. McFarlane From the Royal United Hospital, Bath, United Kingdom

Purpose: With more men being diagnosed and radically treated for prostate cancer there is an increasing number of patients requiring followup. A proportion of radically treated patients have recurrence and require early salvage treatment. Tradi- tionally followup involved physical examination, urinalysis, imaging and biopsy. Since the development of the prostate specific antigen assay, followup has largely consisted of digital rectal examination and prostate specific antigen determination. Although digital rectal examination is routinely used, its efficacy for detecting recurrent cancer in the absence of biochemical evidence of disease progression was questioned in recent studies. Materials and Methods: We performed a literature search using the key words digital rectal examination, per rectal examination, radical prostatectomy and radical radiotherapy, and cross-referenced all results. Results: The literature that supports digital rectal examination as part of patient followup after radical prostatectomy is based on case studies and it is less applicable with more sensitive prostate specific antigen assays. In almost 5,000 patients after prostatectomy a prostate specific antigen increase reliably preceded disease recurrence, making digital rectal examination superfluous to requirements. No published literature supports repeat digital rectal examination after radical radiotherapy. Conclusions: Prostate specific antigen allows the early detection of disease recurrence. Although digital rectal examination is widely used to follow patients, contemporary studies consistently show that disease progression does not occur in the absence of increasing prostate specific antigen. This suggests that remote followup of patients with prostate specific antigen alone is a safe practice, although caution should be exercised in those with higher grade tumors, which may not produce significant amounts of prostate specific antigen. Key Words: prostate, prostate-specific antigen, prostatic neoplasms, digital rectal examination, prostatectomy

fter definitive treatment for prostate cancer a propor- ticed followup examination and it is recommended by tion of patients have recurrent disease. Potentially several sources for patients after undergoing definitive A curative salvage treatments are now available, pro- therapy.3–6 A survey of American Urological Association vided that recurrence is detected at an early stage, and so urologists to determine followup practice after radical pros- these men require careful followup. Traditionally followup tatectomy showed that most of the 1,050 respondents rec- involved physical examination, urinalysis, biopsy and imag- ommended an office visit with DRE, PSA and urinalysis 3 or ing (bone scans, radiographs, magnetic resonance imaging 4 times a year for year 1, tapering off to once or twice yearly and computerized tomography) but latterly it is usually beyond this. These investigations were more frequently per- achieved with PSA measurement and DRE. formed in patients with T3 disease.7 DRE has a place in disease detection and staging. It is The increasing number of men being diagnosed with and currently recommended as an annual screening test along treated for early prostate cancer worldwide is causing a with PSA for men older than 50 years without other risk large increase in the number of patients being followed. This factors by the American Urological Association.1 However, is becoming a logistical and financial burden for urology the European trial to assess screening for prostate cancer departments. Although DRE is routinely performed, its ef- changed the screening protocol when it was found that DRE ficacy for detecting disease recurrence in men with no symp- in patients with low PSA (less than 3 ng/ml) was an ineffi- tomatic or biochemical evidence of disease progression was cient screening tool, in that 289 DREs were needed to detect questioned by some recent studies. It is also an intrusive 1 clinically significant tumor.2 examination but there are sparse data on the acceptability of Repeat DRE after radical treatment or as part of a sur- DRE to patients. A community based screening trial showed veillance protocol allows the detection of palpable abnormal- that 568 of 856 men 55 to 70 years old accepted an invitation ities in the prostate or prostatic fossa that may suggest local for screening PSA and DRE. Of the 448 patients who replied recurrence or disease progression. It is a commonly prac- to a postal questionnaire 95% declared that they would be prepared to undergo the screening exercise again.8

Submitted for publication May 12, 2006. MATERIALS AND METHODS * Correspondence: Urology Department, Royal United Hospital, Bath BA1 3HG, United Kingdom (e-mail: katherinewarren@ We performed a literature search to evaluate the value of hotmail.com). DRE in the followup of men with prostate cancer. We used

0022-5347/07/1781-0115/0 115 Vol. 178, 115-119, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.010 116 ROUTINE DIGITAL RECTAL EXAMINATION AND PROSTATE CANCER FOLLOWUP the key words digital rectal examination, per rectal exami- ng/ml as well as tumor involving each lobe, extensive cap- nation, radical prostatectomy, radical radiotherapy and sular penetration and seminal vesicle involvement. Thus, it prostate cancer. We cross-referenced all articles to ensure a is likely that this tumor was not producing much PSA. Two comprehensive review and set no time limit on our search. cases showed poorly differentiated disease at diagnosis. It is possible that some of these tumors underwent dedifferenti- RESULTS ation to a more aggressive form following treatment or that there were undetected small volume, high grade tumors in Followup of Patients After Radical Prostatectomy the radical prostatectomy specimen. Alternatively the PSA After radical prostatectomy if all prostatic tissue is removed, assays may have been unreliable or insufficiently sensitive. 9 PSA should decrease to undetectable levels within 21 days. Regardless of the mechanism, this seems to be a rare Detectable PSA after radical prostatectomy indicates resid- event. In the 2 retrospective series only 0.5% of men had ual disease but it cannot differentiate between local and recurrence with undetectable PSA. Moreover, DRE was the systemic recurrence. Detectable PSA precedes clinical dis- only indicator of recurrence in only 3 men. The question is ease recurrence by months to years.10 Oefelein et al found whether DRE is really a worthwhile followup examination that PSA lead time was related to Gleason score, including for such a small pickup rate and an equivocal survival ad- 4.5, 2.4 and 1.3 years for Gleason 5–6, 7 and 8, respectively.5 vantage. In the early days of PSA there was some skepticism about These reports, except the Roemeling case study,11 are its ability to reliably predict recurrent disease before this now relatively old and the detectable threshold level of PSA was clinically detectable. There were a few case reports in each case is higher than that in routine practice today. It describing disease recurrence after radical prostatectomy is likely that a lower PSA detection limit would continue to despite undetectable PSA (table 1).3,4,11 In addition, 2 large, decrease the number of such cases. This is borne out by more retrospective series described 1,022 men who underwent recent published studies examining PSA after radical pros- radical prostatectomy, of whom 210 showed disease recur- tatectomy (table 2).9,10,13–16 rence. In the majority an increase in PSA was the first sign A total of almost 5,000 patients of recurrence but 6 men had recurrence with undetectable were followed after radical prostatectomy in these studies PSA (table 1).5,6 Each of these 9 cases represents an inter- and there were no instances of disease recurrence with un- esting phenomenon in which local or distant clinical recur- detectable PSA. Several of these studies showed abnormal rence preceded an increase in serum PSA. The investigators DRE rates of up to 12% but there were no cases of positive advocate the importance of continued clinical evaluation, DRE due to tumor with undetectable PSA. All 4 patients in including PSA and DRE. the study by Obek et al who had abnormal DRE were at high It is recognized that some poorly differentiated tumors risk for disease recurrence, including 1 with a preoperative 10 produce little or no PSA.12 Only 1 of the 9 patients was truly PSA of 62 ng/ml and 3 of 4 with a final Gleason score of 8. at low risk with the remaining 8 having risk factors for Three of the 4 men had positive surgical margins and all had recurrence, such as high preoperative PSA, high Gleason extracapsular invasion. Pound et al included 47 patients at score, positive surgical margins, seminal vesicles or lymph high risk but despite this the disease recurrence rates were node involvement. It is possible that some well or moder- low and no patient had disease recurrence in the absence of 9 ately differentiated tumors produced little PSA and under- a PSA increase. A total of 57 patients had local recurrence, went de-differentiation to a more aggressive form following including 29 in whom it occurred after 5 years. Lattouf and treatment, or there were undetected small volume high Saad found that detectable PSA preceded positive DRE find- grade tumors in the radical prostatectomy specimen. Alter- ings by 14 months.13 natively, the PSA assays may have been unreliable or insuf- Laboratory analysis of PSA levels is less variable than ficiently sensitive. human interpretation of findings on DRE. After radical pros- The most recent case describing undetectable PSA with tatectomy there is a wide range of palpable transrectal con- local recurrence found on DRE years after radical prostatec- tours, making DRE interpretation difficult. Lightner et al tomy11 raises concern that it is still possible in the ultrasen- followed 63 patients with biochemical relapse after radical sitive PSA era to have disease recurrence without increasing retropubic prostatectomy.15 In the 57 men without metasta- PSA. However, this patient had an initial PSA of only 1.3 ses there was poor correlation between DRE findings and

TABLE 1. Disease progression with undetectable PSA after radical prostatectomy DRE PSA References Disease Parameters Recurrence Detection Method Findings (ng/ml)

Goldrath and Messing3 Moderately differentiated DRE Abnormal Less than 0.05 Goldrath and Messing3 Poorly differentiated, pos lymph nodes Bone scan Normal Less than 0.05 Takayama et al4 Gleason 5, preop PSA 30 ng/ml Coccygeal pain, pos biopsy Normal Less than 0.03 Oefelein et al5 Gleason 6, T2b, PSA 10.8 ng/ml, pos DRE, bone scan Abnormal Less than 0.03 margins ϩ seminal vesicles Oefelein et al5 Gleason 6, organ conﬁned Lung metastases on chest x-ray Normal Less than 0.05 pos for prostate adenoca Oefelein et al5 Gleason 9, organ conﬁned DRE Abnormal Less than 0.03 Leibman et al6 Gleason 7, T2c, preop PSA 20 ng/ml Lung metastases on chest x-ray Normal Less than 0.04 pos for prostate adenoca Leibman et al6 Gleason 7, T2b, extracapsular Thigh pain, bone scan Normal Less than 0.04 Roemeling et al11 Gleason 7, T3, preop PSA 1.3 ng/ml, extensive DRE Abnormal Less than 0.02 capsular penetration ϩ pos seminal vesicles ROUTINE DIGITAL RECTAL EXAMINATION AND PROSTATE CANCER FOLLOWUP 117

TABLE 2. Followup of PSA and disease recurrence after radical prostatectomy % Abnormal DRE Undetectable % ϩ References No. Pts Followup PSA (ng/ml) Recurrence Av PSA at Recurrence (ng/ml) Recurrence

Lightner et al15 63* 6–240 Mos Less than 0.04 100 10 (metastasis), 5.6 (local) Partin et al14 955 12–120 Mos (median 53) Less than 0.02 19.4 Pound et al9 1,916 5.5 Ϯ 3.5 Yrs Less than 0.02 7.7 28.6 (metastasis), 5.8 (local) Obek et al10 501 25 Ϯ 20 Mos Less than 0.02 14.4 0.8 Lattouf and Saad13 423 Retrospective Less than 0.03 7.3 4.35 7.3 Chaplin et al16 1,118 3 Mos–15 yrs (median 4 yrs) Less than 0.01 4.7 2.8 9 No undetectable PSA associated with disease recurrence. * Biochemical relapse in all.

the biopsy result. A total of 30 control patients who had published on the Internet looked at the effects of PSA and undetectable PSA after radical prostatectomy underwent DRE on the followup of 194 patients who underwent hor- biopsy, which was negative in all. Of these men 18 had monal manipulation (68), orchiectomy (8), radiotherapy with induration to some extent on DRE that was suspicious for hormonal manipulation (15), radical radiotherapy (48), recurrence. There was significant disagreement in DRE brachytherapy (1) and active surveillance (33).19 Increasing scoring among urologists. Published data show that it is PSA was the most common factor resulting in a change of difficult to justify this invasive examination, which has con- management. In only 2 cases did DRE findings alter man- siderable interobserver variability in the absence of PSA agement and this was only to shorten the interval between evidence of recurrence. followup visits. Further studies would be required before DRE can confidently be eliminated as a followup examina- Followup of Patients After Radiotherapy tion in this group of patients. Two recent studies suggest that routine DRE after radiotherapy in the absence of increasing PSA is unnecessary. DISCUSSION Despite this, it is still often performed. Johnstone et al studied 235 patients after definitive ra- The incidence of biochemical recurrence after radical pros- diotherapy, including 194 after radiotherapy only, 39 after tatectomy is up to 35% in the years following surgery with radical retropubic prostatectomy and radiotherapy, and 2 95% of recurrences developing in the first 5 years.13 After 17 after cryotherapy. Patients were followed with PSA and radiotherapy the 10-year rate of local disease progression is DRE. A total of 1,544 DREs were performed, of which 81% approximately 20%.20 Patients who are likely to be at high were normal. Only 5.6% of all examinations provided infor- risk for recurrence are those with poorly differentiated dis- mation that was not previously known and most was related ease, high pathological stage, positive surgical margins, pos- to bleeding rather than cancer recurrence. Eight new nod- itive lymph nodes and high preoperative PSA.21 Salvage ules were found for a frequency of 0.5%. Therefore, 200 treatment is possible with radiotherapy for surgical failures DREs were performed to find a single recurrent prostate and cryotherapy or salvage prostatectomy for recurrence nodule and all were in the context of increasing PSA. Thus, following radiotherapy. the overall yield of DRE after radiotherapy is negligible with PSA has revolutionized the diagnosis and followup of respect to cancer recurrence. prostate cancer. It is one of the best markers in oncology, Doneux et al studied 899 patients undergoing radio- allowing disease surveillance using only a blood test. Detect- therapy and neoadjuvant hormone therapy for clinically able PSA precedes clinical failure by months to years.5,10 18 localized prostate cancer. Followup with PSA and DRE Originally commercially available PSA assays had a disease detected recurrence in 39 patients. Mean time from con- detection limit of between 0.1 and 0.3 ng/ml. In 1993 Stamey firmation of PSA failure to detectable local recurrence was et al studied an assay with a biological detection limit of 0.07 10 months. The lowest PSA with recurrence was 1.7 ng/ml. ng/ml.22 Compared to the standard test at that time (greater No recurrences were detected by DRE alone. than 0.3 ng/ml) the new assay detected recurrent cancer an Biochemical recurrence reliably precedes local recurrence average of 310 days earlier. Now there are second-genera- and positive DRE findings after external beam radiotherapy. tion ultrasensitive assays that measure PSA concentrations There are no data in favor of performing DRE after radical well below 0.1 ng/ml. Yu et al found that using an ultrasen- radiotherapy. Therefore, it may be safely restricted to sitive assay it was possible to detect relapses after treatment asymptomatic patients with increasing PSA or patients with 14 and 29 months earlier than using the 0.1 and 0.3 ng/ml symptoms compatible with local recurrence after radiother- limits, respectively.23 apy. There is no published information about the usefulness Early in the PSA era several groups advocated regular of DRE following brachytherapy but it seems likely that the DRE after radical prostatectomy to identify a small cohort of same is true. patients with disease recurrence despite undetectable PSA. However, in the 2 decades since then, only 9 such cases have Followup of Nondefinitively Treated Prostate Cancer been reported, of which only 4 were identified by DRE. There There is little information on the usefulness of routine DRE is only 1 reported case of disease recurrence with undetect- in patients on surveillance or those being treated with hor- able PSA using modern PSA assays but this was likely a mones. It is common practice to review these cases regularly nonPSA producing tumor. In addition, it is not unusual to with sequential DRE and PSA estimation. A small study have abnormal DRE findings despite undetectable PSA. Al- 118 ROUTINE DIGITAL RECTAL EXAMINATION AND PROSTATE CANCER FOLLOWUP though this was never shown to herald disease recurrence in tatectomy DRE can safely be omitted. Regular PSA estima- modern series, it may prompt unnecessary investigations, tion should be performed to assess disease recurrence. including biopsy. Increasing PSA should trigger investigations to look for There is less information on the usefulness of DRE after recurrence, including DRE. Followup should concentrate on radiotherapy but 2 series of more than 1,100 patients the functional and emotional recovery of the patient. After showed no disease recurrence detected by DRE in the ab- this complete remote followup with PSA alone is acceptable. sence of increasing PSA. All published evidence in the last 2) Patients with Gleason 8–10 tumors should be followed decade suggests that DRE is not useful in the followup of with regular DRE because these tumors rarely do not se- patients with prostate cancer following radical treatment. crete PSA. In addition, followup of nonPSA producing tu- There is virtually no published information about the mors of any grade should include DRE. 3) There are no usefulness of DRE in patients on surveillance or hormonal published data on DRE after brachytherapy. Because the treatment. Although it seems likely that PSA will prove to biological effects of external beam radiotherapy and brachy- be a superior test in the majority of these patients, DRE therapy are similar, one might expect DRE to have little must still be recommended until more studies are per- value following brachytherapy but until data are forthcom- formed. DRE should also be regularly performed in the fol- ing regular DRE is recommended. 4) There are little pub- lowup of men with any poorly differentiated tumor that is lished data on DRE in patients on active surveillance and it suspected of not producing PSA. should continue to be performed in this group. 5) There are In some health care systems physicians are reimbursed sparse published data on the usefulness of DRE in patients for regular followup visits. Physical examinations may be on hormonal therapy. However, it is our view that in this associated with higher reimbursement rates, which is a con- palliative situation there would be no justification in chang- sideration in understanding why DRE is still widely done. ing therapy based purely on DRE findings. More robust However, we must justify our practice using evidence based evidence of disease progression would be required, such as medicine and the literature published in peer reviewed jour- new symptoms or increasing PSA. From a practical stand- nals does little to support the usefulness of DRE as a fol- point regular DRE is not required in the absence of other lowup tool for treated prostate cancer. signs of disease progression.

Remote Followup CONCLUSIONS In most developed countries there has been a sharp increase in the number of men diagnosed with and treated for pros- With modern PSA assays DRE is unnecessary in the fol- tate cancer in the last 15 years. To accommodate the larger lowup of the majority of patients following radical treatment number of patients requiring followup at some centers ini- for prostate cancer. Poorly differentiated tumors may not tiatives have been developed, such as nurse run PSA clinics. secrete PSA reliably, and so they should be followed more Studies show that such clinics are acceptable to patients and carefully. For most patients on surveillance protocols or they may be preferred as well as being safe and cost-effec- hormonal treatment DRE is unlikely to provide useful addi- 24 tive. However, even these clinics can be stretched to ca- tional clinical information but further clinical studies are pacity and methods of remote followup are evolving. This is needed in this group. Many of the increasing number of usually implemented following radical treatment after post- patients diagnosed and treated for prostate cancer could be treatment side effects are addressed or for patients with followed remotely with sequential PSA measurements, sav- stable disease on surveillance or hormonal therapy. After ing money and decreasing the outpatient burden on second- posttreatment urinary, bowel and sexual function problems ary and tertiary care with no compromise of patient care. are addressed and stabilized patients may be followed using PSA alone. Remote followup using telephone clinics and computer software has been described.25–27 Abbreviations and Acronyms Telephone clinics rely on regular contact between the patient and a clinician or specialist nurse. A consultation is DRE ϭ digital rectal examination ϭ performed via telephone to assess any symptoms or prob- PSA prostate specific antigen lems, usually in combination with PSA testing in primary care. Studies show high levels of patient satisfaction with such arrangements.25,26 REFERENCES Computerized followup uses a central database that 1. Prostate-specific antigen (PSA) best practice policy. American stores demographic and disease related information, includ- Urological Association (AUA). Oncology 2000; 14: 267. 27 ing sequential PSA values. PSA tests are performed at 2. Roobol MJ, Kirkels WJ and Schroder FH: Features and pre- regular intervals by a primary care physician and the re- liminary results of the Dutch centre of the ERSPC (Rotter- sults fed into the database to allow a clinician to decide dam, the Netherlands). BJU Int 2003; 92: 48. whether it is safe to leave the patient in the community or 3. Goldrath DE and Messing EM: Prostate specific antigen: not whether he should be recalled for outpatient review. Pa- detectable despite tumor progression after radical prosta- tients are warned about symptoms that may indicate dis- tectomy. J Urol 1989; 142: 1082. 4. Takayama TK, Krieger JN, True LD and Lange PH: Recurrent ease progression and given contact details to discuss any prostate cancer despite undetectable prostate specific anti- problems. gen. J Urol 1992; 148: 1541. 5. Oefelein MG, Smith N, Carter M, Dalton D and Schaeffer A: Recommendations for Followup The incidence of prostate cancer progression with undetect- Based on the published literature we suggest certain recom- able serum prostate specific antigen in a series of 394 rad- mendations. 1) After radical radiotherapy and radical pros- ical prostatectomies. J Urol 1995; 154: 2128. ROUTINE DIGITAL RECTAL EXAMINATION AND PROSTATE CANCER FOLLOWUP 119

6. Leibman BD, Dillioglugil O, Wheeler TM and Scardino PT: 17. Johnstone PA, McFarland JT, Riffenburgh RH and Amling CL: Distant metastasis after radical prostatectomy in patients Efficacy of digital rectal examination after radiotherapy for without an elevated serum prostate specific antigen level. prostate cancer. J Urol 2001; 166: 1684. Cancer 1995; 76: 2530. 18. Doneux A, Parker CC, Norman A, Eeles R, Howich A, Huddart 7. Oh J, Colberg JW, Ornstein DK, Johnson ET, Chan D, Virgo R et al: The utility of digital rectal examination after rad- KS et al: Current follow up strategies after radical prosta- ical radiotherapy for prostate cancer. Clin Oncol (R Coll tectomy: a survey of American Urological Association urol- Radiol) 2004; 17: 172. ogists. J Urol 1999; 161: 520. 19. Ragavan N, Sangar VK, Gupta S, Herdman J, Matanhelia SS, 8. Kirby RS, Kirby MG, Feneley MR, McNicholas T, McLean A Watson ME et al: Is DRE essential for the follow up of and Webb JA: Screening for carcinoma of the prostate: a GP prostate cancer patients? A prospective audit of 194 pa- based study. Br J Urol 1994; 74: 64. tients. BMC Urol 2005; 5: 1. 9. Pound CR, Chistens-Barry OW, Gurganus RT, Partin AW and 20. Coen JJ, Zietman AL, Thakral H and Shipley WU: Radical Walsh PC: Digital rectal examination and imaging studies are radiation for localized prostate cancer: local persistence of unnecessary in men with undetectable prostate specific anti- disease results in a late wave of metastases. J Clin Oncol gen following radical prostatectomy. J Urol 1999; 162: 1337. 2002; 20: 3199. 10. Obek C, Neulander E, Sadek S and Soloway MS: Is there a role 21. Grossfeld GD, Chang JJ, Broering JM, Miller DP, Yu J, Flanders S et al: Impact of positive surgical margins on for digital rectal examination in the followup of patients prostate cancer recurrence and the use of secondary cancer after radical prostatectomy? J Urol 1999; 162: 762. treatment: data from the CaPSURE database. J Urol 2000; 11. Roemeling S, van Leenders GJ and Schroder FH: Very late 163: 1171. local recurrence after surgery for prostate cancer unaccom- 22. Stamey TA, Graves HC, Wehner N, Ferrari M and Freiha FS: panied by detectable PSA levels. Prostate Cancer Prostatic Early detection of residual prostate cancer after radical Dis 2006; 9: 192. prostatectomy by an ultrasensitive assay for prostate spe- 12. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, cific antigen. J Urol 1993; 149: 787. Rock RC et al: Prostate specific antigen in the staging of 23. Yu H, Diamandis EP, Prestigiacomo AF and Stamey TA: localized prostate cancer: influence of tumor differentiation, Ultrasensitive assay of prostate-specific antigen used for tumor volume and benign hyperplasia. J Urol 1990; 143: early detection of prostate cancer relapse and estimation 747. of tumor-doubling time after radical prostatectomy. Clin 13. Lattouf JB and Saad F: Digital rectal exam following prosta- Chem 1995; 41: 430. tectomy: is it still necessary with the use of PSA? Eur Urol 24. Faithfull S, Corner J, Meyer L, Huddart R and Dearnaley D: 2003; 43: 333. Evaluation of nurse-led follow up for patients undergoing 14. Partin AW, Pound CR, Clemens JQ, Epstein JI and Walsh PC: pelvic radiotherapy. Br J Cancer 2001; 85: 1853. Serum PSA after anatomic radical prostatectomy. The 25. Booker J, Eardley A, Cowan R, Logue J, Wylie J and Caress Johns Hopkins experience after 10 years. Urol Clin North AL: Telephone first post-intervention follow-up for men Am 1993; 20: 713. who have had radical radiotherapy to the prostate: evalu- 15. Lightner DJ, Lange PH, Reddy PK and Moore L: Prostate ation of a novel service delivery approach. Eur J Oncol Nurs specific antigen and local recurrence after radical prosta- 2000; 8: 325. tectomy. J Urol 1990; 144: 921. 26. Helgesen F, Andersson SO, Gustafsson O, Varenhorst E, 16. Chaplin BJ, Wildhagen MF, Schroder FH, Kirkels WJ and Goben B, Carnock S et al: Follow-up of prostate cancer Bangma CH: Digital rectal examination is no longer neces- patients by on-demand contacts with a specialist nurse: a sary in the routine follow-up of men with undetectable randomized study. Scand J Urol Nephrol 2000; 34: 55. prostate specific antigen after radical prostatectomy: the 27. PSA Tracker. Available at www.psatracker.co.uk. Accessed implications for follow-up. Eur Urol 2005; 48: 906. March 31, 2006. Standard Versus Limited Pelvic Lymph Node Dissection for Prostate Cancer in Patients With a Predicted Probability of Nodal Metastasis Greater Than 1%

Karim Touijer,* Farhang Rabbani,* Javier Romero Otero,* Fernando P. Secin,* James A. Eastham,† Peter T. Scardino‡ and Bertrand Guillonneau§ From the Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, New York

Purpose: We determined the yield of standard vs limited pelvic lymphadenectomy in patients with a predicted risk of lymph node metastasis greater than 1% according to the Partin tables predicted probability of pathological stage. We also determined the feasibility of laparoscopic standard pelvic lymph node dissection. Materials and Methods: Of 1,269 patients with clinically localized prostate cancer undergoing radical prostatectomy, 648 had a Partin’s table predicted probability of lymph node invasion greater than 1%. Of the 648 patients 177 underwent limited pelvic lymph node dissection performed laparoscopically (group 1), and 471 underwent standard pelvic lymph node dissection performed open (367) or laparoscopically (104) (group 2). Templates of limited pelvic lymph node dissection included the external iliac lymph nodes whereas standard pelvic lymph node dissection included the external iliac, obturator and hypogastric lymph nodes. Multivariate logistic regression analyses were performed to compare the node positivity rate between groups 1 and 2. Results: On multivariate logistic regression analysis controlling for prostate speciﬁc antigen, biopsy Gleason sum, clinical stage and surgical approach, the odds of node positivity were 7.15-fold higher (95% CI 2.49–20.5, p Ͻ0.001) for standard vs limited pelvic lymph node dissection. The median (mean) number of nodes retrieved was 9 (10) and 14 (15) after limited and standard pelvic lymph node dissection, respectively (p Ͻ0.001). A similar impact was observed in patients treated laparoscopically with standard vs limited pelvic lymph node dissection (odds ratio 15.6, 95% CI 3.7–66.4, p Ͻ0.001). Conclusions: Standard lymph node dissection yields positive nodes more frequently and retrieves a higher total nodal count than the often performed pelvic lymph node dissection limited to the external iliac nodes. Standard pelvic lymph node dissection is feasible through a transperitoneal laparoscopic approach. Key Words: lymph node excision, nomograms, laparoscopy, prostatic neoplasms

he advent of PSA and aggressive screening has led to lymphadenectomy is indicated. General consensus is lacking a downward stage migration of prostate cancer with a regarding the anatomical limits of pelvic lymphadenectomy, T significant decrease in the incidence of nodal metas- raising the concern that pelvic lymph node dissection limited tasis at the time of initial therapy. These findings have led a to the external iliac nodes might leave a number of meta- number of surgeons to forego pelvic lymph node dissection static lymph nodes undetected. Recent data suggest that during radical prostatectomy in select patients deemed to be extended lymph node dissection at radical prostatectomy at low risk.1,2 Moreover, for similar reasons the anatomical may be necessary to detect occult positive lymph nodes, and limits of PLND for prostate cancer have decreased over the that extended node dissection may also have a positive im- years from original descriptions.3,4 This surgical evolution, pact on disease-free survival.5–7 particularly prevalent with the advent of minimally invasive Certainly the presence of lymph node metastases is a approaches, is questionable for several reasons. The defini- negative prognostic factor and lymphadenectomy remains tion of high risk remains highly variable, and surgeons use largely a staging procedure. However, in men with nodal different criteria and algorithms to decide for whom pelvic micrometastases only the therapeutic benefit cannot be ignored.5–7 The purpose of this study is to determine the value of standard PLND including the external iliac, obturator Submitted for publication October 19, 2006. and hypogastric nodal groups vs PLND limited to the exter- Supported by the Allbritton Foundation and the Lowenstein Foun- nal iliac lymph nodes, and to evaluate the feasibility of such dation. * Nothing to disclose. a dissection performed laparoscopically. † Financial interest and/or other relationship with Novartis. ‡ Financial interest and/or other relationship with Steba Pharma- ceuticals, Sanofi Aventis, Oncovance Inc., National Cancer Insti- tute, National Institutes of Health, Prostate Cancer Foundation and Nature Urology. Editor’s Note: This article is the second of 5 published § Correspondence: Sidney Kimmel Center for Prostate and Uro- in this issue for which category 1 CME credits can be logic Cancers, Memorial Sloan-Kettering Cancer Center, 353 East 68th St., New York, New York 10021 (telephone: 646-422-4406; earned. Instructions for obtaining credits are given FAX: 212-988-0806; e-mail: [email protected]). with the questions on pages 358 and 359.

0022-5347/07/1781-0120/0 120 Vol. 178, 120-124, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.018 STANDARD VERSUS LIMITED PELVIC LYMPH NODE DISSECTION FOR PROSTATE CANCER 121

MATERIALS AND METHODS necessary. Statistical analysis was performed using commercially available software. Patient Population A total of 1,305 consecutive men with clinically localized RESULTS (cT1–cT3a) adenocarcinoma of the prostate underwent radical prostatectomy through an open or laparoscopic ap- Standard vs Limited PLND in proach between January 1, 2003 and October 30, 2005. The Patients With PPLNI Greater Than 1% 36 patients who received neoadjuvant hormonal therapy The preoperative and pathological parameters for patients were excluded from analysis leaving 1,269 patients (577 in groups 1 (limited PLND) and 2 (standard PLND) were LRP and 692 RRP). Using the Partin tables for prediction of comparable (table 1). Standard PLND detected a higher rate pathological stage, the probability of lymph node invasion of positive lymph nodes than limited PLND (11.4% vs 4.1%, 8 for each patient was calculated. In the laparoscopic experi- respectively, p ϭ 0.009), and retrieved higher median ence between January 1, 2003 and January 31, 2005 a (mean) nodal counts at 12 (13.1) vs 9 (10.1), respectively, PPLNI cutoff of 1% was used to decide if PLND was indi- p Ͻ0.001. On multivariate logistic regression analysis con- cated. Patients with a PPLNI of 1% or less did not undergo trolling for PSA, biopsy Gleason sum, clinical stage and PLND while those with PPLNI greater than 1% underwent approach (LRP vs RRP), the odds of node positivity were limited PLND (external iliac nodes only). Since February 1, 7.15-fold higher (95% CI 2.49–20.5, p Ͻ0.001) for standard 2005 all patients (214) undergoing LRP have had standard vs limited PLND (table 2). The odds of node positivity were pelvic lymphadenectomy (external iliac, obturator and hypo- 8.31-fold higher (95% CI 2.78–24.84, p Ͻ0.001) for standard gastric nodes) regardless of PPLNI. In the RRP group all vs limited PLND on multivariate logistic regression analysis patients regardless of PPLNI underwent standard PLND controlling for pathological parameters such as pathological except for 23 patients with PPLNI 1% or less who did not Gleason sum, seminal vesicle invasion and pathological undergo PLND. Overall there were 648 patients with stage as well as surgical approach (table 3). In group 2 the PPLNI greater than 1%, 177 of whom underwent LRP median (mean) number of nodes retrieved was 13.5 (14) vs with limited PLND, and 471 of whom underwent RRP 12 (12.8) after LRP and RRP, respectively (p ϭ 0.13), and the (367) or LRP (104) with standard PLND. These 648 pa- detection of nodal metastasis was 15.1% with LRP and tients constitute the final patient population that is the 10.2% with RRP (p ϭ 0.62). In lower risk patients the Partin subject of the present study. tables probability of lymph node invasion correlated well with observed lymph node positivity (table 4). Methodology Laparoscopic Standard vs Limited Patients were classified into group 1—177 patients with PLND in Patients With PPLNI Greater Than 1% PPLNI greater than 1% undergoing limited PLND (laparo- When considering patients treated with LRP only, the com- scopically) and group 2—471 patients with PPLNI greater parison between group 1 (PPLNI greater than 1%, limited than 1% undergoing standard PLND (either open or laparo- laparoscopic PLND) and the laparoscopically treated pa- scopic). tients in group 2 (PPLNI greater than 1%, standard laparoscopic PLND) revealed that the median (mean) number of Pathological Examination nodes retrieved was 9 (10) and 14 (15) after limited and The lymph nodes retrieved were submitted in 2 separate standard PLND, respectively (p Ͻ0.001), and that the node packets (right and left). All lymph node specimens removed positivity rate increased from 4.1% in group 1 to 15.4% in the during surgery were fixed in neutral buffered 4% formalde- laparoscopically treated patients in group 2 (p ϭ 0.003). On hyde for 24 hours, and then searched and counted manually. Each node retrieved was cut in 3 mm slices which were separately embedded in paraffin, stained with hematoxylin TABLE 1. Clinical and pathological features of patients treated and eosin, and examined microscopically. The results were with limited vs standard PLND stated as number of lymph nodes involved and total number Group 1 Group 2 p Value of lymph nodes retrieved per side (right and left). The prostate and seminal vesicles specimens were examined in a Mean Ϯ SD ng/ml PSA 8.1 Ϯ 6 8.3 Ϯ 8.3 0.14 No. clinical stage (%): 0.02 whole mount fashion, and several variables were prospec- cT1 95 (53.7) 197 (41.8) tively collected such as Gleason sum, pathological stage, cT2 74 (41.8) 242 (51.4) SVI, ECE and bladder neck invasion. cT3 8 (4.5) 32 (6.8) No. biopsy Gleason sum (%): 0.47 6 or Less 55 (31.1) 143 (30.4) 7 101 (57.1) 260 (55.2) Statistical Analysis 8 or Greater 21 (11.8) 68 (14.4) Mean/median % PPLNI 5.8/3 6.6/4 0.83 Multivariate logistic regression analyses were performed to No. pathological stage (%): 0.9 compare the node positivity rate between groups 1 and 2. We pT0 1 (0.6) 2 (0.4) controlled for preoperative parameters (PSA [analyzed as pT2 101 (57.1) 272 (57.7) pT3 71 (40.1) 186 (39.5) the logarithmic transformation], clinical stage, biopsy Glea- pT4 4 (2.3) 15 (2.3) son sum, type of approach [LRP and RRP]). Then we con- No. pathological Gleason sum (%): 0.2 trolled for pathological parameters (pathological Gleason 6 or Less 43 (14.7) 93 (19.9) 7 113 (64.9) 314 (67.1) sum and stage, ECE, SVI). The nodal status and total num- 8 or Greater 18 (10.3) 61 (13) ber of lymph nodes retrieved were compared between groups Mean/median nodes retrieved 10.1/9 13.1/12 0.001 1 and 2 using the chi-square test or Fisher’s exact test as % Node pos 4.1 11.4 0.009 122 STANDARD VERSUS LIMITED PELVIC LYMPH NODE DISSECTION FOR PROSTATE CANCER

TABLE 2. Multivariate analysis including preoperative TABLE 4. Comparison of predicted and observed parameters only lymph node positivity 95% No. Pts With Confidence % PPLNI No. Pts Pos Lymph Nodes (%) Odds Ratio Interval p Value 2 94 3 (3.2) Laparoscopic vs open surgical 2.58 1.26–5.29 0.009 3 201 5 (2.5) approach 4 101 9 (10) PSA* 1.78 1.30–2.43 Ͻ0.001 5 21 1 (5) Clinical stage: 0.001 6–10 117 16 (13.6) cT2 vs cT1 2.93 1.48–5.81 0.002 11–15 18 3 (16.7) cT3 vs cT1 5.49 2.06–14.63 0.001 15–20 42 9 (21.4) Biopsy Gleason sum: Ͻ0.001 Greater than 20 28 13 (44) 7 Vs 6 or less 5.15 1.74–15.23 0.003 8 or Greater vs 6 or less 26.26 8.36–82.45 Ͻ0.001 Standard vs limited PLND 7.15 2.49–20.50 Ͻ0.001 Only significant predictors are listed. tutional specific prevalence of positive lymph nodes with * Odds ratio is for doubling in PSA. improved prognostic accuracy (area under the receiver operator characteristics curve) of 0.76.14 Others have included detailed information from systematic prostate biopsies, and multivariate logistic regression analysis controlling for PSA, stratified cases into low, intermediate and high risk groups. biopsy Gleason sum, clinical stage, pathological Gleason In the low risk group patients were predicted to have a 2.1% sum, pathological stage and seminal vesicle invasion, the to 2.2% probability of lymph node metastasis. A review of odds of node positivity were 15.6-fold higher (95% CI 3.7– the literature shows wide variability in the indications for 66.4, p Ͻ0.001) for standard vs limited PLND (table 5). and the rate of PLND, reflecting a lack of consensus regarding the indications for PLND.1,2,7,15,16 Thus, several ques- DISCUSSION tions are raised. Does the downward stage migration seen in prostate cancer solely justify this tendency of performing the The presence of nodal metastasis in patients with presumed most limited PLND on as small a number of patients as clinically localized prostate cancer negatively impacts prog- possible? Are the time and money saved by limiting or omit- nosis. According to the literature PSA screening and stage ting PLND during radical prostatectomy worth the risk of migration have resulted in a sharp decrease in lymph node having occult nodal metastases go undiagnosed? 9 metastasis from 20% to 40% in the 1970s and 1980s to 4% Evidence exists demonstrating that the more we extend 10,11 to 6% in recent years. This trend led many surgeons to the indications for and the anatomical limits of PLND, the omit PLND during radical prostatectomy in low risk pa- more positive lymph nodes we detect.7 The risk of limiting tients and perform limited PLND in patients at higher the PLND template is not only under staging the disease, 1,2 risk. However, the definition of risk of nodal metastasis but also depriving a number of patients with nodal micro- remains controversial and the indication for PLND in pa- metastases of a chance for cure. Large series of patients tients with prostate cancer varies greatly among urologists. undergoing radical prostatectomy with long-term followup Given the low sensitivity of conventional radiographic im- all demonstrated a therapeutic benefit of PLND, particu- aging techniques for detecting microscopic lymphatic metas- larly in those with a low burden of cancer in the pelvic lymph 12,13 tases, several algorithms and nomograms have been nodes.5–7 In the present study we have shown, as have created to predict lymph node status but have been used as others before us, the inadequacies of limited PLND for pros- an individual decision tool for whether to perform PLND tate cancer.5,11 On the other hand our understanding of the 1,2,8 during radical prostatectomy. Partin et al combined pre- anatomical lymphatic spread of prostate cancer can only treatment PSA, biopsy Gleason sum and clinical stage to increase. The detection of prostate cancer cells in lymph predict pathological stage and lymph node invasion with an nodes by using immunohistochemistry and reverse tran- overall accuracy measured by the area under the receiver scriptase-polymerase chain reaction based assays for PSA 14 operator characteristics curve of 0.74. Cagiannos et al and prostate specific membrane antigen has been shown to reported a preoperative nomogram that takes into consider- be superior to that of routine hematoxylin and eosin stains. ation PSA, clinical stage, biopsy Gleason sum and the insti- This raises the question of whether current surgical and pathological techniques are under staging the nodal status of patients with prostate cancer.17,18 However, until the TABLE 3. Multivariate analysis with pathological parameters clinical implications of positive lymph nodes detected only 95% with immunohistochemistry and reverse transcriptase-poly- Confidence Odds Ratio Interval p Value

Laparoscopic vs open surgical 2.73 1.27–5.88 0.01 TABLE 5. Multivariate analysis of patients approach treated laparoscopically PSA* 1.39 1.03–1.86 0.027 Pathological stage: Ͻ0.001 Odds 95% Confidence pT3 vs pT2 7.36 2.94–18.41 Ͻ0.001 Ratio Interval p Value pT4 vs pT2 8.51 1.80–40.13 0.007 Pathological Gleason sum 0.17 0.087–0.34 Ͻ0.001 Clinical stage cT3 vs cT1c 11.15 1.89–65.80 0.008 7 vs 8 or greater ECE 5.28 1.52–18.35 0.009 Standard vs limited PLND 8.31 2.78–24.84 Ͻ0.001 SVI 36.99 9.29–147.31 Ͻ0.001 Standard vs limited PLND 15.64 3.68–66.39 Ͻ0.001 Only significant predictors are listed. * Odds ratio is for doubling in PSA. Only significant predictors are listed. STANDARD VERSUS LIMITED PELVIC LYMPH NODE DISSECTION FOR PROSTATE CANCER 123 merase chain reaction assays are determined, their role in select patients with prostate cancer. J Urol 1994; 151: remains investigational. 1315. PLND including the external iliac, hypogastric and obtu- 2. Bishoff JT, Reyes A, Thompson IM, Harris MJ, St Clair SR, rator nodal packets has been shown in open radical prosta- Gomella L et al: Pelvic lymphadenectomy can be omitted tectomy series to yield a higher nodal count, and detect more in selected patients with carcinoma of the prostate: de- positive lymph nodes than the often performed PLND lim- velopment of a system of patient selection. Urology 1995; ited to external lymph nodes.7 To our knowledge this is the 45: 270. first study in the laparoscopic experience to demonstrate the 3. McCullough DL, Prout GR Jr and Daly JJ: Carcinoma of the benefit and prove the feasibility of standard PLND through prostate and lymphatic metastases. J Urol 1974; 111: 65. 4. McLaughlin AP, Saltzstein SL, McCullough DL and Gittes RF: a transperitoneal laparoscopic approach. By performing Prostatic carcinoma: incidence and location of unsuspected standard rather than limited PLND in patients with PPLNI lymphatic metastases. J Urol 1976; 115: 89. greater than 1% treated with transperitoneal LRP, we sig- 5. Bader P, Burkhard FC, Markwalder R and Studer UE: Disease nificantly increased the detection rate of positive lymph progression and survival of patients with positive lymph nodes from 4.1% to 15.4% and the median nodal count from nodes after radical prostatectomy. Is there a chance of cure? 9 to 14 lymph nodes in patients with comparable cancer J Urol 2003; 169: 849. characteristics. Although studies comparing transperitoneal 6. Daneshmand S, Quek ML, Stein JP, Lieskovsky G, Cai J, vs extraperitoneal laparoscopic radical prostatectomy have Pinski J et al: Prognosis of patients with lymph node posi- not demonstrated any significant differences in positive sur- tive prostate cancer following radical prostatectomy: long- gical margins and convalescence, the quality of the pelvic term results. J Urol 2004; 172: 2252. lymphadenectomy was not studied.19 It is our belief as well 7. Allaf ME, Palapattu GS, Trock BJ, Carter HB and Walsh PC: as that of others that an extraperitoneal laparoscopic ap- Anatomical extent of lymph node dissection: impact on men proach can be a hindrance to performing thorough PLND. with clinically localized prostate cancer. J Urol 2004; 172: Because minimally invasive radical prostatectomy is gain- 1840. ing popularity whether purely laparoscopic or robotically 8. Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, assisted, meticulous PLND should be routinely performed to Oesterling JE et al: Combination of prostate-specific anti- achieve cancer control. PLND including the external, hypo- gen, clinical stage, and Gleason score to predict pathological gastric and obturator nodal packets is standard rather than stage of localized prostate cancer. A multi-institutional up- extended, and remains the most accurate staging procedure date. JAMA 1997; 277: 1445. today because currently available imaging techniques re- 9. Zincke H: Extended experience with surgical treatment of main insufficient. Development of lymph node mapping stage D1 adenocarcinoma of prostate. Significant influences of immediate adjuvant hormonal treatment (orchiectomy) techniques with monoclonal antibodies or lymphotropic on outcome. Urology 1989; 33: 27. superparamagnetic nanoparticles is promising, but until 10. Petros JA and Catalona WJ: Lower incidence of unsuspected then meticulous pelvic lymph node dissection through an lymph node metastases in 521 consecutive patients with open or laparoscopic approach is the best method to stage clinically localized prostate cancer. J Urol 1992; 147: 1574. and perhaps treat clinically localized prostate cancer in pa- 11. Han M, Partin AW, Pound CR, Epstein JI and Walsh PC: 20 tients who have opted for surgery. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North CONCLUSIONS Am 2001; 28: 555. 12. Hinkle GH, Burgers JK, Neal CE, Texter JH, Kahn D, Lymph node dissection including the external iliac, obtura- Williams RD et al: Multicenter radioimmunoscintigraphic tor and hypogastric lymph node groups yields positive nodes evaluation of patients with prostate carcinoma using more frequently and retrieves a higher total nodal count indium-111 capromab pendetide. Cancer 1998; 83: 739. than the often performed PLND limited to external iliac 13. Flanigan RC, McKay TC, Olson M, Shankey TV, Pyle J and nodes. This standard pelvic lymph node dissection is feasible Waters WB: Limited efficacy of preoperative computed to- through a transperitoneal laparoscopic approach. mographic scanning for the evaluation of lymph node metastasis in patients before radical prostatectomy. Urology 1996; 48: 428. 14. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Abbreviations and Acronyms Gerigk C et al: A preoperative nomogram identifying de- ECE ϭ extracapsular extension creased risk of positive pelvic lymph nodes in patients with LRP ϭ laparoscopic radical prostatectomy prostate cancer. J Urol 2003; 170: 1798. PLND ϭ pelvic lymph node dissection 15. Guillonneau B, el-Fettouh H, Baumert H, Cathelineau X, ϭ PPLNI Partin’s tables probability of lymph Doublet JD, Fromont G et al: Laparoscopic radical pros- node invasion tatectomy: oncological evaluation after 1,000 cases at Mont- PSA ϭ prostate specific antigen ϭ souris Institute. J Urol 2003; 169: 1261. RRP retropubic radical prostatectomy 16. Stolzenburg JU, Rabenalt R, Do M, Ho K, Dorschner W, Wald- SVI ϭ seminal vesicle invasion kirch E et al: Endoscopic extraperitoneal radical prostatectomy: oncological and functional results after 700 procedures. J Urol 2005; 174: 1271. REFERENCES 17. Ferrari AC, Stone NN, Eyler JN, Gao M, Mandeli J, Unger P et al: Prospective analysis of prostate-specific markers in 1. Bluestein DL, Bostwick DG, Bergstralh EJ and Oesterling JE: pelvic lymph nodes of patients with high-risk prostate can- Eliminating the need for bilateral pelvic lymphadenectomy cer. J Natl Cancer Inst 1997; 89: 1498. 124 STANDARD VERSUS LIMITED PELVIC LYMPH NODE DISSECTION FOR PROSTATE CANCER

18. Edelstein RA, Zietman AL, de las Morenas A, Krane RJ, approach for laparoscopic radical prostatectomy: a false Babayan RK, Dallow KC et al: Implications of prostate debate over a real challenge. J Urol 2004; 171: 714. micrometastases in pelvic lymph nodes: an archival tissue 20. Harisinghani MG, Barentsz J, Hahn PF, Deserno WM, study. Urology 1996; 47: 370. Tabatabaei S, van de Kaa CH et al: Noninvasive detection 19. Cathelineau X, Cahill D, Widmer H, Rozet F, Baumert H, of clinically occult lymph-node metastases in prostate can- Vallancien G et al: Transperitoneal or extraperitoneal cer. N Engl J Med 2003; 348: 2491. Population Based Incidence and Age Distribution of Spermatocytic Seminoma

Philippe Carrière,* Peter Baade and Lin Fritschi From the Viertel Centre for Research in Cancer Control, Brisbane, Queensland (PC, PB), and Western Australian Institute for Medical Research, Perth (LF), Australia

Purpose: Spermatocytic seminoma is a rare subtype of testicular germ cell tumor which has been reported to occur in elderly men. We report the first population based estimate of incidence, temporal trends and age distribution of this tumor. Materials and Methods: All cases of primary testicular cancer identified by cancer registries in Australia between 1982 and 2002 were available for analysis. The International Classification of Diseases for Oncology code M-9063/3 was used to identify spermatocytic seminomas. Incidence trends were modeled using Poisson regression. Results: There were 58 cases of spermatocytic seminoma out of 9,658 cases of primary malignant testicular neoplasms identified by the cancer registries. This tumor comprised 1.1% of all seminoma and the age standardized incidence rate was 0.4 per million (95% CI 0.3–0.6). A temporal increase in incidence was found but not one reaching statistically significance. Age at diagnosis ranged from 19 to 92 years with a mean of 53.5 (SD 16.7) and a median of 54 years. Conclusions: Spermatocytic seminoma should be considered in the differential diagnosis for testicular germ cell tumors presenting in young adults because this tumor occurs as often in men younger than 55 years as it does in older men. Although rare, the occurrence of this tumor is not as singular as the current literature suggests. Key Words: neoplasms, germ cell and embryonal; testicular neoplasms; seminoma; incidence; age distribution

he World Health Organization classifies testicular noma has not been reported previously in children or ado- germ cell tumors into 3 distinct subgroups based on lescents. T clinical features, histology and genetic characteristics: Incidence estimates of spermatocytic seminoma have so the teratomas and yolk sac tumors of childhood (type I), the far been limited to reporting their frequencies in relation to seminomas and nonseminomas of adolescents and young classic seminomas (ranging from 2% to 12%) by case se- adults (type II), and spermatocytic seminomas (type III).1 ries9–12 or tumor registry reports.13 However, as with the The incidence of type II testicular germ cell cancer, the most age distribution, the incidence has not yet been properly common subtype, has been increasing consistently in the reported by using population based data collected during the last several decades but the patterns of occurrence of the 2 necessary period required to capture an adequate sample less common types of testicular germ cell tumors have not size of this rare tumor. Therefore, the aim of this study was yet been well described.2 to estimate the incidence, temporal trends and age distribu- Spermatocytic seminoma is a rare testicular neoplasm tion of spermatocytic seminoma using population based data which presents as a slow growing mass with or without pain. collected by the Australian cancer registries in the last 20 It arises more commonly in the right testis, serum tumor years. markers are always negative and there is no association 3 with cryptorchidism or intraepithelial neoplasia. Unlike MATERIALS AND METHODS other germ cell tumors, metastasis is extremely rare so that orchiectomy and surveillance are usually sufficient thera- All cases of testicular cancer were identified for analysis by peutic management unless the tumor is associated with the Australian state and territory cancer registries, which sarcoma.4–8 Reviews describe spermatocytic seminoma as are located in the Australian Capital Territory, New South usually presenting in the elderly or in men who are at least Wales, the Northern Territory, Queensland, Tasmania, older than 50 years, and only occurring sporadically in South Australia, Victoria and Western Australia. In Australia younger men.1,5–8 To our knowledge spermatocytic semi- notification of cancer diagnoses is a legal requirement which has been mandatory since 1982. Each state and territory operate their own registry and attempt to collect every case Submitted for publication November 7, 2006. of histologically confirmed cancer in the jurisdiction (adults Study received ethical approval from the University of Queensland Behavioral and Social Sciences Ethical Review Committee and the AIHW Ethics Review Board. Nothing to disclose. * Correspondence: Epidemiology Unit, Viertel Centre for Research Editor’s Note: This article is the third of 5 published in in Cancer Control, 553 Gregory Terrace, Fortitude Valley, Brisbane, this issue for which category 1 CME credits can be Queensland 4006, Australia (telephone: 61 7 9807 3726; FAX: 61 7 9325 4699; e-mail: [email protected]; philippe. earned. Instructions for obtaining credits are given [email protected]). with the questions on pages 358 and 359.

0022-5347/07/1781-0125/0 125 Vol. 178, 125-128, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.024 126 POPULATION BASED INCIDENCE OF SPERMATOCYTIC SEMINOMA and children). The notified, applicable state/territory cancer counts were modeled using Poisson regression with the log registry assigns a diagnostic code directly from the pathol- of the population used as the offset variable. Analyses were ogy report using the ICD-O. The ICD is the most widely used conducted using SAS® for Windows (version 9.2) and Stata® classification system of diseases, and is commonly used by statistical software version 9.2. Ethical approval for this clinical epidemiologists to study patterns of disease, pat- study was granted by the University of Queensland Behav- terns of care and outcomes.14 ioral and Social Sciences Ethical Review Committee as well Data quality is assessed on a continuous basis by cancer as the AIHW Ethics Review Board. registries. All coding on pathology reports and the details entered in the database are checked by a second member of RESULTS the registry staff, and disagreements are referred to a registry medical officer. In addition, registry databases systems There were 9,658 malignant, primary tumors of the testis incorporate various case flagging systems which identify registered between 1982 and 2002 in Australia, of which 58 discrepancies among data items such as site and tissue code (0.60%) were spermatocytic seminoma. These tumors repre- combinations, sex, age, and date of diagnosis. Registry com- sented 0.61% of all testicular germ cell tumors and 1.1% of pleteness is assessed using multiple notification sources the entire set of seminoma (mixed tumors excluded) identi- such as pathology report, radiotherapy, hospital, nursing fied during this period. Combining the 58 cases from 1982 to home and birth/death registrar records. However, the ma- 2002 the Australian age standardized incidence rate for jority of notifications to cancer registries are received from spermatocytic seminoma was 0.4 cases per million (95% CI pathology laboratories which supply pathology reports on 0.3–0.6). The mean number of cases diagnosed per year was paper or computer data file, and all notifications are traced 2.8, ranging from 0 to 7. back to the original histological report for coding. Registries Mean patient age at diagnosis was 53.5 years (SD 16.7) and exchange case information when there is cause to suspect 50% of men were diagnosed at 54 years or younger (fig. 1). duplicate registration.14 Approximately 25% of patients were younger than 40 years. Therefore, each case included in this study was initially One patient was diagnosed at 19 years old and the oldest diagnosed histologically by a pathologist. In these analyses a patient was 92 years old. Using the median of 54 years to spermatocytic seminoma case was defined as any histologi- separate the patients into 2 age groups, mean age at diag- cally confirmed malignant tumor originating in the testis nosis for men younger than 55 years was 39.5 (SD 8.8) and (code “C62._” according to the ICD, Revision 10, 1989), and 67.4 (SD 9.2) for men 55 years or older. Stratified by age which also had an ICD-O morphology code of M-9063/3, the group the age standardized incidence was 0.3 cases per unique code used for spermatocytic seminoma (according to million (95% CI 0.2–0.4) for men younger than 55 years and the ICD-O: Morphology of Neoplasms, 3rd ed., 2000). A code 0.8 cases per million (95% CI 0.6–1.2) for men 55 years or of M-9063/3 would have been entered into a cancer registry older. database only where the diagnosis “spermatocytic semi- The annual percent change estimated by Poisson regres- noma” was specified as the histological diagnosis in the sion was 2.6% per year but with a wide and nonsignificant pathology report. In the rare instances in which other tumor CI (95% CI Ϫ1.8–7.1). The lack of a statistically significant elements were identified in a spermatocytic seminoma tu- trend remained whether collapsing the years into 3-year mor (such as sarcoma), then these tumors would have been periods (7.2% per 3 years, 95% CI Ϫ6.0–22.2, fig. 2) or 5-year assigned by the cancer registries the diagnostic code reflect- periods (2.9% per 5 years, 95% CI Ϫ18.1–29.4). These esti- ing the most malignant tumor element. mates corresponded to an average annual change in inci- At the investigators’ request the state and territory can- dence rates of 2.3% (95% CI Ϫ2.0–6.9) and 1.0% (95% cer registries collated and sent all cases of testicular cancer CI Ϫ6.5–9.0), respectively. No statistically significant from 1982 to 2002 to the AIHW in the form of de-identified changes in incidence trends were detected in men younger unit record files. For each case the cancer registries also provided the year of birth, year of diagnosis and the state/ territory where the diagnosis was made. The ethnic origin of patients was not available. However, the majority of Aus- tralia’s population (92%) identify themselves as white, 7% as Asian, and approximately 1% as Aboriginal and Torres Strait Islander (Indigenous) people (Australian Census 2001). To conserve the confidentiality of the potentially small number of cases, programs for the analyses were sent to the AIHW where the data were reserved and only the outputs were subsequently made available to the investigators. Age standardized (Australia 2001) incidence rates were calculated per year. Given the small number of cases per year, annual counts were combined into 3 and 5-year periods to obtain larger numbers of cases within each period, and the incidence rates were recalculated for each period. This was done to verify that any observed trend of incidence over time was not simply the result of random variation in the incidence estimates, but rather was a stable observation FIG. 1. Age distribution of spermatocytic seminomas identified be- seen across different period aggregates. Trends in incidence tween 1982 and 2002 in Australia (58). POPULATION BASED INCIDENCE OF SPERMATOCYTIC SEMINOMA 127

cytic seminoma are sensitive to radiotherapy but orchiectomy followed by surveillance is the treatment of choice.4–8 Avoiding unnecessary radiotherapy and chemotherapy is an especially important consideration in a young patient with a protracted life expectancy. Although the morphological features of spermatocytic seminoma have been well described, the infrequency has created diagnostic challenges for pathologists.18,19 A large number of spermatocytic seminoma may be identified only after diagnosis of classic seminoma and receiving radiotherapy.9 In a recent study by Chung et al 7 of 12 patients referred to a tertiary care hospital had been originally diagnosed as having classic seminoma and 1 as having embryonal carcinoma.10 Confusion with lymphoma and yolk sac tumors has also been described.1,9,15 In con- FIG. 2. Trend in age standardized incidence of spermatocytic seminoma per 3-year periods between 1982 and 2002 in Australia. trast, false-positive diagnoses may be uncommon in that Trend line fitted using Poisson regression shown with 95% CI, once a pathologist is aware of the histological criteria to where incidence rate ratio was 1.072 (95% CI 0.940–1.222). recognize spermatocytic seminoma, these tumors are easy to identify.19 We were able to find only 1 report of false-positive diagnoses, a case series in which 2 of 12 diagnoses of sper- than 55 years (Ϫ0.37% per 3 years, 95% CI Ϫ17.1–19.7) or in matocytic seminoma were revised after histological re- men 55 years or older (12.8% per 3 years, 95% CI Ϫ6.6– view.16 36.2). Trends examined in 5-year periods in these age groups There has been some debate as to whether some sper- were also nonsignificant. matocytic seminoma tumors should be described as anaplas- tic when foci of cells resembling embryonal carcinoma are DISCUSSION present. However, the clinical history and prognosis do not seem different from tumors lacking this feature.8 Sarcoma- To our knowledge we report on the first population based tous elements are sometimes admixed within a spermato- incidence estimate for spermatocytic seminoma (0.4 per mil- cytic seminoma tumor but only a dozen cases have been lion, 95% CI 0.3–0.6). Although rare, these tumors are more reported of this highly aggressive tumor.9 Although several common than is suggested by the approximately 200 cases primary sarcomas were identified as primary tumors of the that are currently documented in the literature in the form testis within the large sample of all testicular neoplasms for of case reports and case series. For example, assuming a this study, the lack of an ICD-O code for the spermatocytic background risk similar to that of Australia, a country such seminoma/sarcoma tumor variant resulted in an inability to as the United States could expect approximately as many as identify any such cases. 40 cases per year. Thus, it is possible that an important number of sper- We could detect no statistical increase in the incidence of matocytic seminomas are under diagnosed. Although not spermatocytic seminoma in the last 20 years but our ability feasible in the context of this study, a histological review of to identify trends was limited by the small number of cases a population based sample could reveal that the true inci- available. Given the background rate of 0.4 per million, a dence is higher than that reported here. However, the age power of 84% was achieved to detect a change in incidence of distribution would not likely be affected unless there is a 0.15 per million at a significance level of 0.05. However, the tendency for older cases to be under diagnosed more often average annual percent change in rates remained fairly than younger cases. Given the therapeutic implications of stable whether the data were analyzed by single calendar histological misdiagnosis and the rarity of spermatocytic year or by aggregates of 3 and 5 years (2.6%, 2.3% and 1.0% seminoma (and of testicular tumors in general), a salient per year, respectively), thus suggesting the possibility of an argument can be made for the pathology review of all tes- increasing trend between 1982 and 2002. ticular cancer cases at expert centers before treatment is It has been commonly reported that one of the main commenced.20 clinical features that distinguishes spermatocytic seminoma from classic seminoma is the age at which it occurs. Mean patient age at presentation has been reported within the CONCLUSIONS range of 54 to 62 years, sometimes with a qualification that they intermittently occur in men in their mid 20s.8–10,12,15,16 Spermatocytic seminoma is a rare subtype of testicular germ Our findings reveal an age distribution with a similar mean cell tumor, although it is not as singular as the current (53.5 years) but with a much wider spread than expected literature suggests. It is unclear if there has been a temporal (SD 16.7 years). Spermatocytic seminoma occurred just as increase in incidence during the last 20 years. Spermatocytic frequently in young men as in older men (median age 54 seminoma presents as often in younger as in older adult years). We also identified the youngest (19 years) and oldest men, and in a wider age range than previously reported (92 years) cases of spermatocytic seminoma reported so far. which has important implications in terms of differential These results indicate that the age distribution of spermato- diagnosis. Correct histological identification is a challenge in cytic seminoma overlaps with that of nonseminoma (20 to 40 the community given the infrequency of this tumor. How- years) and classic seminoma (35 to 50 years).17 ever, it is critical because histologically misdiagnosed cases The correct diagnosis of spermatocytic seminoma is clin- may be subjected to unnecessary and potentially harmful ically important because this tumor is curable. Spermato- therapies. 128 POPULATION BASED INCIDENCE OF SPERMATOCYTIC SEMINOMA

ACKNOWLEDGMENTS 5. Gori S, Porrozzi S, Roila F, Gatta G, De Giorgi U and Marangolo M: Germ cell tumours of the testis. Crit Rev The AIHW participated in this study. The Queensland Cancer Oncol Hematol 2005; 53: 141. Fund provided financial assistance for the costs associated 6. Hoei-Hansen CE, Rajpert-De Meyts E, Daugaard G and with the AIHW’s participation. Cancer registries across Aus- Skakkebaek NE: Carcinoma in situ testis, the progenitor of tralia collaborated in this study, including the Australian testicular germ cell tumours: a clinical review. Ann Oncol Capital Territory Cancer Registry, the New South Wales 2005; 16: 863. Central Cancer Registry, the Northern Territory Cancer 7. Oosterhuis JW and Looijenga LH: Testicular germ-cell tu- Registry, the Queensland Cancer Registry, the South Aus- mours in a broader perspective. Nat Rev Cancer 2005; 5: 210. tralian Cancer Registry, the Tasmanian Cancer Registry, 8. Ulbright T: Tumours of the testis: rare tumours of the testis. the Victorian Cancer Registry and the Western Australian Histopathology 2002; 41: 376. Cancer Registry. Dr. Mark Short of the Health Registers and 9. Eble JN: Spermatocytic seminoma. Hum Pathol 1994; 25: Cancer Monitoring Unit, AIHW, set up the data files and ran 1035. the remotely submitted analysis programs. Danny Youlden 10. Chung PW, Bayley AJ, Sweet J, Jewett MA, Tew-George B, assisted with the statistical analyses. Gospodarowicz MK et al: Spermatocytic seminoma: a review. Eur Urol 2004; 45: 495. 11. Talerman A: Spermatocytic seminoma: clinicopathological study of 22 cases. Cancer 1980; 45: 2169. Abbreviations and Acronyms 12. Burke A and Mostofi F: Spermatocytic seminoma: a clinico- AIHW ϭ Australian Institute of Health and pathological study of 79 cases. J Urol Pathol 1993; 1: 21. Welfare 13. Krag Jacobsen G, Barlebo H, Olsen J, Schultz HP, Starklint H, ICD ϭ International Classification of Diseases Sogaard H et al: Testicular germ cell tumours in Denmark ICD-O ϭ International Classification of Diseases for 1976–1980. Pathology of 1058 consecutive cases. Acta Oncology Radiol Oncol 1984; 23: 239. 14. Australasian Association of Cancer Registries, Australian In- stitute of Health and Welfare. Available at http://www.aihw. gov.au/cancer/aacr/. Accessed January 15, 2007. REFERENCES 15. Cummings OW, Ulbright TM, Eble JN and Roth LM: Sper- matocytic seminoma: an immunohistochemical study. Hum 1. Mostofi F and Sesterhenn I: Tumours of the testis and Pathol 1994; 25: 54. paratesticular tissue. In: World Health Organization Clas- 16. Pendlebury S, Horwich A, Dearnaley DP, Nicholls J and Fisher C: sification of Tumours: Pathology and Genetics–Tumours of Spermatocytic seminoma: a clinicopathological review of the Urinary System and Male Genital Organs. Edited by ten patients. Clin Oncol 1996; 8: 316. JN Eble, G Sauter, JI Epstein and IA Sesterhenn. Lyon: 17. Kundra V: Testicular cancer. Semin Roentgenol 2004; 39: 437. International Agency for Research on Cancer (IARC) Press 18. Parkinson MC, Harland SJ, Harnden P and Sandison A: The 2004; chapt 4, pp 217-278. role of the histopathologist in the management of testicular 2. Huyghe E, Matsuda T and Thonneau P: Increasing incidence of germ cell tumour in adults. Histopathology 2001; 38: 183. testicular cancer worldwide: a review. J Urol 2003; 170: 5. 19. Ulbright TM: Germ cell tumors of the gonads: a selective 3. Reuter VE: Origins and molecular biology of testicular germ review emphasizing problems in differential diagnosis, cell tumors. Mod Pathol 2005; 18: S51. newly appreciated, and controversial issues. Mod Pathol 4. Warde P, Gospodarowicz MK, Panzarella T, Catton CN, 2005; 18: S61. Sturgeon JF, Moore M et al: Stage I testicular seminoma: 20. Lee AH, Mead GM and Theaker JM: The value of central results of adjuvant irradiation and surveillance. J Clin On- histopathological review of testicular tumours before treat- col 1995; 13: 2255. ment. BJU Int 1999; 84: 75. Bilateral Testicular Germ Cell Tumors in Turkey: Increase in Incidence in Last Decade and Evaluation of Risk Factors in 30 Patients

Akdogan Bulent, Divrik Rauf Taner, Tombul Tolga, Yazici Sertac, Tasar Celik, Zorlu Ferruh and Ozen Haluk* From the Departments of Urology, Hacettepe University, School of Medicine, Ankara and Tepecik Research and Training Hospital (DRT, ZF), Izmir, Turkey

Purpose: The relative risk of germ cell testicular tumor is significantly higher in patients with a testicular tumor history. We reviewed histological and clinical features in 30 patients with bilateral tumors treated at 2 academic centers in Turkey. Materials and Methods: Of 987 patients with testicular germ cell tumors 30 (3.0%) were diagnosed with bilateral disease. Data on clinical information, histopathology and followup records were reevaluated. Contralateral testis biopsy was not performed in any patient at initial orchiectomy. Results: Of 30 patients 24 had sequential tumors at a median interval of 75 months (range 3 to 260) and 6 (20.0%) had synchronous tumors. Mean age at presentation was 32.3 and 26.7 years, respectively. The second tumor occurred within 2 and 5 years in 20.8% and 41.7% of patients, respectively. Patients with seminoma were at significantly higher risk for bilateral disease (4.5% vs 2.3%), whereas patients with nonseminoma had more advanced disease at presentation. Synchronous tumors had similar tumor histology on each side and more advanced stage at presentation than metachronous tumors. Most patients with metachronous tumors had stage 1 disease, including 81% originally and 95.2% subsequently. Primary tumors were significantly larger than secondary tumors (4.78 vs 2.59 cm). Median time after the first and second germ cell tumors was 128 and 47 months, respectively. At last followup all patients had no evidence of disease. Conclusions: The risk of contralateral testicular germ cell tumor in patients with seminoma was 2 times higher than in those without a history of tumor. Synchronous tumors present at advanced stage and have similar histology on each side. Clinical outcome is excellent with appropriate treatment. Contralateral testis biopsy at initial diagnosis is not mandatory. Key Words: testis; testicular neoplasms; neoplasms, germ cell and embryonal; seminoma; risk

pidemiological studies have revealed an increased in- ters, of whom 30 (3.0%) had bilateral disease. Clinical char- cidence of testis cancer in the United States1 and in acteristics, histopathology and followup data were obtained E almost all developed countries during the last 2 de- from patient medical records and special followup files. cades.2 Although mean patient age at presentation seems to All patients underwent radical inguinal orchiectomy af- be decreasing in the United States and the survival of pa- ter diagnostic procedures, as described previously.4 How- tients with unilateral tumors has improved,3 the incidence ever, only 1 patient underwent TSS, which was done for of bilateral TGCTs is expected to increase. right metachronous testicular tumor. He subsequently un- We have also noted an increase in the incidence of bilat- derwent right orchiectomy due to tumor recurrence in the eral TGCT in our patient population in the last decade. We remaining testis parenchyma. On the other hand, contralat- defined the incidence, risk factors and treatment outcome in eral testis biopsy was not performed routinely. The Royal patients with bilateral TGCT who were treated and followed Marsden Hospital Staging System was used for surgical at 2 academic tertiary referral centers in Turkey. staging.5 According to histopathology results all cases were classified into 2 groups as seminomatous if histopathology MATERIALS AND METHODS revealed pure seminoma, and as NSGCT. The choice of treatment modality was based on histo- Data on 22 and 8 patients were gathered from 2 large urol- logical type, clinical tumor stage and earlier treatment ogy departments in Turkey, including Hacettepe University modalities, as defined previously.4 Patients with stage 1, School of Medicine, Ankara, and Tepecik Research and 2A seminoma received radiotherapy focused on the retro- Training Hospital, Izmir, respectively, between 1980 and peritoneum. Patients with metachronous stage 1 seminoma 2005 for this retrospective study. During the study years a who had received radiotherapy initially and those with stage total of 987 patients with TGCT were treated at these cen- 1 NSGCT were included in the surveillance protocol. All other patients with metastasis received chemotherapy. Indications for surgery following chemotherapy were nor- Submitted for publication November 5, 2006. malization of markers (␣-fetoprotein and/or ␤-human * Correspondence: Kuleli Sokak 9/2, Gazi Osman Pasa, Ankara 06700, Turkey (telephone: ϩ90 312 4424042; FAX: ϩ90 312 chronic gonadotropin) and partial remission of metastatic 4424136; e-mail: [email protected]). disease. Only 3 patients received testosterone gel since tes-

0022-5347/07/1781-0129/0 129 Vol. 178, 129-133, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.027 130 BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY tosterone gel is available in Turkey only recently (50 mg 66.3% vs 13.3%, p ϭ 0.007 and 42.9% vs 6.3%, p ϭ 0.018, testosterone daily). All other patients received testosterone respectively). depot injections (200 to 250 mg testosterone enanthate every 3 weeks) as androgen replacement therapy. Synchronous Tumors All 6 patients with synchronous tumors had similar tumor RESULTS histology on the 2 sides and metastatic disease at presentation. In addition, synchronous tumors carried significantly The prevalence of bilateral TGCT was 2% in 552 patients in more risk since they presented at advanced stage compared 4 1998, which increased to 3.1% (22 of 718) for this particular with metachronous tumors (100.0% vs 25.0%, p ϭ 0.001). series at the Department of Urology, Hacettepe University Four of 6 patients had nonseminomatous histology and the School of Medicine. remaining 2 had seminoma. Furthermore, increased serum Bilateral disease developed in 30 of the 987 patients tumor markers were observed in 66.7% of the patients with (3.04%) with TGCT who were treated at these 2 centers synchronous tumors. (table 1). Three patients had a history of cryptorchidism, which was bilateral in 1, and 4 had an atrophic testis. Of 30 Metachronous Tumors patients 24 had sequential tumors occurring within a me- Of 24 patients with metachronous tumors the initial tumor dian interval of 75 months (range 3 to 260) and 6 (20.0%) had was seminoma in 13 and NSGCT in 11. Ten patients with synchronous tumors. Mean Ϯ SD age at presentation was initial seminoma had a second seminoma and 6 of the 11 32.3 Ϯ 8.6 (median 31.5) and 26.7 Ϯ 6.3 years (median 26) in who presented with NSGCT as the initial tumor had a patients presenting with synchronous and metachronous secondary NSGCT. Disease was stage 1 in 75% of the tumors, respectively (p ϭ 0.191). Of 24 patients with metach- original lesions and in 95.8% of the subsequent tumors ronous tumors the second tumor occurred within 2 years in (p ϭ 0.077, table 2). In addition, primary tumors were 5 (20.8%) and within 5 years in 10 (41.7%). In patients with significantly larger than secondary tumors (mean largest nonseminomatous primary tumors the secondary tumor de- diameter 4.78 Ϯ 1.76 vs 2.59 Ϯ 1.62 cm, p ϭ 0.001). Seven of veloped in a shorter mean interval than in those with semi- the 24 patients (29.2%) with metachronous tumor had ECa nomatous tumors without attaining statistically significant components at initial presentation, of whom 6 (85.7%) also value (62.9 vs 102.4 months, p ϭ 0.152). Most of the second had ECa components at subsequent presentation (p Ͻ0.001). tumors had already been detected by self-examination. Self- Considering metachronous tumors, ␣-fetoprotein and/or examination was strongly recommended for followup. ␤-human chronic gonadotropin were increased in 13 (54.2%) and 7 patients (29.2%) at initial and subsequent presenta- Seminoma vs Nonseminoma tion, respectively (p ϭ 0.047). Secondary tumors received Patients with seminoma were at significantly higher risk significantly less adjuvant radiotherapy but more surveil- for bilateral disease than those with NSGCT (4.5% vs lance policy compared to initial treatment (table 2). 2.3%, p ϭ 0.048). Of all patients with seminoma only 2 with synchronous tumors had metastatic disease. Ad- Treatment vanced stage at initial presentation and subsequently was Of the 24 metachronous tumors 13 (54.2%) received radio- more common in patients with NSGCT compared with therapy to the retroperitoneum, 6 (25%) received chemother- those who had seminoma (initial and secondary tumor apy and 5 (20.8%) received surveillance as initial therapy. However, only 1 patient needed surgery after chemotherapy. Radiotherapy, chemotherapy and surveillance were done in 20.8%, 16.7% and 62.5% of patients, respectively, for subse- TABLE 1. Synchronous and metachronous tumor quent tumors. Only 1 of the 24 patients (4.2%) with me- histopathological features tachronous tumor had metastasis at second orchiectomy. Tumor Histology 1/2 No. Pts (%) Serum markers remained high in 2 patients with stage 1 Synchronous: disease, who received chemotherapy. Seminoma/seminoma 1 (16.7) All synchronous tumors were associated with metastatic Seminoma/seminoma ϩ ECa 1 (16.7) Seminoma subtotal 2 (33.4) diseases at presentation. All patients with metastatic dis- Teratoma/teratoma 1 (16.7) ease responded well to chemotherapy. Three patients with Mixed GCT/mixed GCT 3 (50) synchronous tumors underwent surgery after chemotherapy Total No. 6 due to partial remission. Median followup after the first and Metachronous: Seminoma/seminoma 10 (41.7) second TGCTs was 128 (range 41 to 348) and 47 months Seminoma/seminoma ϩ ECa 1 (4.2) (range 12 to 204), respectively. All patients had no evidence Seminoma/teratoma 1 (4.2) of disease at last followup. Seminoma/yolk sac tumor 1 (4.2) Seminoma subtotal 13 (54.2) ECa/ECa 3 (12.5) Testosterone Replacement ECa/ECa ϩ teratoma 1 (4.2) ECa/seminoma 1 (4.2) Libido and erectile function was satisfactory in most pa- ECa subtotal 5 (20.8) tients with proper testosterone replacement therapy, includ- Teratoma/seminoma 3 (12.5) Mixed GCT/seminoma 1 (4.2) ing testosterone enanthate injection and testosterone gel. Mixed GCT/ECa 1 (4.2) Three patients treated with injections complained of de- Mixed GCT/seminoma ϩ ECa 1 (4.2) creased libido resulting from subtherapeutic androgen at Mixed GCT subtotal 3 (12.5) the end of the dose interval. However, none reported any Total No. 24 symptoms associated with androgen fluctuation or pain BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY 131

arm of chromosome 12).11 In addition, familial clustering TABLE 2. Metachronous tumor clinical and histopathological features and bilateral tumors favor the influence of genetic factors as a potential etiological factor. It was proposed that 25% to Initial Tumor Second Tumor p Value 33% of all patients with TGCT have a genetic predisposi- Mean Ϯ SD age at diagnosis 27.1 Ϯ 6.5 tion.12 Furthermore, patients in TGCT prone families are Mean mos followup (range) 128 (41–348) 47 (12–204) — younger at diagnosis compared with patients with a sporadic % Seminoma histology 54.2 62.5 0.113 % ECa 29.2 29.2 Ͻ0.001* TGCT and the tumors tend to be bilateral more frequently % Vascular invasion 26.7 13.3 0.423 (15% vs 5%). However, studies of bilateral testicular tumors, % Increased serum markers 54.2 29.2 0.047* Mean Ϯ SD tumor size (cm) 4.78 Ϯ 1.76 2.59 Ϯ 1.62 0.001* including the current study, show that patients with bilat- % Stage 1 disease 75.0 95.8 0.077 eral TGCT are the same age at clinical presentation as % Chemotherapy 25 16.7 1.0 patients with familial disease. In addition, a series showed a % Radiotherapy 54.2 20.8 0.006* % Surveillance 20.8 62.5 0.027* high prevalence of androgen receptor gene mutations in patients with TGCT and the investigators suggested that * Statistically significant. some CAG/GGC combinations might be more frequently associated with an increased risk of testicular cancer.13 Con- sequently animal models would probably better define this issue in the near future by testing various hypotheses in caused by injection. Furthermore, patients were advised to etiopathogenetic and genetic studies. modify the suggested interval between injections according to libido. With this policy erectile function and libido were maintained as satisfactory. Two patients experienced a tran- Tumor Histology sient increase in hepatic transaminases, which resolved fol- Tumor histology is a major risk factor for contralateral lowing the cessation of injections. TGCT recurrence.3,14 In the current series patients with seminoma were at significantly higher risk for bilateral dis- ϭ DISCUSSION ease than patients with NSGCT (4.5% vs 2.3%, p 0.048). Similarly Che et al reported that the contralateral testis Incidence and Interval tumor risk was 1.8% in patients with seminoma and 0.6% in Yossepowitch and Baniel calculated that the crude incidence those with NSGCT.3 Moreover, a higher risk in patients of bilateral TGCT was 1% to 3.6% by analyzing data from 9 with seminoma was also reported in other series.15,16 On the published series including more than 10,000 patients.6 An- contrary, 2 reports showed a higher incidence of bilateral other recent review showed that reported cumulative inci- cases in patients with NSGCT compared to those with sem- dence rates increased from 1.2% to 5.2% in 15 years.7 Our inoma (8.4% vs 3.6%).8,14 Tabernero et al failed to observe an data correlated well with these rates (3.0%). Only few stud- effect of tumor histology on tumor bilaterality.7 It should be ies have focused on the increase in the incidence of bilateral emphasized that this conclusion was reached with only 6 cases.8 Although survival in these particular patients has patients in that study. improved dramatically during the last 20 years and con- For secondary tumors the incidence of patients with clin- tralateral tumors may develop many years after the first ical stage 1 is 44% to 91%.8,17 However, to our knowledge the one, the increase in the incidence is not surprising. There stage distribution of seminoma and NSGCT at presentation was a similar trend at Hacettepe University, where the has not been previously analyzed in detail. In the current incidence of bilateral cases increased from 2% to 3.0% in the study we noted that advanced stage at initial presentation last decade.4 On the other hand, an increase was not re- and subsequently at presentation was significantly more ported in a recent series from Spain.7 common in NSGCT than that in seminoma cases. Parallel to the literature findings, synchronous tumors were metastatic at presentation and they had similar histology on the 2 Risks sides. The exception is the study by Holzbeierlein et al, who Although there is controversy about chemotherapy for tes- reported that most patients in the synchronous and meta- ticular cancer, chemotherapy for the initial testis tumor chronous tumor groups presented with low stage disease in could potentially prevent or delay the development of a a series of 58 with bilateral TGCT.18 contralateral tumor.7 In the current series most patients with bilateral metachronous tumors had stage 1 disease as the primary and secondary tumors and, therefore, they did Self-Examination vs CTB not need chemotherapy. However, only 25% of the patients The current study demonstrates that regular self-examina- with metachronous tumors received chemotherapy for the tion of the testis was extremely important for leading pa- initial tumor in the current series. In the study from Spain tients to seek medical advice and, thus, for early referral and 50% of patients received chemotherapy and the investiga- diagnosis. Of presented patients 95.2% had stage 1 disease tors argued that this observation may have been a causative at secondary tumor diagnosis. Furthermore, secondary tu- factor.7 On the other hand, chemotherapy did not affect the mors were significantly smaller than primary tumors (4.78 rate of secondary tumor development in a series reported by vs 2.59 cm). All of these patients were diagnosed by self- Pamenter et al,9 while Thompson et al reported the con- examination or at routine followup examination by the cli- trary.10 nician. Two recent published series also demonstrated the Genetic and molecular mechanisms have been speculated small size of secondary tumors (mean 1.5 and 3.0 cm, re- about as potential carcinogenic factors for increasing the spectively).3,15 Similarly Albers et al reported that 25 of 30 risk of bilateral testicular cancer. Most adult TGCTs have a patients with bilateral tumors were detected by self-exami- characteristic isochromosome 12p (telomeric region of long nation, of whom 83% had stage 1 disease at presentation.19 132 BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY

All of our patients were in a disease-free state at the time of this report. Similarly in a recently reported series none of Abbreviations and Acronyms the 47 patients with bilateral testicular tumors died of tes- CTB ϭ contralateral testicular biopsy ticular cancer. However, capitalizing on the excellent sur- ECa ϭ embryonal carcinoma ϭ vival rates, routine CTB is usually not recommended.20 In GCT germ cell tumor NSGCT ϭ nonseminomatous GCT addition, none of our patients underwent routine biopsy at TGCT ϭ testicular GCT initial presentation. Although a few of them presented with TSS ϭ testis sparing surgery metastatic disease, all were cured by appropriate treatment modalities.

REFERENCES

TSS 1. Pharris-Ciureg ND, Cook LS and Weis NS: Incidence of testic- To maintain adequate testosterone in patients with bilateral ular cancer in the United States: has the epidemic begun to tumors TSS may be done. However, a main problem of TSS abate? Am J Epidemiol 1999; 150: 45. is the concern for carcinoma in situ foci adjacent to the 2. Huyghe E, Matsuda T and Thonneau P: Increasing incidence of tumor, which was reported to be present in 82% of 73 pa- testicular cancer worldwide: a review. J Urol 2003; 170: 5. tients with bilateral or solitary tumor treated with TSS. 3. Che M, Tamboli P, Ro JY, Park DS, Ro JS, Amato RJ et al: Bilateral testicular germ cell tumors: 20 year experience at Nevertheless, the German Testicular Cancer Study Group M. D. Anderson Cancer Center. Cancer 2002; 95: 1228. reported no local relapse following primary TSS with adju- 4. Tekin A, Aygun YC, Aki FT and Ozen H: Bilateral germ cell vant radiotherapy (18 Gy) and 85% of patients had normal cancer of the testis: a report of 11 patients with a long term testosterone at long-term followup.15 Even tumor enucle- followup. BJU Int 2000; 85: 864. ation might be considered as an alternative approach under 5. Peckham MJ, McElwain TJ, Barret A and Hendry WF: Com- certain conditions, including cold ischemia, organ con- bined management of malign teratoma of testis. Lancet fined tumor (less than 20 mm), multiple negative biopsies 1979; 2: 267. of the tumor bed and adjuvant local irradiation postoper- 6. Yossepowitch O and Baniel J: Role of organ-sparing surgery in germ cell tumors of the testis. Urology 2004; 63: 421. atively to avoid local recurrence. Furthermore, secondary 7. Tabernero J, Paz-Ares L, Salazar R, Lianes P, Guerra JA, tumors have had more favorable disease stage with sig- Borra SJ et al: Incidence of contralateral germ cell testicu- nificantly smaller size, as reported in the current series lar tumors in South Europe: report of the experience at 2 and others.3,15 These features make these patients ame- Spanish university hospitals and review of the literature. nable to this management policy. TSS might be more J Urol 2004; 171: 164. widely accepted in the future based on more studies with 8. Colls BM, Harvey VJ, Skelton L, Thompson PI and Frampton long-term data, as reported by Hentrich et al.20 However, CM: Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch 1978–1994. TSS necessitates close followup and high patient compli- J Clin Oncol 1996; 14: 2061. ance, which could prove to be difficult due to cultural, 9. Pamenter B, de Bono JS, Brown IL, Nandini M, Kaye SB, economic and geographic reasons. Russel JM et al: Bilateral testicular cancer: a preventable problem? Experience from a large cancer centre. BJU Int 2003; 92: 43. CONCLUSIONS 10. Thompson J, Williams CJ, Whitehouse JMA and Mead GM: Bilateral testicular germ cell tumours. An increasing inci- Randomized studies are impracticable for drawing certain dence and prevention by chemotherapy. Br J Urol 1988; 62: conclusions about bilateral testis cancer. Our large series 374. 11. van Echten J, Oosterhuis JW, Looijenga LHJ, van de Pol M, showed an incidence of 3.0% for bilateral TGCT, parallel to Wiersema J, te Meerman GJ et al: No recurrent structural the literature. As suggested in our study, patients with abnormalities apart from i(12p) in primary germ cell tu- initial seminoma were at higher risk for disease recur- mors of the adult testis. Genes Chromosomes Cancer 1995; rence on the other side and they had more favorable 14: 133. disease stage compared to those with NSGCT. Seminoma 12. Nicholson PW and Harland SJ: Inheritance and testicular is the most common histology in bilateral testicular can- cancer. Br J Cancer 1995; 71: 421. cer. Although they are infrequently detected, synchronous 13. Garolla A, Ferlin A, Vinanzi C, Roverato A, Sotti G, Artibani W tumors presented at more advanced stage with similar et al: Molecular analysis of the androgen receptor gene in testicular cancer. Endocr Relat Cancer 2005; 12: 645. histology on the 2 sides. Treatment for the first and second 14. Osterlind A, Berthelsen JG, Abildgaard N, Hansen SO, Hjal- testicular tumor should be based on primary tumor his- grim H, Johansen B et al: Risk of bilateral testicular germ tology and stage. cell cancer in Denmark: 1960–1984. J Natl Cancer Inst Patients with a history of TGCT require careful fol- 1991; 83: 1391. lowup and self-examination of the contralateral testicle 15. Heidenreich A, Weissbach L, Holtl W, Albers P, Kliesch S, due to the risk of bilateral disease and the potentially long Köhrmann KU et al: Organ sparing surgery for malignant latent period for a second tumor. Since long-term survival germ cell tumors of the testis. J Urol 2001; 166: 2161. is excellent with appropriate management and followup, 16. Bokemeyer C, Schmoll HJ, Schoffski P, Harstrick A, Bading M and Poliwoda H: Bilateral testicular tumours: prevalence CTB at initial orchiectomy is generally not recommended. and clinical implications. Eur J Cancer 1993; 29A: 874. TSS might be more widely accepted in the future based on 17. Coogan CL, Foster RS and Simmons GR: Bilateral testicular more studies with long-term data, as reported by Hentrich tumours—management and outcome in 21 patients. Cancer et al.20 1998; 83: 547. BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY 133

18. Holzbeierlein JM, Sogani PC and Sheinfeld J: Histology and at academic centers with a large volume of testis cancer clinical outcomes in patients with bilateral testicular germ are 1) long-term followup and self-examination are needed, cell tumors: the Memorial Sloan Kettering Cancer Center 2) seminoma is the most common histology in bilateral tes- experience 1950 to 2001. J Urol 2003; 169: 2122. ticular cancer, 3) treatment for the ﬁrst and second testicu- 19. Albers P, Goll A, Bierhoff-Schoeneich G and Muller C: Clinical course and histopathologic risk factor assessment in pa- lar tumors should be based on primary tumor histology and tients with bilateral testicular germ cell tumours. Adult stage, 4) TSS might be more widely accepted based on the Urol 1999; 54: 714. long-term followup, as reported by Hentrich et al (reference 20. Hentrich M, Weber N, Bergsdorf T, Liedl B, Hartenstein R and 20 in article), and 5) biopsy of the contralateral testis at Gerl A: Management and outcome of bilateral testicular initial orchiectomy is generally not recommended. germ cell tumors: twenty-ﬁve year experience in Munich. Acta Oncol 2005; 44: 529. W. Bedford Waters EDITORIAL COMMENT Division of Urology Bilateral testis cancers are rare. These authors present ex- University of Tennessee Medical Center perience with 30 patients at 2 institutions during 25 years. Knoxville, Tennessee The largest series were reported by groups from Memorial- Sloan Kettering Cancer Center (reference 18 in article) and 1. Geczi L, Gomez F, Bak M and Bodrogi I: The incidence, prog- 1 Hungary. nosis, clinical and histological characteristics, treatment, Take-home points for practicing urologists, who may see and outcome of patients with bilateral germ cell testicular 1 case in a lifetime, urology residents in training and those cancer in Hungary. J Cancer Res Clin Oncol 2003; 129: 309. Urological Survey

UROLOGICAL ONCOLOGY: PROSTATE CANCER

Decreased Risk of Prostate Cancer After Skin Cancer Diagnosis: A Protective Role of Ultraviolet Radiation? E. de Vries, I. Soerjomataram, S. Houterman, M. W. Louwman and J. W. Coebergh, Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands Am J Epidemiol Jan 25, 2007; Epub. Ultraviolet radiation causes skin cancer but may protect against prostate cancer. The authors hypothesized that skin cancer patients had a lower prostate cancer incidence than the general population. In the southeastern part of the Netherlands, a population-based cohort of male skin cancer patients diagnosed since 1970 (2,620 squamous cell carcinomas, 9,501 basal cell carcinomas, and 1,420 cutaneous malignant melanomas) was followed up for incidence of invasive prostate cancer until January 1, 2005, within the framework of the Eindhoven Cancer Registry. The incidence rates of prostate cancer among skin cancer patients were compared with those in the reference population, resulting in standardized incidence ratios. Skin cancer patients were at decreased risk of developing prostate cancer compared with the general population (standardized incidence ratio (SIR) ϭ 0.89, 95% confidence interval (CI): 0.78, 0.99), especially shortly after diagnosis. The risk of advanced prostate cancer was significantly decreased (SIR ϭ 0.73, 95% CI: 0.56, 0.94), indicating a possible antiprogression effect of ultraviolet radiation. Patients with a skin cancer in the chronically ultraviolet radiation-exposed head and neck area (SIR ϭ 0.84, 95% CI: 0.73, 0.97) and those diagnosed after the age of 60 years (SIR ϭ 0.86, 95% CI: 0.75, 0.97) had decreased prostate cancer incidence rates. These results support the hypothesis that ultraviolet radiation protects against prostate cancer. Editorial Comment: It is known that exposure to ultraviolet light increases the risk of skin cancer and conversely may decrease the risk of prostate cancer. To test whether these 2 are interrelated, these authors have looked at a large cohort of patients with skin cancer to see whether or not their risk of prostate cancer was decreased. It was by 11%. More impressively, their risk of advanced prostate cancer was decreased by 27%. They found that the patients who benefited the most were those who had chronic ultraviolet exposure to the head and neck areas and those diagnosed after age 60. In a smaller study published around the same time a similar inverse relationship between skin cancer and prostate cancer was demonstrated.1 Patrick C. Walsh, M.D.

1. Rukin NJ, Zeegers MP, Ramachandran S, Luscombe CJ, Liu S, Saxby M et al: A comparison of sunlight exposure in men with prostate cancer and basal cell carcinoma. Br J Cancer 2007; 96: 523.

A Prospective Cohort Study of Red Wine Consumption and Risk of Prostate Cancer S. Sutcliffe, E. Giovannucci, M. F. Leitzmann, E. B. Rimm, M. J. Stampfer, W. C. Willett and E. A. Platz, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Int J Cancer 2007; 120: 1529–1535. In light of recent, strong inverse ﬁndings between lifetime red wine consumption and prostate cancer among younger men, we revisited our previous cohort analysis to more thoroughly investigate red wine consumption and prostate cancer in the Health Professionals Follow-up Study (HPFS). In 1986, HPFS participants reported their average consumption of red wine, white wine, beer and liquor during the past year, and their change in alcohol consumption over the prior 10 years. Prostate cancer diagnoses were ascertained on each biennial questionnaire and conﬁrmed by medical record review. Between 1986 and 2002, 3,348 cases of prostate cancer were diagnosed among 45,433 eligible participants. Using men who did not consume red wine as the reference, no linear trend was observed between red wine consumption and prostate cancer in the full analytic cohort (p-trend ϭ 0.57). Among men with unchanged alcohol consumption in the prior 10 years, and those additionally Ͻ65 years of age, slightly lower risks were observed for men who consumed Ͻ/ϭ4 glasses of red wine/week, whereas null or slight increased risks were observed for men who consumed

0022-5347/07/1781-0134/0 134 Vol. 178, 134-139, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.149 PROSTATE CANCER 135

Ͼ4 glasses/week, resulting in a lack of linear trend. These findings suggest that red wine does not contribute appreciably to the etiology of prostate cancer. Editorial Comment: Recently, I reviewed an article which demonstrated a beneficial effect of red wine on the incidence of prostate cancer.1 However in this study, using the Health Profes- sionals Follow-Up Study cohort of patients, these authors were unable to demonstrate this effect. Although they did find a slightly lower risk of prostate cancer for men who drank fewer than 4 glasses of red wine per week, but not in men who consumed more, they felt that this pattern of association was difficult to explain biologically, assuming that men who drank more red wine would accumulate higher levels of protective agents such as resveratrol. They believe that the difference in the 2 studies may lie in selection bias in the prior study, whereby health conscious controls aware of the purported benefits of red wine for heart disease may have been more likely to participate in the study which showed a beneficial effect than less health conscious controls. Bad news for those of us who wanted an excuse to drink red wine. Patrick C. Walsh, M.D.

1. Schoonen WM, Salinas CA, Kiemeney LA and Stanford JL: Alcohol consumption and risk of prostate cancer in middle-aged men. Int J Cancer 2005; 113: 133.

Statin Drugs and Risk of Advanced Prostate Cancer E. A. Platz, M. F. Leitzmann, K. Visvanathan, E. B. Rimm, M. J. Stampfer, W. C. Willett and E. Giovannucci, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland J Natl Cancer Inst 2006; 98: 1819–1825. Background: Statins are commonly used cholesterol-lowering drugs that have proapoptotic and anti- metastatic activities that could affect cancer risk or progression. Results from previous epidemiologic studies of the association between statin use and cancer have been inconsistent. We investigated the association of statin use with total and advanced prostate cancer, the latter being the most important endpoint to prevent. Methods: We analyzed data from an ongoing prospective cohort study of 34,989 US male health professionals who were cancer free in 1990 and were followed to 2002. Participants reported their use of cholesterol-lowering drugs on biennial questionnaires. Prostate cancer diagnosis was confirmed by medical record review. Multivariable-adjusted relative risks (RRs) were estimated from Cox proportional hazards regression models. Statistical tests were two-sided. Results: During 376,939 person-years of follow-up, we ascertained 2579 prostate cancer cases, 316 of which were advanced (regionally invasive, metastatic, or fatal). The age-standardized incidence rates of advanced prostate cancer were 38 and 89 per 100,000 person-years in current statin users and in past or never users, respectively. The multivariable- adjusted relative risk of advanced disease was 0.51 (95% confidence interval [CI] ϭ 0.30 to 0.86) and of metastatic or fatal disease was 0.39 (95% CI ϭ 0.19 to 0.77) for current statin use compared with no current use. The associations remained after adjusting for prostate-specific antigen screening history (advanced disease: RR ϭ 0.57, 95% CI ϭ 0.30 to 1.11; metastatic or fatal disease: RR ϭ 0.35, 95% CI ϭ 0.14 to 0.92). Risk of advanced disease was lower with longer statin use (P(trend) ϭ .003); compared with never use, the relative risk for less than 5 years of use was 0.60 (95% CI ϭ 0.35 to 1.03) and for 5 or more years of use was 0.26 (95% CI ϭ 0.08 to 0.83). We found no association between statin use and risk of total prostate cancer (RR ϭ 0.96, 95% CI ϭ 0.85 to 1.09). Conclusions: In this cohort of male health professionals, use of statin drugs was not associated with risk of prostate cancer overall but was associated with a reduced risk of advanced (especially metastatic or fatal) prostate cancer. Editorial Comment: Using the same population of patients described in the aforementioned study (the Health Professionals Follow-Up Study), these authors demonstrated that although the use of statin drugs did not decrease the overall risk of being diagnosed with prostate cancer, it had a substantial effect on reducing the risk of development of advanced disease. They speculate that the beneficial effect may involve the reduced availability of cholesterol for incorporation into the cell membrane, which could influence membrane associated signaling that promotes cancer cell survival. Patrick C. Walsh, M.D. 136 PROSTATE CANCER Seasonality of Serum Prostate-Specific Antigen Levels, a Population-Based Study G. Salama, O. Noirot, V. Bataille, S. Malavaud, X. Rebillard, A. Villers and B. Malavaud for the French Arm of the ERSPC Study, Laboratoire de Biologie, Centre Hospitalier General Castres-Mazamet, Castres, France Eur Urol Nov 28, 2006; Epub. Objective: The measurement of PSA serum levels is central to all early detection programs for prostate cancer. Although individual PSA values were known to fluctuate in the short and long term, the influence of insolation and seasons on PSA had not been addressed to date. To assert the relationship between total and free PSA and meteorological data in 8644 participants (55–70 years) in the French arm of the ERSPC study. Methods: Blood sample was taken at the local laboratory after informed consent and frozen sera were sent for central testing of total and free PSA. PSA measurement was performed within 7 days on the Access 1.0 automat with Hybritech reagents. Monthly meteorological data - insolation, daily temperatures and rain precipitations - were obtained from the local branches of the National Meteorology Agency. Results: Total PSA - but not free PSA - was correlated with insolation - that is the monthly accrual in hours of sunshine during which the intensity was higher than 120Watt.m(Ϫ2), (rϭ0.05 (95%CI: 0.03–0.07; pϽ0.0001) while no relationships were shown between insolation and percent-free PSA (free PSA divided by the total PSA). Interdependence between total PSA and insolation was also apparent with respect to the 3ng/mL ERSPC cutoff for recommending biopsies (213.1 vs 206.2hours, pϭ0.004). Such relationship was even more evident in summer when the tested participants more often had a PSAϾ3ng/mL (17.1% vs 14.3%, pϭ0.0006) than in the rest of the year, resulting in 23% more chances of being referred for biopsies (Odds ratio 1.23, 95%CI: 1.10–1.40). Conclusions: Total PSA was shown to be strongly associated with insolation and seasons while the percent-free PSA was not influenced. Editorial Comment: This article suggests that it is important to consider what time of year a prostate specific antigen is drawn. The authors demonstrate a significant increase in PSA during the summer months, resulting in 23% more patients being referred for biopsies because their PSA was greater than 3 ng/ml. The reason for this is unclear but the authors speculate that it may have something to do with the effect of sunshine on biorhythms. Patrick C. Walsh, M.D.

Long-Term Prediction of Prostate Cancer up to 25 Years Before Diagnosis of Prostate Cancer Using Prostate Kallikreins Measured at Age 44 to 50 Years H. Lilja, D. Ulmert, T. Bjork, C. Becker, A. M. Serio, J. A. Nilsson, P. A. Abrahamsson, A. J. Vickers and G. Berglund, Department of Laboratory Medicine, Lund University, University Hospital UMAS, Malmo, Sweden J Clin Oncol 2007; 25: 431–436. Purpose: We examined whether prostate-speciﬁc antigen (PSA) forms and human kallikrein 2 (hK2) measured at age 44 to 50 years predict long-term risk of incident prostate cancer. Methods: From 1974 to 1986, 21,277 men age 50 years in Malmo, Sweden, enrolled onto a cardiovascular study (74% participation). The rate of PSA screening in this population is low. According to the Swedish Cancer Registry, 498 were later diagnosed with prostate cancer. We measured hK2, free PSA, and total PSA (tPSA) in archived blood plasma from 462 participants later diagnosed with prostate cancer and from 1,222 matched controls. Conditional logistic regression was used to test for association of prostate cancer with hK2 and PSA forms measured at baseline. Results: Median delay between venipuncture and prostate cancer diagnosis was 18 years. hK2 and all PSA forms were strongly associated with prostate cancer (all P Ͻ .0005). None of the 90 anthropometric, lifestyle, biochemical, and medical history variables measured at baseline was importantly predictive. A tPSA increase of 1 ng/mL was associated with an increase in odds of cancer of 3.69 (95% CI, 2.99 to 4.56); addition of other PSA forms or hK2 did not add to the predictive value of tPSA. tPSA remained predictive for men diagnosed Ͼ or ϭ 20 years after venipuncture, and the predictive value remained unchanged in an analysis restricted to palpable disease. Conclusion: A single PSA test at age 44 to 50 years predicts subsequent clinically diagnosed prostate cancer. This raises the possibility of risk stratiﬁcation for prostate cancer screening programs. Editorial Comment: This article provides valuable information on men under the age of 50 who have relatively low PSA levels. The odds ratio for prostate cancer developing before the age of 75 years was 3.7 for men with PSA levels of 1 ng/ml prior to age 50, 7 for PSA levels between 1 and 2 ng/ml, 19 for PSA levels between 2 and 3 ng/ml, and 39 for PSA levels greater than 3 ng/ml. TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY 137

These results are all the more impressive because they occurred in a country where screening for prostate cancer is low. The ﬁndings in this study are similar to those previously reported from the Baltimore Longitudinal Study of Aging, which showed that men in their 40s who had PSA levels greater than 0.6 ng/ml had a 4-fold higher risk of developing prostate cancer over time.1 Thus, a man in his 40s with a PSA level of 1.0 ng/ml or greater needs to be followed very carefully. Patrick C. Walsh, M.D.

1. Fang J, Metter EJ, Landis P, Chan DW, Morrell CH and Carter HB: Low levels of prostate-speciﬁc antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging. Urology 2001; 58: 411.

Effect of 1 mg/Day Finasteride on Concentrations of Serum Prostate-Specific Antigen in Men With Androgenic Alopecia: A Randomised Controlled Trial A. V. D’Amico and C. G. Roehrborn, Department of Radiation Oncology, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute, Boston, Massachusetts Lancet Oncol 2007; 8: 21–25. Background: Use of 5 mg/day finasteride (Proscar) for benign prostatic hyperplasia is known to affect serum concentrations of prostate-specific antigen (PSA). When men taking this treatment undergo screening for prostate cancer, a compensatory adjustment of the PSA concentration (to multiply the value by two) is recommended. Whether this recommendation should apply to men taking 1 mg/day finasteride (Propecia) for the treatment of androgenic alopecia is unknown. We aimed to assess the effect of 1 mg/day finasteride on serum PSA in men aged 40–60 years with male-pattern hair loss. Methods: Between March 13, 1998, and Jan 12, 2000, 355 men aged 40–60 years with male-pattern hair loss were stratified by age decade (40–49 years and 50–60 years), and randomised in a ratio of four to one to 1 mg/day finasteride or placebo. The primary endpoint was the effect of this treatment for 48 weeks on serum PSA concentration compared with placebo. This trial is in the process of being registered on the US National Institutes of Health website. Analyses were according to protocol. Findings: Within 48 weeks of randomisation, men aged 40–49 years and 50–60 years who were assigned 1 mg/day finasteride had a median decrease in serum PSA concentration of 40% (95% CI 34–46) and 50% (44–57), respectively. In men assigned placebo, the median changes were 0% [Ϫ14 to 14] and a median increase of 13% [2 to 24], respectively. Interpretation: In men aged 40–60 years, 1 mg/day finasteride for 48 weeks lowers serum PSA concentration. Therefore, the existing recommendation for the adjustment of serum PSA concentration in prostate-cancer screening in men taking 5 mg/day finasteride should also apply to men taking the 1 mg/day preparation for male-pattern hair loss. Research is needed to assess the effect of 1 mg/day finasteride preparation beyond 48 weeks of treatment. Editorial Comment: I thought that most physicians knew that Propecia® (finasteride 1 mg) had the same effect on lowering PSA as finasteride 5 mg (Proscar®). They both lower dihydrotestosterone levels similarly. Apparently I am wrong, because this article received widespread coverage in the press. Patrick C. Walsh, M.D.

UROLOGICAL ONCOLOGY: TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY

Risk Factors for Testicular Cancer—Differences Between Pure Non-Seminoma and Mixed Seminoma/Non-Seminoma? E. L. Aschim, T. B. Haugen, S. Tretli, A. K. Daltveit and T. Grotmol, Andrology Laboratory, Department of Gynaecology and Obstetrics, Rikshospitalet University Hospital, Oslo, Norway Int J Androl 2006; 29: 458–467.

The origin of testicular germ cell cancer (TGCC) is believed to be carcinoma in situ cells developed in utero. Clinically, TGCCs are divided into two major histological groups, seminomas and non-seminomas, where 138 BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY

the latter group includes non-seminomatous TGCCs with seminomatous components (mixed S/NS TGCC). Recent studies, however, have suggested that non-seminomas and mixed S/NS TGCCs could have certain differences in aetiology, and in this study the TGCCs were divided into three, rather than the conventional two histological groups. A large case-control study was undertaken on data on all live-born boys registered in the Medical Birth Registry of Norway during the period 1967–1998 (nϭ961 396). Among these were 1087 TGCC cases registered in the Cancer Registry of Norway until February 2004. We found several risk factors for TGCC, including low parity, low gestational age, epilepsy and retained placenta. Several of the variables studied seemed to be risk factors for specific histological groups, e.g. parity 0 vs. 2 and low gestational age being associated with increased risk of non-seminomas, but not of mixed S/NS TGCC, and low maternal age being associated with increased risk of mixed S/NS TGCC, but not of non-seminomatous TGCC. Therefore, our results might suggest that non-seminomas and mixed S/NS TGCCs have partially different risk factors, whose associations may be obscured by combining these two histological groups. The histological groups were not significantly different, however. Most of our findings on risk factors for TGCC are in agreement with at least some previous studies. An unexplainable exception is low birth weight being associated with reduced risk of TGCC in our study. Editorial Comment: Although the etiology of testicular cancer is uncertain, many investigators propose that changes in utero, especially in the first trimester of pregnancy, may be critical for the development of testicular germ cell cancers. Prior studies have identified associations between maternal health and prenatal and perinatal characteristics during pregnancy, and risk of testicular cancer. The authors have used the Medical Birth Registry of Norway, which covers all live births dating back to 1967, along with the Cancer Registry of Norway, which has compulsory reporting since 1952. A total of 1,125 men had unilateral or bilateral testicular cancer. After exclusions 1,087 testicular germ cell cancer cases were available, along with 113,000 controls (100 controls randomly extracted from the same birth cohort as the index case). Maternal factors such as low parity, low gestational age, epilepsy and retained placenta carried an increased relative risk for the development of testicular cancer. However, there was some discordance of risk factors for the development of pure nonseminomas and mixed germ cell tumors with seminoma and nonseminomatous combinations. Jerome P. Richie, M.D.

UROLOGICAL ONCOLOGY: BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY

A Prospective Study of 100 Cases of Penile Cancer Managed According to European Association of Urology Guidelines P. K. Hegarty, O. Kayes, A. Freeman, N. Christopher, D. J. Ralph and S. Minhas, Urology, Institute of Urology and Pathology, University College Hospital London, London, United Kingdom BJU Int 2006; 98: 526–531.

Objective: To prospectively assess the outcome of patients treated according to the European Association of Urology (EAU) guidelines on the management of penile cancer, a system originally based on retrospective series. Patients and Methods: Between 2002 and 2005, 100 consecutive patients (median age 62 years) with penile cancer were treated at one institution; all were categorized and treated according to EAU guidelines. Data were analysed using the z-test, with significance defined as P Ͻ 0.05. Results: Survival curves were limited to those with Ͼ12 months of follow-up (mean 29); the survival of the whole group was 92%. Of men with palpable nodes, 72% had lymph node involvement, whereas 18% of those with impalpable nodes who had lymphadenectomy according to the guidelines had lymph node disease. The grade of the primary tumour was more predictive than T stage for lymph node involvement and survival. The 3-year disease- specific survival for N0, N1 and N2 disease was 100%, 100% and 73%, respectively, and survival at 12 months for N3 disease was 67%. The median survival for those with metastases was 3 months. Conclusion: The overall survival of men with penile cancer is high, with a clear benefit for early lymphadenectomy in men with positive nodal disease. However, the current EAU guidelines are limited in predicting those patients with micrometastatic disease, with the result that 82% of patients undergo unnecessary prophylactic lymphadenectomy. There is a need to identify more accurate molecular markers for predicting lymph node disease, or the role of novel staging techniques must be assessed. BLADDER, PENIS AND URETHRAL CANCER, AND BASIC PRINCIPLES OF ONCOLOGY 139

Editorial Comment: Many societies and associations have developed treatment guidelines for a variety of diseases. Currently, there are relatively few studies that examine the outcomes of patients who are treated according to these guidelines. This study is unique and noteworthy because it prospectively examined patients with penile carcinoma treated according to the EAU guidelines. The authors identiﬁed the limitations of the EAU guidelines on the treatment of penile cancer, indicating that they were not as helpful as desired in predicting patients with micrometastatic disease, since 82% of those undergoing lymphadenectomy had negative nodes. Similar studies are necessary to evaluate treatment guidelines in a wide variety of urological cancers. James E. Montie, M.D. Infection/Inﬂammation

Combined Prednisone and Mycophenolate Mofetil Treatment for Retroperitoneal Fibrosis

Paul J. Scheel, Jr.,* Jonathan Piccini, M. Haﬁzur Rahman, Leo Lawler and Thomas Jarrett† From the Division of Nephrology, Department of Medicine, The Johns Hopkins Medical Institution (PJS) and Department of International Health, The Johns Hopkins Bloomberg School of Public Health (MHR), Baltimore, Maryland, Division of Cardiology, Department of Medicine, Duke University Medical Center (JP), Durham, North Carolina, Department of Radiology, Mater Misericordiae University Hospital (LL), Dublin, Ireland, and Department of Urology, George Washington University Hospital (TJ), Washington, D. C.

Purpose: We determined the efficacy of a combination of corticosteroids and mycophenolate mofetil for retroperitoneal fibrosis. Materials and Methods: We performed a prospective observational study of the treatment of 7 patients with biopsy proven retroperitoneal fibrosis. Patients were treated with 40 mg prednisone daily with a gradual taper over 6 months. Mycophe- nolate mofetil was administered at a starting dose of 1,000 mg twice daily and continued for 6 months following resolution of systemic symptoms and extubation of affected ureters. Outcomes included normalization of laboratory evidence of inflammation, regression of fibrosis by computerized tomography and the ability to discontinue ureteral stents. Results: Seven patients were treated with mycophenolate mofetil and prednisone. Five of the 7 patients had bilateral ureteral obstruction and 1 had unilateral obstruction requiring ureteral stents. Baseline and followup laboratory values were C-reactive protein 8.9 and 1.3 mg/dl (p ϭ 0.07), hemoglobin 10.7 and 12.7 gm/dl (p ϭ 0.001), erythrocyte sedimentation rate 76 and 14.5 mm per hour (p ϭ 0.015) and serum creatinine 3.32 and 1.08 mg/dl (p ϭ 0.07), respectively. Six of the 7 patients had a mean 32% regression of the retroperitoneal mass on computerized tomography. Ten of the 11 obstructed ureters were free of obstruction following ureteral stent removal. The mean time to stent removal was 10.5 months. One patient had a distal ureteral stricture and continued to require decompression. There were no treatment related side affects. Conclusions: Mycophenolate mofetil combined with prednisone was safe and efficacious in this small cohort of patients with retroperitoneal fibrosis. Larger trials are needed to confirm these results. Key Words: ureter, retroperitoneal fibrosis, mycophenolate mofetil, prednisone, ureteral obstruction

etroperitoneal fibrosis is a condition characterized by novo purine synthesis. MMF has been shown to be effective inflammation and fibrosis in the retroperitoneal as monotherapy or in combination with low dose corticoste- R space. The disease process begins with clinical symp- roids for multiple inflammatory diseases, including trans- toms of flank pain and unexplained weight loss. Radiograph- plant rejection, lupus nephritis, inflammatory bowel disease ically fibrosis starts by surrounding the infrarenal aorta. It and more recently primary glomerulopathies.2 Additionally, progresses inferior toward the iliac bifurcation, and lateral MMF was reported to arrest RPF progression in a single toward the renal hilum and surrounding structures, ulti- case report.3 mately leading to ureteral obstruction and acute renal fail- The pathophysiology of RPF is poorly understood. How- ure. Historically treatment has been focused on relieving ever, there is clear evidence for a role of the immune system obstruction with percutaneous or cystoscopic assisted place- in the initiation or progression of the disease.4–6 There is ment of ureteral stents followed by more definitive resolu- also evidence to suggest that MMF has efficacy for treating tion of ureteral obstruction with open or laparoscopic ure- B and T-cell mediated diseases with limited side affects and terolysis with or without omental wrapping. In the last toxicity.7 We offered MMF therapy combined with cortico- several years case reports and small series have documented steroids in patients who refused definitive surgical correc- successful nonsurgical management with various immuno- tion or who were viewed as poor operative candidates. suppressive agents, including prednisone, cyclosporine, methotrexate, azathioprine, MMF and the selective estrogen METHODS receptor antagonist tamoxifen.1 MMF is an immunosuppressive agent that antagonizes Patient Population lymphocyte proliferation and function by the inhibition of de Between September 2002 and March 2005, 9 patients were referred to the nephrology clinic with suspected RPF for nonsurgical management. Two patients refused therapy and Submitted for publication November 22, 2006. were lost to followup. Seven patients agreed to therapy and * Correspondence: Division of Nephrology, The Johns Hopkins they are the topic of this report. University School of Medicine, 1830 East Monument St., Room 416, All patients underwent cross-sectional imaging with CT Baltimore, Maryland 21205 (telephone: 410-955-5268; FAX: 410- 955-0485; e-mail: [email protected]). and core biopsies were obtained with histological confirma- † Financial interest and/or other relationship with ACMI/Gyros. tion of RPF before the initiation of therapy. Patients were

0022-5347/07/1781-0140/0 140 Vol. 178, 140-144, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.057 PREDNISONE AND MYCOPHENOLATE MOFETIL FOR RETROPERITONEAL FIBROSIS 141 queried on the historical or current use of methysergide, mild—0% to 50%, moderate—50% to 75%, severe—75% to ␤-blockers, hydralazine, pergolide, bromocriptine, ergota- 95% and occluded—100%. mine, methyldopa, or a history of external beam radiation, recent abdominal trauma, or abdominal or pelvic surgery. Statistical Analysis Patients had up-to-date age appropriate cancer screening Descriptive statistics were used to summarize and compare including, digital rectal and testicular examination with laboratory measures before and after medical therapy, in- prostate specific antigen in men, and Papanicolaou smear cluding ESR, creatinine and hemoglobin. The mean values and mammography in woman. All patients underwent of measures before and after medical therapy were com- colonoscopy with chest and abdomen imaging before the pared using the paired t test. Absolute p values for the initiation of therapy. Baseline laboratory screening included differences are reported. Statistical analyses were per- chemistry profile, complete blood count, ESR, C-reactive formed using STATA®, version 9. protein, thyroid stimulating hormone and antinuclear antibodies. RESULTS Seven patients began chemotherapy and completed the pro- Treatment tocol. Mean age of the patient population was 52 years Chemotherapy consisted of 1,000 mg MMF administered (range 39 to 74). Four of the 7 patients (57%) were female. orally twice daily until 6 months following the resolution of The racial makeup was Hispanic in 1 patient, white in 2, systemic symptoms and the extubation of affected ureters. African in 2, black American in 1 and Middle Eastern in 1. All patients were initially started on 40 mg prednisone ad- Table 1 lists the clinical presentations of all 7 patients. ministered orally for 6 weeks with monthly tapering by 10 Only 1 of 7 patients had an identified risk factor for RPF mg until a daily dose of 10 mg daily for 1 month was at- (external beam radiation for spinal cord tumor). Five of the tained. Subsequently prednisone was decreased to 5 mg 7 patients had bilateral and 1 had unilateral ureteral ob- daily day for 1 month and then 5 mg every other day for 1 struction. Patient 7 had biopsy proven RPF without obstruc- month for a total of 6 months of corticosteroid therapy. tion. A total of 11 ureters required stenting. Ten stents were successfully removed. One ureter had a distal ureteral stric- Followup ture, requiring continued decompression. Mean followup in All patients were seen at least quarterly with followup lab- this cohort was 34.3 months (range 19 to 52). oratory assessment and serial cross-sectional imaging. De- All patients completed the 6 months of prednisone. The cisions to remove Double-J® stents or percutaneous ne- mean time of MMF treatment was 19.2 months (range 10 to phrostomy tubes were made in conjunction with the 30). One patient who had type II diabetes mellitus before referring urologist. Patients had to have laboratory and therapy and was noninsulin dependent required insulin dur- clinical resolution of systemic symptoms and radiographic ing the prednisone arm of therapy. No patient had identifi- evidence of fibrotic regression. For patients with bilateral able side affects of MMF. obstruction ureteral stents or percutaneous nephrostomy Table 2 shows the laboratory and clinical followup of all 7 tubes were removed several weeks apart. After each stent or patients. Mean time to stent removal was 10.5 months percutaneous nephrostomy tube was removed the patient (range 2 to 17). Weight loss and flank pain were dominant underwent nuclear medicine flow scans with delayed images clinical features before the initiation of therapy. No patient to ensure that there was no evidence of obstruction. had complaints of pain following the completion of therapy and all were restored to self-reported body weight before the onset of illness. There were no disease relapses. Of the 3 Radiographic Review males in the study none had physical examination evidence All CT images were reviewed by a single radiologist experi- of hydrocele or varicocele. No patient had history or sero- enced with cross-sectional imaging who was blinded to clin- logical evidence of autoimmune disease. One patient had ical results. Scans were evaluated for fibrosis type. From the ADPKD. radiological perspective classic RPF was defined as a disease A total of 24 CT images were reviewed (range 3 to 6, mean process centered in the retroperitoneum and extending from 3.4 per patient). On the initial CT images before therapy 6 of the level of the renal pedicles to the iliac bifurcation with 7 patients had classic RPF. The single patient with nonclas- variable lateral extension. Other forms of RPF were defined based on the affected anatomical site or end organ. When multiple sites were involved, RPF was defined as contiguous TABLE 1. Clinical characteristics at first visit to nephrology clinic or noncontiguous. No. pts 7 The extent of disease and temporal change of the disease No. wt loss greater than 10 pounds 6 was defined by changes in enhancement, objective soft tissue Av pounds wt loss (range) 40.8 (25–60) No. fatigue 7 measures and the end organ. The disease burden was deter- No. pain 7 mined by measuring the thickness of soft tissues relative to No. hypothyroidism 3 a fixed anatomical landmark on successive images, typically No. history: Hypertension 0 the aorta. For nonclassic RPF the largest cross-sectional Coronary artery, peripheral or cerebral vascular 0/7 measurement was considered an index of disease burden disease with time. The aorta, inferior vena cava, and renal and iliac Tobacco use 2 Av mos between symptom onset ϩ chemotherapy 6.5 (3–15) vasculature were evaluated for signs of encasement, stenosis (range) or occlusion. The aorta was also evaluated for aneurysmal No. ureters requiring percutaneous nephrostomy or 11/14 changes. The degree of vascular stenosis was identified as ureteral stent/total No. ureters 142 PREDNISONE AND MYCOPHENOLATE MOFETIL FOR RETROPERITONEAL FIBROSIS

there is little agreement on the appropriate definition of a TABLE 2. Initial and followup laboratory data clinically significant response. Some groups analyzed regres- Mean Ϯ SD Mean Ϯ SD sion of the retroperitoneal mass, as assessed by cross-sec- Variable Normal Baseline Followup p Value tional imaging,9,12 while others defined therapeutic success C-reactive protein 0.0–0.5 8.9 Ϯ 8.6 1.3 Ϯ 1.4 0.08 in terms of patient and renal survival or the relief of obstruc- (mg/dl) Hemoglobin (gm/dl) 12–15 10.8 Ϯ 1.9 12.8 Ϯ 1.8 0.001 tion sufficient to obviate the need for a percutaneous ne- ESR (mm/hr) 4–30 76.1 Ϯ 51.0 14.5 Ϯ 11.8 0.016 phrostomy tube or internal Double-J stents.13 Serum creatinine 0.5–1.2 3.3 Ϯ 2.9 1.1 Ϯ 0.3 0.07 In this prospective cohort we clearly defined the popula- (mg/dl) tion under study. All patients had RPF. One of the 7 patients had a known risk factor for RPF. All patients underwent biopsy with histological review and all had clinical and lab- sic RPF had a history of external beam radiation, and multi- oratory testing performed in prospective fashion. Our deci- focal and noncontiguous fibrosis. Three of the 7 patients had sion to use a combination of prednisone and MMF was based initial enhancement, 5 had lateral extension of the disease on the available literature and what little is known about process, resulting in hydronephrosis that was moderately the pathophysiology of this disease. severe, and 3 had unilateral atrophy. There were no cases of RPF begins histopathologically as an aggregation of aortic dilatation or aneurysmal formation. Four patients round mononuclear cells composed of B and T lymphocytes, 14 had left renal vein encasement but only 1 had renal vein and a plasmacytic infiltrate. As disease progresses, there narrowing. The inferior vena cava was involved in all 7 is capillary proliferation and an eosinophilic inflammatory cases. Involvement was considered mild in 3 patients, mod- infiltrate. It is during this phase that one sees the accumu- erate in 1, severe in 7 and occlusion in 1. Six patients had lation of lymphocytes and plasma cells around blood ves- 14 regression of the fibrotic mass with a mean reduction of 32% sels. Immunohistochemistry reveals that these cells are (range 16% to 62%). One of the 6 patients had no regression. predominantly CD20ϩ B lymphocytes with a smaller com- 4 No patients showed disease progression during the entire ponent of CD45ϩ T lymphocytes and CD6ϩ macrophages. series of images or disease enhancement on the final scans. This active inflammatory infiltrate changes in appearance The figure shows representative baseline and followup im- with time to appear as a dense fibrous mass with rare, aging in this cohort. interspersed inflammatory cells. Ideally one would like to intervene in the early inflam- DISCUSSION matory phase of the disease, at the time before progression to dense fibrosis. Corticosteroids are known to inhibit the RPF is a condition that is poorly characterized and of un- cellular cascade of inflammation and the immune response clear etiology. It is a disease for which the most appropriate at all levels. The overall effect of corticosteroids is inhibition therapy is not defined. of the recruitment of cells to the inflammatory site, and Currently RPF is classified with other disease states that blockade of the production and effects of pro-inflammatory lead to inflammation and fibrosis surrounding the infrarenal mediators. Kardar et al were the first to report in prospec- aorta.1 These conditions, collectively referred to as periaor- tive fashion their experience with 2 years of corticosteroids titis, include inflammatory abdominal aortic aneurysm, combined with ureteral decompression in 12 patients with peri-aneurysmal RPF and RPF. These 3 disease states share biopsy proven RPF.15 Of their patients 81% had regression similar histopathological characteristics but it is unclear of the retroperitoneal mass without recurrence at a median whether they share similar initiating events or a common followup of 63.1 months. Although Kardar et al did not pathological progression, or merely pathologically reflect the report any treatment related complications, side effects of end product of several different disease states. long-term corticosteroids are common, including osteopenia, Radiographically RPF can be distinguished from other myopathy, glucose intolerance and infection. In other dis- forms of periaortitis by absent dilatation of the infrarenal ease states the side affects of corticosteroids are related to aorta.1 RPF can be classified as primary (idiopathic) or sec- the dose and duration of therapy.16 Therefore, we elected to ondary based on the presence or absence of conditions minimize the use of corticosteroids. known to be associated with RPF. These associative condi- Mycophenolic acid, the active metabolite of MMF, inhib- tions are certain drugs, infections and trauma.1 Depending its T and B-lymphocyte proliferation, B-lymphocyte anti- on the series 10% to 25% of RPF cases have had an identifiable associated condition.8 There are currently no standardized criteria for the diagnosis of RPF. The absence of such criteria make comparison of case reports and small series challenging. Many physicians make the diagnosis of RPF based on clinical symptoms and cross-sectional imaging without biopsy and appropriate histological review.9–12 Several groups reported that biopsy may actually change the diagnosis in 25% of cases, making interpretation of series without biopsy potentially mislead- Abdominal CT with intravenous contrast medium in patient with 8 ing. Others pooled data on all forms of periaortitis, al- idiopathic RPF and ADPKD. A, pretreatment view shows typical though there are sparse data to support a common patho- ADPKD cystic changes (arrows) with partially enhancing soft tissue physiological mechanism.11 Most groups that analyzed mass surrounding abdominal aorta (arrowhead). B, at month 10 of therapy ADPKD cystic changes persisted (arrows) and there was outcomes did so retrospectively, therefore, limiting the col- significant reduction in soft tissue mass surrounding abdominal lection of all necessary data elements.9–11 Additionally, aorta (arrowhead) without enhancement. PREDNISONE AND MYCOPHENOLATE MOFETIL FOR RETROPERITONEAL FIBROSIS 143 body production, and the glycosylation and expression of 4. Vaglio A, Corradi D, Manenti L, Ferretti S, Garini G and Buzio adhesion molecules, while it was shown to induce apoptosis C: Evidence of autoimmunity in chronic periaortitis: a pro- in activated T cells.7 Additionally, MMF was shown to have spective study. Am J Med 2003; 114: 454–62. antifibrotic properties in nonimmune experimental models 5. Parums DV, Chadwick DR and Mitchinson MJ: The localisa- of acute and chronic kidney disease.17–19 tion of immunoglobulin in chronic periaortitis. Atheroscle- rosis 1986; 61: 117. The pathology of RPF shows components of immune me- 6. Parums DV, Brown DL and Mitchinson MJ: Serum antibodies diated inflammation and clear evidence of fibrosis. Given the to oxidized low-density lipoprotein and ceroid in chronic characteristics of immune mediated and fibrotic disease, periaortitis. Arch Pathol Lab Med 1990; 114: 383. MMF would appear to be a suitable drug to study for the 7. Moder KG: Mycophenolate mofetil: new applications for this treatment of RPF. Before this report there was a solitary immunosuppressant. Ann Allergy Asthma Immunol 2003; report on 1 patient who was successfully treated with MMF 90: 15. for RPF.3 Unlike long-term use of corticosteroids MMF is 8. Gilkeson GS and Allen NB: Retroperitoneal fibrosis. A true generally well tolerated. The most common side affects at- connective tissue disease. Rheum Dis Clin North Am 1996; tributable to MMF are gastrointestinal complaints of dys- 22: 23. pepsia and/or loose stool. These symptoms are mild to mod- 9. Moroni G, Gallelli B, Banfi G, Sandri S, Messa P and Ponticelli C: Long-term outcome of idiopathic retroperitoneal fibrosis erate and can be treated with H2-blockers, proton pump treated with surgical and/or medical approaches. Nephrol inhibitors or dose reduction. None of these symptoms devel- Dial Transplant 2006; 21: 2485. oped in any of our patients. In cases of solid organ trans- 10. Marcolongo R, Tavolini IM, Laveder F, Busa M, Noventa F, plants and primary glomerulopathy leukopenia with various Bassi P et al: Immunosuppressive therapy for idiopathic infections has been reported, requiring frequent monitor- retroperitoneal fibrosis: a retrospective analysis of 26 cases. ing.2 Again, no such side affects were found in any of our Am J Med 2004; 116: 194. patients. 11. Warnatz K, Keskin AG, Uhl M, Scholz C, Katzenwadel A, Six of the 7 patients studied had idiopathic RPF. All 6 Vaith P et al: Immunosuppressive treatment of chronic patients with idiopathic RPF had significant constitutional periaortitis: a retrospective study of 20 patients with symptoms of weight loss, fatigue and pain, and laboratory chronic periaortitis and a review of the literature. Ann Rheum Dis 2005; 64: 828. evidence of systemic inflammation. All 6 patients with idio- 12. van Bommel EF, Hendriksz TR, Huiskes AW and Zeegers AG: pathic RPF had regression of the periaortic fibrotic mass. Brief communication: tamoxifen therapy for nonmalignant One patient had nonclassic RPF. The decision to treat that retroperitoneal fibrosis. Ann Intern Med 2006; 144: 101. patient was based on progressive fibrosis during 15 months 13. Baker LR, Mallinson WJ, Gregory MC, Menzies E, Cattell W, with lateral extension and bilateral obstruction. Although Whitefield H et al: Idiopathic retroperitoneal fibrosis. A radiographically there was no regression of fibrosis in this retrospective analysis of 60 cases. Br J Urol 1987; 60: 497. patient, the 2 internal Double-J stents were successfully 14. Wu J, Catalano E and Coppola D: Retroperitoneal fibrosis removed without evidence of recurrence of obstruction. (Ormond’s disease): clinical pathologic study of eight cases. We acknowledge the limitations inherent in this report. Cancer Control 2002; 9: 432. The results are not those of a controlled clinical trial with 15. Kardar AH, Kattan S, Lindstedt E and Hanash K: Steroid therapy for idiopathic retroperitoneal fibrosis: dose and randomization. Patients were treated with corticosteroids duration. J Urol 2002; 168: 550. and MMF, and we cannot exclude the possibility that a 16. Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister similar outcome would have been achieved with MMF or LF, Zimmerman B et al: Low dose long-term corticosteroid corticosteroids alone. As with all novel treatment strategies, therapy in rheumatoid arthritis: an analysis of serious ad- the proper role for MMF in the management of RPF can only verse events. Am J Med 1994; 96: 115. be determined by prospective, well designed clinical trials in 17. Kramer S, Loof T, Martini S, Sebastian M, Matthias R, Yingrui appropriately stratified, large patient cohorts. W et al: Mycophenolate mofetil slows progression in anti- thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril. Am J Physiol Renal Physiol 2005; 289: F359. Abbreviations and Acronyms 18. Goncalves RG, Biato MA, Colosimo RD, Martinusso CA, Pecly ADPKD ϭ autosomal dominant polycystic kidney I, Farias E et al: Effects of mycophenolate mofetil and disease lisinopril on collagen deposition in unilateral ureteral ob- CT ϭ computerized tomography struction in rats. Am J Nephrol 2004; 24: 527. ESR ϭ erythrocyte sedimentation rate 19. Morath C and Zeier M: Review of the antiproliferative proper- MMF ϭ mycophenolate mofetil ties of mycophenolate mofetil in non-immune cells. Int RPF ϭ retroperitoneal fibrosis J Clin Pharmacol Ther 2003; 41: 465.

EDITORIAL COMMENT REFERENCES RPF is a rare disease characterized by an inflammatory 1. Vaglio A, Salvarani C and Buzio C: Retroperitoneal fibrosis. fibrotic process, leading frequently to ureteral obstruction Lancet 2006; 367: 241. (reference 1 in article). While the surgical approach to RPF 2. Choi MJ, Eustace JA, Gimenez LF, Attta MG, Scheel PJ, Sothinathan R et al: Mycophenolate mofetil treatment for is straightforward, ie ureterolysis and stenting, medical primary glomerular diseases. Kidney Int 2002; 61: 1098. treatment to stop and regress the disease is not well estab- 3. Grotz W, von Zedtwitz I, Andre M and Schollmeyer P: Treat- lished. To date steroids have been generally considered the ment of retroperitoneal fibrosis by mycophenolate mofetil primary choice (reference 1 in article). These authors report and corticosteroids. Lancet 1998; 352: 1195. a prospective, small case series documenting that the lym- 144 PREDNISONE AND MYCOPHENOLATE MOFETIL FOR RETROPERITONEAL FIBROSIS phocyte inhibitor MMF combined with steroids effectively ideal platform through which we can achieve good clinical decreases patient symptoms, systemic inflammation mark- evidence even in rare diseases. ers and the periaortic fibrotic mass. These results are encouraging. They argue strongly for controlled trials in RPF Sebastian Martini and Harm Peters with a sufficient number of patients and the time has come Department of Nephrology for this. We should be aware that the actually ongoing glob- Charité Universitätsmedizin Berlin alization in medicine via the World Wide Web provides an Berlin, Germany Effect of Comestibles on Symptoms of Interstitial Cystitis

Barbara Shorter, Martin Lesser,* Robert M. Moldwin†,‡ and Leslie Kushner From the Department of Nutrition, C. W. Post Campus of Long Island University (BS), Brookville, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System (ML, LK), Manhasset and Institute for Urology, Long Island Jewish Medical Center (RMM, LK), New Hyde Park, New York

Purpose: Anecdotal evidence suggests that patients with painful bladder syndrome/interstitial cystitis report symptom exacerbation after consuming particular foods, beverages and/or supplements. We determined the prevalence of the effect of comestibles on painful bladder syndrome/interstitial cystitis symptoms and identified particular comestible items more likely to affect such symptoms. Materials and Methods: A validated questionnaire designed to detect whether food, beverages and/or supplements have an effect on bladder symptoms was administered to 104 patients meeting National Institute for Diabetes and Digestive and Kidney Diseases criteria for interstitial cystitis. In addition to answering general questions about the effect of comestibles on painful bladder syndrome/interstitial cystitis symptoms, subjects were asked to indicate whether each of 175 individual items worsened, improved or had no effect on symptoms. Each response was numerically scored on a scale of Ϫ2 to 2 and mean values were generated for each comestible item. Results: Of the surveyed patients with painful bladder syndrome/interstitial cystitis 90.2% indicated that the consumption of certain foods or beverages caused symptom exacerbation. There was no correlation between allergies and the effect of comestibles on symptoms. Patients who reported that specific foods worsened symptoms tended to have higher O’Leary-Sant interstitial cystitis symptom index and problem index, and/or pelvic pain and urgency/frequency patient symptom scale scores. A total of 35 comestible items had a mean score of lower than Ϫ1.0, including caffeinated, carbonated and alcoholic beverages, certain fruits and juices, artificial sweeteners and spicy foods. Conclusions: There is a large cohort of patients with painful bladder syndrome/interstitial cystitis in whom symptoms are exacerbated by the ingestion of specific comestibles. The most frequently reported and most bothersome comestibles were coffee, tea, soda, alcoholic beverages, citrus fruits and juices, artificial sweeteners and hot pepper. Key Words: bladder; cystitis, interstitial; diet; nutritional status; questionnaires

ainful bladder syndrome/interstitial cystitis is a and how many foods should be eliminated from the diet to chronic condition characterized by pain of the bladder improve symptoms. Of particular concern is that patients P and pelvic region, urinary urgency, frequency and may eliminate more foods than necessary to avoid increas- nocturia. Despite intense investigation to our knowledge the ing painful symptoms, resulting in a diet inadequate for etiology of this disease is unknown, diagnostic criteria are maintaining health and long-term symptom improvement. debated and treatment is empirical. More than 180 thera- We systematically determined whether specific comestible pies are used to treat PBS/IC with no single modality suc- items exacerbate and/or ameliorate PBS/IC symptoms and cessful for all patients.1 Factors such as stress, medication, whether any generalizations concerning the effect of comes- allergic reactions, sexual intercourse, hormonal changes and tibles on PBS/IC symptoms could form the basis for further diet may exacerbate bladder symptoms. investigation. Patients with PBS/IC frequently report that specific foods, beverages and dietary supplements increase symptoms. In response many physicians recommend changes to MATERIALS AND METHODS the diet of patients with PBS/IC and IC diets have been A validated questionnaire designed to detect whether food, developed and distributed by patient support organizations. beverages and/or supplements have an effect on bladder Nonetheless, the role of diet in affecting symptoms of symptoms (fig. 1),2 and the OSPI3 and PUF4 questionnaires PBS/IC is based on a paucity of information, mostly anec- were mailed to 327 female patients meeting NIDDK crite- dotal reports. In addition, there is controversy about which ria5 for PBS/IC. All patients had been examined and diagnosed with IC by a single physician at a suburban medical center. Patients were asked to complete the questionnaires Submitted for publication October 24, 2006. and return them to the physician in a postage paid envelope. * Financial interest and/or other relationship with Condax. Returned questionnaires had no identifying information and † Correspondence: Institute for Urology, Long Island Jewish Medical data were entered into an encoded database. Center, 270-05 76th Ave., New Hyde Park, New York 11040 (telephone: The IC/nutrition questionnaire included general ques- 718-470-7220; FAX: 718-343-6254; e-mail: [email protected]). ‡ Financial interest and/or other relationship with Ortho-McNeil, tions about the effect of comestibles on PBS/IC symptoms Allergan and Astellas. (fig. 1). Additionally, questions about allergies, medications,

0022-5347/07/1781-0145/0 145 Vol. 178, 145-152, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.020 146 INTERSTITIAL CYSTITIS AND DIET

FIG. 1. IC nutrition questionnaire mailed to subjects. Only portion of question 4 (comestible item list) is shown. dietary and food purchasing habits were included. Re- generated for items that were scored on at least 25 question- sponses to these questions were analyzed and they are re- naires is reported as the mean Ϯ SD. Differences between ported as the frequency and percent. Responses to specific mean scores were determined by ANOVA with post hoc questions were compared by the 2-sided Fisher exact test. pairwise comparisons using the Mann-Whitney U test with Individual comestible items were arranged into catego- the Bonferroni correction for multiple comparisons. ries. In each category items were arranged alphabetically, To determine the relationship between symptom score such that their arrangement in the survey would have no and sensitivity to individual comestibles, subjects were di- influence on the response. Subjects were asked to indicate vided into 2 groups, including 1) those who reported the item whether each of 175 individual comestible items worsened worsens symptoms (including slightly worsens and worsens symptoms, slightly worsened symptoms, had no effect, symptoms) and 2) those who reported the item does not slightly improved symptoms or improved symptoms by as- worsen symptoms (including no effect, slightly improves signing a score of Ϫ2, Ϫ1, 0, 1 or 2, respectively. “I have symptoms and improves symptoms). Mean OSPI and PUF never eaten this” was a choice for each item. A mean score scores were generated for each group and significant differ- INTERSTITIAL CYSTITIS AND DIET 147

TABLE 1. Yes or no responses to questions No. Response/Total No. (%) Question No. Trait Yes No Does Not Know

1 Comestibles increase symptoms 92/102 (90.2) 5/102 (4.9) 5/102 (4.9) 2 Comestibles decrease symptoms 29/96 (30.2) 51/96 (53.1) 16/96 (16.7) 5 Eats foods that increase symptoms 92/104 (88.5) 0/104 (0.0) 12/104 (11.5) 6 Large meals increase symptoms 78/104 (75.0) 0/104 (0.0) 25/104 (25.0) 7 Purchases decreased acid foods 28/101 (27.7) 72/101 (71.3) 1/101 (1.0) 8 Decreased acid foods cause lesser symptoms 24/68 (35.3) 6/68 (8.8) 38/68 (55.9) 9 Has allergies 76/101 (75.3) 25/101 (24.8) 10 Medications affect symptoms 58/87 (66.7) 8/87 (9.2) 21/87 (24.1)

ences between groups were determined by the Mann-Whit- supplements (p Ͻ0.001, figs. 2 and 3). Of the 175 individual ney test. comestible items 35 had a mean score of lower than Ϫ1.0 (table 2). These items were coffee, tea, soda, alcoholic bev- RESULTS erages, certain fruits and fruit juices, tomatoes and tomato products, hot peppers, spicy foods and certain artificial Of the 327 questionnaires mailed to patients meeting sweeteners. Pairwise comparisons within categories re- NIDDK criteria for IC 104 were returned, giving a response vealed that the mean score of each of the 35 items that rate of 32%. Although all returned questionnaires were com- scored lower than Ϫ1.0 was significantly different than the pleted, sporadic questions were omitted by some respon- mean score of each of the other items within the same dents. Mean respondent age was 53.9 Ϯ 16.3 years. Mean category (p Ͻ0.05). Correlation of OSPI and/or PUF scores OSPI and PUF scores were 21.0 Ϯ 8.2 and 19.3 Ϯ 7.0, with each of the 35 individual comestibles with a mean score respectively. OSPI and PUF scores significantly correlated of lower than Ϫ1.0 demonstrated a trend indicating that with each other (Pearson r ϭ 0.75, p Ͻ0.0001). subjects with higher symptom scores tended to report the Of 102 subjects 92 (90.2%) indicated that certain foods or item as worsening symptoms (table 2). This correlation was beverages increased bladder symptoms (table 1). Five of the significant for beer, horseradish, MSG, NutraSweet®, Sweet 102 subjects (4.9%) indicated that foods or beverages did not ’N Low®, Equal®, hot peppers and tomato/tomato products worsen symptoms and 5 (4.9%) did not know whether foods (p Ͻ0.05). or beverages worsened PBS/IC symptoms. Of 104 subjects Mean scores above 0 were reported for 16 of 175 individ- 92 (88.5%) reported that they consumed substances that ual comestible items, indicating that at least some subjects they knew would exacerbate PBS/IC symptoms (table 1). Of reported that these items improved symptoms. Prelief® and the 104 subjects 78 (75.0%) also reported that larger meals baking soda had the highest mean scores (0.67 Ϯ 0.96 and caused more bladder symptoms than smaller meals (table 1). 0.67 Ϯ 0.87, respectively). Considerably fewer subjects (29 of 96 or 30.2%) indicated Of 101 subjects 76 (75.3%) reported that they had aller- that certain foods or beverages decreased PBS/IC symptoms gies, including seasonal allergies and allergies to medica- (table 1). Of the 96 subjects 51 (53.1%) reported that con- tions, animals or foods (table 1). Of those who reported sumption of foods or beverages did not decrease symptoms, having allergies 97.1% indicated that certain foods, bever- while 16 (16.7%) did not know whether food or beverages ages and/or supplements exacerbated IC symptoms and decreased symptoms. 62.3% indicated that certain foods, beverages and/or supple- Of 87 subjects 58 (66.7%) believed that certain medica- ments ameliorated symptoms. Of those who reported that tions caused a change in PBS/IC symptoms (table 1). They they did not have allergies 91.7% indicated that certain listed medications that alleviated symptoms as well as those foods, beverages and/or supplements exacerbated symptoms that exacerbated symptoms. Medications reported to most and 64.7% reported that certain foods, beverages and/or frequently exacerbate symptoms were antibiotics, aspirin, supplements ameliorated symptoms. The correlation be- ibuprofen and decongestants. Medications that were listed tween having allergies and reporting exacerbation or ame- as improving symptoms were limited to those used as ther- lioration of symptoms due to the consumption of certain apy for PBS/IC. foods, beverages and/or supplements was not significant. Of 104 subjects 28 (27.7%) reported that they purchased decreased acid foods (table 1). While 24 of the 68 subjects DISCUSSION (34.3%) who consumed decreased acid foods believed that those foods exacerbated bladder symptoms less than equiv- These data demonstrate that 90.2% of patients with PBS/IC alent nondecreased acid foods, 38 (55.9%) did not know diagnosed through NIDDK criteria reported exacerbation of whether there is any difference in the effect of decreased and symptoms following the ingestion of specific food items (ta- nondecreased acid foods on symptoms (table 1). ble 1). Although our results are comparable to those in a Comparison of the 175 individual comestible item scores recent Internet based survey of the membership of the In- by ANOVA revealed that the differences were significant terstitial Cystitis Association demonstrating food sensitivity (p Ͻ0.001). When foods were sorted by category, ANOVA in 93% of respondents,6 they vary considerably from a pre- performed on scores for comestible items within categories vious study demonstrating food sensitivity in 50% of pa- revealed that differences were significant for fruit/fruit tients with IC.7 A response rate of 32% may have skewed juices, vegetables, meat/fish/poultry/nuts, bread/desserts/ data toward a greater effect of comestibles on symptoms snack foods, beverages, ethnic foods and condiments/food since individuals with food sensitivity may be more moti- 148 INTERSTITIAL CYSTITIS AND DIET

FIG. 2. Mean Ϯ SEM effect of comestibles on PBS/IC symptoms. Each item was scored as Ϫ2—worsens, Ϫ1—slightly worsens, 0—has no effect, 1—slightly improves or 2—improves symptoms. Differences among scores were signiﬁcant (ANOVA on ranks p Ͻ0.001). Asterisk indicates p Ͻ0.05 vs items scoring above Ϫ1. A, fruits and fruit juices. B, vegetables. C, meat/poultry/ﬁsh/nuts. vated to respond. The low response rate was likely due to the Despite the uncertainty of the prevalence of food sensitivity in length of the questionnaire (13 pages), requiring considerable the PBS/IC population important inferences regarding food effort by the subject and the necessity for return mailing. sensitivity can be drawn from the responses received. INTERSTITIAL CYSTITIS AND DIET 149

The demographics of responders in the current study are similar to the known demographics of PBS/IC. The mean age of 53.9 years is comparable to the mean age previously reported for PBS/IC.6,8 OSPI and PUF scores of 21.0 Ϯ 8.2 and 19.3 Ϯ 7.0, respectively, are comparable to those previously reported.8 Analysis of the scoring of individual comestible items revealed that grapefruit, cranberry, orange and pineapple juice, and grapefruit, lemons, oranges and pineapple scored significantly lower than other fruits and juices (p Ͻ0.05, fig. 2, A), suggesting a role for citrate in worsening symptoms. Tomato/tomato products and hot peppers scored significantly lower than other vegetables (p Ͻ0.05, fig. 2, B). Foods that tended to have hot pepper as an ingredient, including chili, burritos, spicy foods and certain ethnic foods, worsened symptoms. Indian, Mexican and Thai food were significantly different from other ethnic foods (each p Ͻ0.05, fig. 3, C). Together these data suggest that some component of hot peppers, possibly capsaicin, causes the worsening of PBS/IC symptoms. Coffee, decaffeinated coffee, tea, cola soda, noncola soda, caffeine free soda, diet soda, beer, red wine, white wine, champagne and other alcoholic beverages were significantly different from other beverages (each p Ͻ0.05, fig. 3, B), suggesting a role for caffeine, alcohol and carbonation in worsening symptoms. The role of caffeine in worsening PBS/IC symptoms is supported by results revealing that mean values for items in the bread/desserts/snack foods category containing chocolate were significantly different from the mean values of the other items in that category (each p Ͻ0.05, fig. 3, A). The rank order of caffeine containing items in worsening symptoms was coffee Ͼ cola soda Ͼ tea Ͼ decaffeinated coffee Ͼ dark chocolate candy Ͼ milk chocolate candy. The typical caffeine content of regular serving sizes of coffee, cola soda, tea, decaffeinated coffee, dark chocolate and milk chocolate is 135, 34.5, 50, 5, 31 and 10 mg, respectively.9 While the effects of caffeine containing comestibles did not correlate with their caffeine content, it is notable that between similar paired items, including dark and milk chocolate, coffee and decaffeinated coffee, and tea and herbal tea, the item with a higher caffeine content worsened symptoms to a greater degree. The effect of caffeine on PBS/IC symptoms may be related to the diuretic effect of caffeine, resulting in increased bladder filling. In healthy adults caffeine ingestion was shown to result in significantly more frequent voiding and a higher volume of urine production compared to placebo ingestion during the first 24 hours of ingestion.10 In the condiments/food supplements category comparisons between items revealed that the mean values of horseradish, vinegar, MSG, NutraSweet, Sweet ’N Low, Equal and saccharin were significantly lower than the mean values of the other items in that category (each p Ͻ0.05, fig. 3, D). Of all of the comestible items included in the questionnaire 35 had a mean score of lower than Ϫ1.0 and the mean value of each of these items was significantly different from the mean value of items scoring above Ϫ1.0 in each category FIG. 3. Mean Ϯ SEM effect of comestibles on PBS/IC symptoms. Each item was scored as Ϫ2—worsens, Ϫ1—slightly worsens, (table 2 and fig. 1). Items scoring less than Ϫ1.0 included 0—has no effect, 1—slightly improves or 2—improves symptoms. caffeinated beverages, citrus fruits and juices, alcoholic bev- Differences among scores were significant (ANOVA on ranks erages, carbonated beverages, foods containing hot peppers, p Ͻ0.001). Asterisk indicates p Ͻ0.05 vs items scoring above Ϫ1. A, grains/desserts/snack foods. B, beverages. C, ethnic foods. D, condi- certain artificial sweeteners, pineapple/pineapple juice, ments/dietary supplements. cranberry juice, horseradish, vinegar and pickled herring. Many of these items are relatively acidic foods that have been suggested to exacerbate symptoms of IC.6,9,11–13 150 INTERSTITIAL CYSTITIS AND DIET

TABLE 2. Comestible item scoring vs OSPI and PUF scores Mean Ϯ SD Symptom Score (No. pts) Item (instrument) No. Pts Food Score Item Worsens Symptoms Does Not Worsen Symptoms

Grapefruit juice: 58 Ϫ1.67 Ϯ 0.60 OSPI 22.9 Ϯ 8.3 (52) 20.0 Ϯ 2.3 (4) PUF 21.3 Ϯ 6.4 (49) 17.5 Ϯ 5.6 (4) Spicy foods: 75 Ϫ1.64 Ϯ 0.69 OSPI 22.5 Ϯ 8.2 (66) 19.1 Ϯ 3.1 (7) PUF 20.6 Ϯ 6.4 (59) 20.8 Ϯ 5.8 (6) Caffeinated coffee: 67 Ϫ1.60 Ϯ 0.74 OSPI 21.5 Ϯ 7.5 (61) 21.6 Ϯ 2.9 (5) PUF 20.0 Ϯ 6.5 (53) 19.8 Ϯ 4.4 (5) Grapefruit: 68 Ϫ1.53 Ϯ 0.66 OSPI 22.3 Ϯ 8.3 (60) 22.7 Ϯ 5.5 (6) PUF 20.5 Ϯ 6.5 (55) 21.3 Ϯ 4.0 (6) Chili: 61 Ϫ1.51 Ϯ 0.72 OSPI 22.6 Ϯ 8.1 (52) 17.9 Ϯ 3.6 (8) PUF 20.7 Ϯ 6.5 (45) 20.3 Ϯ 5.2 (7) Red wine: 60 Ϫ1.45 Ϯ 0.87 OSPI 21.9 Ϯ 7.4 (51) 17.1 Ϯ 8.3 (8) PUF 20.6 Ϯ 5.8 (44) 16.5 Ϯ 8.3 (8) Hot peppers: 52 Ϫ1.44 Ϯ 0.85 OSPI 22.3 Ϯ 7.6 (39) 17.3 Ϯ 4.4 (12)* PUF 20.9 Ϯ 5.9 (36) 18.6 Ϯ 5.1 (11) Lemons: 76 Ϫ1.43 Ϯ 0.74 OSPI 22.4 Ϯ 8.0 (64) 19.1 Ϯ 5.7 (11) PUF 20.5 Ϯ 6.8 (59) 19.4 Ϯ 6.6 (10) Beer: 51 Ϫ1.43 Ϯ 0.83 OSPI 21.6 Ϯ 7.3 (41) 19.0 Ϯ 6.9 (9) PUF 20.9 Ϯ 5.6 (35) 14.0 Ϯ 8.6 (7)* Tomato/tomato products: 88 Ϫ1.42 Ϯ 0.74 OSPI 22.7 Ϯ 7.8 (75) 15.3 Ϯ 5.0 (11)† PUF 20.6 Ϯ 6.0 (62) 15.0 Ϯ 5.9 (10)‡ Oranges: 83 Ϫ1.40 Ϯ 0.84 OSPI 22.5 Ϯ 8.2 (69) 18.5 Ϯ 5.7 (13) PUF 20.5 Ϯ 6.8 (61) 18.0 Ϯ 5.9 (10) Champagne: 53 Ϫ1.40 Ϯ 0.86 OSPI 21.9 Ϯ 7.7 (46) 23.7 Ϯ 7.0 (6) PUF 20.9 Ϯ 6.2 (41) 21.6 Ϯ 4.7 (5) MSG: 48 Ϫ1.40 Ϯ 0.87 OSPI 23.2 Ϯ 7.9 (35) 17.5 Ϯ 7.9 (12)* PUF 21.6 Ϯ 6.0 (33) 20.1 Ϯ 5.2 (11) Vinegar: 69 Ϫ1.39 Ϯ 0.75 OSPI 22.1 Ϯ 8.1 (57) 18.8 Ϯ 6.5 (11) PUF 20.7 Ϯ 6.9 (51) 21.6 Ϯ 3.3 (10) Orange juice: 77 Ϫ1.39 Ϯ 0.78 OSPI 22.0 Ϯ 8.3 (67) 17.6 Ϯ 5.1 (9) PUF 20.4 Ϯ 7.0 (59) 17.9 Ϯ 5.7 (8) White wine: 65 Ϫ1.35 Ϯ 0.91 OSPI 22.4 Ϯ 7.6 (52) 17.8 Ϯ 7.6 (12) PUF 21.0 Ϯ 6.1 (44) 17.1 Ϯ 6.9 (12) Mexican food: 60 Ϫ1.33 Ϯ 0.77 OSPI 21.7 Ϯ 7.8 (47) 19.3 Ϯ 7.0 (11) PUF 20.4 Ϯ 5.8 (43) 20.2 Ϯ 6.6 (10) Pineapple juice: 61 Ϫ1.31 Ϯ 0.92 OSPI 21.9 Ϯ 8.4 (47) 21.5 Ϯ 8.1 (13) PUF 20.7 Ϯ 6.9 (43) 20.2 Ϯ 4.9 (13) Cola soda: 70 Ϫ1.30 Ϯ 0.84 OSPI 22.0 Ϯ 8.0 (53) 19.4 Ϯ 8.5 (15) PUF 20.1 Ϯ 7.0 (48) 20.6 Ϯ 7.5 (14) Thai food: 39 Ϫ1.26 Ϯ 0.85 OSPI 21.3 Ϯ 6.9 (28) 22.3 Ϯ 8.3 (10) PUF 20.2 Ϯ 5.2 (24) 20.7 Ϯ 4.7 (9) Diet soda: 63 Ϫ1.25 Ϯ 0.82 OSPI 21.3 Ϯ 7.8 (47) 19.9 Ϯ 8.3 (15) PUF 20.4 Ϯ 6.6 (44) 20.3 Ϯ 7.7 (14) Other alcoholic beverages: 60 Ϫ1.25 Ϯ 1.00 OSPI 22.0 Ϯ 7.8 (45) 22.6 Ϯ 6.5 (14) PUF 21.1 Ϯ 6.0 (41) 19.5 Ϯ 6.7 (10) Indian food: 36 Ϫ1.22 Ϯ 0.87 OSPI 23.5 Ϯ 6.9 (25) 21.2 Ϯ 5.1 (10) PUF 21.7 Ϯ 5.3 (23) 20.4 Ϯ 3.5 (8) NutraSweet: 48 Ϫ1.21 Ϯ 0.90 OSPI 22.3 Ϯ 7.6 (32) 16.7 Ϯ 6.5 (15)* PUF 20.9 Ϯ 6.7 (29) 18.6 Ϯ 4.7 (14) Cranberry juice: 70 Ϫ1.16 Ϯ 1.11 OSPI 22.9 Ϯ 8.5 (51) 19.4 Ϯ 6.2 (18) PUF 21.1 Ϯ 6.8 (44) 18.2 Ϯ 5.8 (17) Caffeinated tea: 69 Ϫ1.13 Ϯ 0.89 OSPI 21.0 Ϯ 7.8 (49) 22.4 Ϯ 8.0 (18) PUF 19.7 Ϯ 6.4 (46) 20.4 Ϯ 9.2 (13)

(continued) INTERSTITIAL CYSTITIS AND DIET 151

TABLE 2. Continued Mean Ϯ SD Symptom Score (No. pts) Item (instrument) No. Pts Food Score Item Worsens Symptoms Does Not Worsen Symptoms

Pineapple: 78 Ϫ1.13 Ϯ 0.84 OSPI 21.8 Ϯ 8.7 (55) 21.0 Ϯ 7.6 (22) PUF 20.2 Ϯ 6.9 (48) 19.6 Ϯ 6.5 (19) Saccharin: 35 Ϫ1.11 Ϯ 0.93 OSPI 22.3 Ϯ 7.9 (21) 17.3 Ϯ 6.0 (13) PUF 21.9 Ϯ 6.2 (19) 18.5 Ϯ 5.3 (13) Sweet ’N Low: 48 Ϫ1.08 Ϯ 0.94 OSPI 23.0 Ϯ 8.0 (27) 17.8 Ϯ 8.0 (19)* PUF 21.9 Ϯ 6.2 (27) 18.2 Ϯ 5.2 (18) Horseradish: 50 Ϫ1.08 Ϯ 0.88 OSPI 22.9 Ϯ 6.9 (32) 19.5 Ϯ 7.2 (17) PUF 21.6 Ϯ 5.1 (30) 17.9 Ϯ 5.6 (14)* Caffeine-free soda: 63 Ϫ1.05 Ϯ 0.94 OSPI 22.9 Ϯ 7.8 (40) 20.0 Ϯ 7.7 (21) PUF 21.5 Ϯ 6.3 (36) 19.4 Ϯ 7.3 (20) Burritos: 46 Ϫ1.04 Ϯ 0.87 OSPI 21.2 Ϯ 7.3 (29) 20.5 Ϯ 6.9 (16) PUF 18.8 Ϯ 5.8 (29) 21.9 Ϯ 5.3 (16) Equal: 48 Ϫ1.04 Ϯ 0.94 OSPI 22.7 Ϯ 8.3 (27) 17.6 Ϯ 6.7 (20)* PUF 22.1 Ϯ 6.4 (25) 17.5 Ϯ 4.7 (17)‡ Noncola soda: 64 Ϫ1.03 Ϯ 0.96 OSPI 22.0 Ϯ 8.0 (42) 21.1 Ϯ 7.4 (21) PUF 21.1 Ϯ 6.8 (37) 20.9 Ϯ 6.2 (20) Decaffeinated coffee: 67 Ϫ1.01 Ϯ 0.90 OSPI 22.1 Ϯ 7.8 (47) 20.5 Ϯ 7.3 (19) PUF 21.1 Ϯ 6.4 (42) 16.2 Ϯ 7.5 (13)* The number of patients per food item represents the number who responded to that question minus the number who responded “I have never eaten this,” subjects in the worsens symptoms group indicated worsened and slightly worsened and subjects in the does not worsen symptoms group indicated “no effect, slightly improved and improved.” * Mann-Whitney U test p Ͻ0.05. † Mann-Whitney U test p Ͻ0.005. ‡ Mann-Whitney U test p Ͻ0.02.

To our knowledge the mechanism of the effect of consum- Patients with PBS/IC tend to have concurrent allergic ing generally acidic foods on bladder symptoms has not been disease.12,13 More than 75% of respondents to our question- elucidated. Nonetheless, patients reported symptom relief naire indicated that they have allergies, including seasonal following the ingestion of alkalizing agents, such as calcium allergies or allergies to medications, animals or foods (table glycerophosphate (Prelief) or sodium bicarbonate (baking 1). Of respondents who indicated that they have allergies soda). These data demonstrate that Prelief and baking soda 97.1% also reported that certain foods, beverages and/or seem to improve symptoms slightly but with mean scores supplements exacerbated symptoms. Similarly 91.7% of re- that were not significantly different than those of other spondents who indicated that they do not have allergies supplements thought to improve PBS/IC symptoms (fig. 3, reported that certain foods, beverages and/or supplements D). In addition, almost a third of the subjects reported that exacerbated symptoms. Not surprisingly there was no cor- they purchased decreased acid foods but only about a third relation between having allergies and reporting that comes- of those subjects believed that decreased acid foods exacer- tible items exacerbate PBS/IC symptoms. That is, more than bate symptoms less than the equivalent nondecreased acid 90% of patients with PBS/IC reported that comestible items food and 56% did not know whether decreased acid foods exacerbate symptoms in the group with allergies as well as lessen symptoms (table 1). Changes in intravesical pH has in the group without allergies. Thus, it is unlikely that food insignificant effects on bladder pain in patients with IC,11 sensitivity in patients with PBS/IC is an allergic response. suggesting that the effect of comestibles on PBS/IC symp- In addition to the observation that certain foods worsen toms is not due to changes in intravesical acidity. PBS/IC symptoms, avoiding certain foods or beverages ap- Even among the 35 comestible items that scored lowest pears to improve symptoms.12 As a result, certain elimina- there were differences in individual subject responses. That tion diets have been developed and used to treat patients is, subjects seemed to have unique profiles of foods and/or with PBS/IC. The current study suggests that eliminating beverages that exacerbated symptoms, suggesting that elim- irritant foods such as coffee, tea, alcoholic beverages, citrus ination diets should be tailored to meet individual responses fruits/juices, spicy foods, hot peppers and certain artificial to comestibles. When subjects were grouped as to whether sweeteners may have a beneficial effect in most patients each specific item worsened or did not worsen symptoms with PBS/IC. (table 2), there was a trend indicating that subjects who tended to report an item as worsening symptoms also had CONCLUSIONS higher symptom scores. These data should be interpreted with caution because each of the “not worsen” groups had Based on a validated questionnaire PBS/IC symptoms ap- fewer subjects than the “worsen” groups to which they were pear to be influenced by ingested comestibles in the majority compared. Thus, the comparisons may have lacked enough of patients. The most frequently reported and most bother- power to attain significance. some comestibles were caffeinated, carbonated and alcoholic 152 INTERSTITIAL CYSTITIS AND DIET beverages, citrus fruits and juices, artificial sweeteners and 3. O’Leary MP, Sant GR, Fowler FJ, Whitmore KE and Spo- spicy foods. These data corroborate previous anecdotal ex- larich-Kroll J: The interstitial cystitis symptom index and periences and they may serve as a guide to patient counsel- problem index. Urology, suppl., 1997; 49: 58. ing. 4. Parsons CL, Dell J, Stanford EJ, Bullen M, Kahn BS, Waxell T et al: Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potas- ACKNOWLEDGMENTS sium sensitivity. Urology 2002; 60: 573. Julia Tai assisted with statistical analyses and Priti Joshi 5. Gillenwater JY and Wein AJ: Summary of the National Insti- assisted with entering questionnaire data. tute of Diabetes, Digestive and Kidney Diseases workshop on interstitial cystitis, National Institutes of Health, Be- thesda, MD. J Urol 1987; 140: 203. 6. Interstitial Cystitis Association. Your Opinion Counts! ICA Abbreviations and Acronyms Survey: IC and Diet-Results. Available at http://www.ichelp. com/youropinion/Survey-Diet-Results.html. Accessed March IC ϭ interstitial cystitis 15, 2005. MSG ϭ monosodium glutamate 7. Koziol JA, Clark DC, Gittes RF and Tan EM: The natural NIDDK ϭ National Institute of Diabetes and history of interstitial cystitis: a survey of 374 patients. Digestive and Kidney Diseases J Urol 1993; 149: 465. OSPI ϭ O’Leary-Sant Interstitial Cystitis 8. Kushner L and Moldwin RM: Efficiency of questionnaires used Symptom Index and Problem Index to screen for interstitial cystitis. J Urol 2006; 176: 587. PBS/IC ϭ painful bladder syndrome/IC 9. Barrone JJ and Roberts HR: Caffeine consumption. Food PUF ϭ Pelvic Pain and Urgency/Frequency Chem Toxicol 1996; 34: 119-129. Patient Symptom Scale 10. Bird ET, Parker BD and Kim HS: Caffeine ingestion and lower urinary tract symptoms in healthy volunteers. Neurourol Urodyn 2005; 24: 611. REFERENCES 11. Nguan C, Franciosi LG, Butterfield N, Mashadi-Sharif S, Mac- Leod BA, Talling D et al: A prospective, double-blind, ran- 1. Rovner E, Propert DJ, Brensinger C, Wein AJ, Foy M, domized cross-over study evaluating changes in urinary pH Kkirkemo A et al: Treatments used in women with inter- for relieving the symptoms of interstitial cystitis. BJU Int stitial cystitis: the interstitial cystitis data base (ICDB) 2005; 95: 86. study experience. The Interstitial Cystitis Data Base Study 12. Clemens JQ, Brown SO, Kosloff L and Calhoun EA: Predictors Group. Urology 2000; 56: 940. of symptoms severity in patients with chronic prostatitis 2. Shorter B, Moldwin RM and Kushner L: Validation of a ques- and interstitial cystitis. J Urol 2006; 175: 963. tionnaire addressing the role of dietary factors affecting 13. Yamada T: Significance of complications of allergic diseases in symptoms of painful bladder disease (PBS)/interstitial cys- young patients with interstitial cystitis. Int J Urol 2003; 10: titis (IC). Unpublished data. S56. Results of Cystocele Repair: A Comparison of Traditional Anterior Colporrhaphy, Polypropylene Mesh and Porcine Dermis

LiAnn N. Handel, Tara L. Frenkl and Young H. Kim From the Rhode Island Hospital, Brown University, Providence, Rhode Island, and Merck and Co., Inc. (TLF), Rahway, New Jersey

Purpose: Because traditional anterior colporrhaphy can have a high recurrence rate, we assessed the recurrence rate of 3 methods of cystocele repair, including 1) traditional anterior colporrhaphy, 2) repair using porcine dermis interposition graft and 3) repair using polypropylene mesh. Additionally, we compared the rate of erosion of porcine dermal graft with that of polypropylene mesh. Materials and Methods: The records of patients who underwent cystocele repair by the same urologist using porcine dermal graft, polypropylene mesh or traditional repair from January 1999 to August 2005 were reviewed. Data were collected on history, physical examination, outcomes and complications. Using the Baden-Walker system a cystocele of grade 2 or higher on followup examination was considered recurrence. Results: A total of 119 patients underwent cystocele repair from January 1999 to August 2005. Followup was available on 99 patients and it averaged 13.5 months (range 2 to 46). Of the patients 56 (57%) underwent cystocele repair using porcine dermal graft, 25 (25%) received polypropylene mesh and 18 (18%) underwent traditional repair. Of the 99 patients 22 (22%) had cystocele recurrence. Based on the type of repair 36% of patients (20 of 56) with porcine dermal grafts had recurrence compared to 4% (1 of 25) and 6% (1 of 18) using polypropylene and traditional repair, respectively. Mean time to cystocele recurrence was 4.9 months (range 0.5 to 20). A total of 12 patients (21%) had extrusion of porcine grafts through the anterior vaginal wall incision compared to 1 (4%) with polypropylene mesh. Conclusions: In our patient population the short-term failure rate for anterior vaginal wall prolapse using porcine dermis interposition graft was higher than that for traditional anterior colporrhaphy or polypropylene mesh. In addition, the incidence of vaginal extrusion of porcine graft was unacceptably high. Porcine dermis is a less suitable material for cystocele repair than polypropylene mesh or traditional anterior colporrhaphy. Prospective, randomized trials are necessary to determine the true efﬁcacy and complication rates of these graft materials for anterior vaginal wall prolapse repair. Key Words: prolapse, cystocele, prostheses and implants, urinary incontinence, dermis

ecurrent anterior vaginal wall prolapse can develop MATERIALS AND METHODS in more than 20% of patients undergoing traditional A retrospective chart review of patients who underwent R anterior colporrhaphy.1 In light of this high recur- surgical correction of anterior vaginal wall prolapse from rence rate many surgeons have been incorporating synthetic January 1999 to August 2005 was performed. In the early or allograft mesh to augment the repair. series traditional anterior colporrhaphy was performed but Studies of porcine dermis for pubovaginal sling surgery it was gradually abandoned in favor of a porcine dermal as well as for the correction of high grade cystocele show graft. The most recent cases involved the use of poly- encouraging results in terms of the recurrence and compli- propylene only for cystocele repair. The degree of prolapse 2 cation rates. In terms of synthetics, polypropylene mesh was defined according to the Baden-Walker system (see Ap- has become popular because it promotes the ingrowth of pendix).5 Cure was defined as grade 0 cystocele and success natural tissue and there appears to be a low complication was defined as grade 1 or less cystocele. All patients pro- rate associated with its use.3,4 We report our experience vided a history and underwent physical examination by the with 3 techniques of cystocele repair, including anterior same urologist (YHK). They were examined postoperatively colporrhaphy with porcine dermis, anterior colporrhaphy by the same urologist. At each patient visit the interview with polypropylene mesh and traditional anterior colporrha- included questions regarding any symptoms referable to the phy. cystocele, any voiding abnormalities or complaints and the degree of bother related to the cystocele. Patients were asked preoperatively and postoperatively regarding quality of life and sexual function. Urodynamics were performed before cystocele repair if there were any concurrent voiding abnormalities, such as Submitted for publication November 24, 2006. difficult voiding, urinary urgency, or urge and/or stress in- Study received institutional review board approval for a retrospec- continence. If stress incontinence was identified after pro- tive analysis. *Financial interest and/or other relationship with Merck and lapse reduction on preoperative evaluation, urodynamics GlaxoSmithKline. were done to determine if adequate detrusor contractility

0022-5347/07/1781-0153/0 153 Vol. 178, 153-156, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.041 154 RESULTS OF CYSTOCELE REPAIR existed to allow sling placement at cystocele repair. If there RESULTS was a hypocontractile or acontractile detrusor on urodynamics, the patient was offered a suprapubic catheter at cysto- Of 119 patients who underwent cystocele repair complete cele repair and sling placement or she was counseled against followup data were available on 99. Average followup was a concurrent sling due to the risk of urinary retention. Pro- 13.5 months (range 2 to 46). The table shows cases per- lapse was not reduced during urodynamics. formed, average followup, the number of concomitant proce- Outcome measures, including post-void residual urine dures, the recurrence rate and time to recurrence. The mean evaluation and the Valsalva stress test, were done at base- grade of anterior wall prolapse in all groups was grade III. line. Patients with urge symptoms underwent cystoscopic There were no significant demographic differences among examination before surgical intervention. Other cases of pro- the 3 groups. The time of data collection was at the last lapse identified preoperatively were addressed surgically if patient followup visit. needed at cystocele repair. Postoperatively each patient was Concomitant vaginal hysterectomy and rectocele repair evaluated supine and standing, after voiding, with a full were performed in 90% (89 of 99) and 69% of patients (68 of bladder, and with and without bladder elevation. 99), respectively. A total of 77 patients (78%) underwent concomitant sling procedures, including 50 (65%) with Mer- Surgical Technique silene mesh, 22 (29%) with polypropylene and 5 (6%) with In patients undergoing interposition graft cystocele repair cadaveric fascia lata slings. At followup 82% of the women using porcine dermis or polypropylene the graft materials (63 of 77) were continent by the provocative Valsalva stress were soaked in room temperature antibiotic solution. After test as well as by subjective report of cure or improvement. hydrodissection with 0.25% bupivacaine with epinephrine Two patients (3%) experienced transient urinary retention, the vaginal epithelium was incised from vaginal apex to which resolved within 2 weeks postoperatively. bladder neck and dissected off the pubocervical fascia to the Anterior wall prolapse recurred in 22 patients (22%). endopelvic fascia bilaterally. If a sling was planned, the Average time to recurrence was 4.9 months. Of the 22 pa- epithelium was also dissected off the periurethral fascia tients 16 (73%) had grade II anterior wall prolapse and 6 bilaterally. When performing traditional colporrhaphy, the (27%) had grade III. Of the patients 91% (20 of 22) with uterosacral-cardinal ligament complex and pubocervical fas- recurrence underwent repair using porcine dermal graft. cia were plicated in the midline. Overall 36% of the patients (20 of 56) who received porcine In patients receiving porcine dermis or polypropylene dermal grafts had cystocele recurrence compared to 1 each mesh the lateral edges of a 3 ϫ 7 cm graft segment were in the polypropylene and traditional repair groups. In addi- anchored to the pelvic sidewalls at the level of the levator tion, 12 patients (21%) had extrusion of porcine graft fascia bilaterally using 3 sutures on each side. Initially per- through a dehiscence in the anterior vaginal wall. One pa- manent sutures were used but we later changed to delayed tient with polypropylene mesh had extrusion through the absorbable monofilament sutures. The uterosacral-cardinal anterior vaginal wall incision. ligament complex was plicated in the midline if present and Six patients in the porcine dermis group experienced the apical edge of the graft was then fixed in the midline to vaginal incision dehiscence. All of these patients underwent this area of plication. Additional plication of the pubocervi- concomitant sling procedures. One patient had extensive cal fascia was not performed. The distal edge of the graft was intraoperative bleeding, resulting in a vaginal hematoma affixed in the midline to the bladder at least 1 cm proximal and transfusion of 2 U blood. Subsequently vaginal drainage to the bladder neck. The graft was trimmed as needed. developed with extrusion of the porcine dermal graft and When indicated, the pubovaginal sling was performed mesh sling. At followup this patient had a recurrent grade II using a certain technique. Two less than 1 cm skin stab cystocele and mild SUI, which did not require further treat- incisions 2 cm lateral of the midline were made bilaterally at ment. Another patient presented several weeks after sur- the level of the symphysis pubis. Single Stamey needles gery with persistent vaginal discharge. Examination re- were introduced, and passed through the retropubic space vealed infection with sloughing of the anterior vaginal wall and out the vesicovaginal space on either side of the urethra. epithelium and porcine graft. The vaginal epithelium was In most patients a 2 ϫ 18 cm segment of Mersilene™ mesh débrided and any remaining porcine graft was excised. The was placed. The remaining patients received polypropylene sling mesh was exposed but did not appear infected. The or cadaveric fascia lata slings. The sling was positioned vaginal epithelium healed by secondary intent, ultimately loosely beneath the bladder neck. resulting in severe vaginal shortening and stenosis. For all procedures vaginal packing and a 14Fr urethral There was no obvious cause for the vaginal wall dehis- catheter were placed and subsequently removed on postop- cence in the remaining 4 patients. One patient was returned erative day 2. Postoperatively intravenous or oral antibiotics to the operating room for removal of the sling mesh and the were administered for a total of 5 days. remaining porcine graft. At followup she had recurrent Postoperative followup at each office visit included focused history and physical examination, post-void residual urine evaluation, the provocative Valsalva stress test and Patients based on cystocele repair technique subjective report of cure or improvement. Recurrent vaginal wall prolapse was defined as grade II or higher using the Prolene Porcine Traditional Totals Baden-Walker system. Cured stress urinary incontinence No. pts (%) 25 (25) 56 (57) 18 (18) 99 was defined as no pads postoperatively and improvement Av followup (mos) 13 17 9 No. concomitant sling (%) 20 (26) 48 (62) 9 (12) 77 was defined as fewer than half the pads used preoperatively. No. vaginal hysterectomy (%) 25 (28) 46 (52) 18 (20) 89 The study received institutional review board approval for a No. rectocele repair (%) 18 (26) 38 (56) 12 (18) 68 retrospective analysis. No. anterior wall recurrence (%) 1 (1) 20 (20) 1 (1) 99 RESULTS OF CYSTOCELE REPAIR 155 grade I cystocele and moderate recurrent SUI, which im- Our results demonstrated a higher rate of recurrence proved after 2 collagen injections. Another patient under- using porcine dermis compared to polypropylene mesh (36% went removal of the remaining porcine graft in the office vs 4%) as interposition graft material. Interestingly our without sling removal. The vaginal epithelium healed with- recurrence rate of 6% was also low in patients who under- out further incident. At last followup she had an asymptom- went traditional anterior colporrhaphy. A possible explana- atic grade I cystocele and no SUI. The remaining 2 patients tion for the significantly better outcome with traditional were allowed to heal by secondary intent alone, did well and anterior colporrhaphy involves the surgical technique used required no further surgical treatment. in these patients. Standard repair at our institution involved aggressive medial plication of laterally positioned DISCUSSION pubocervical fascia, which elevated the bladder but also led to narrowing and shortening of the vagina, which was an Recurrent anterior vaginal wall prolapse may develop in unacceptable result. We must acknowledge that overall fol- more than 20% of patients undergoing traditional anterior lowup is still short (average 13.5 months). Thus, we may not colporrhaphy.1 Early reports of anterior colporrhaphy for have captured all patients who subsequently experienced cystocele demonstrated success rates in the range of 80% to 100% in retrospective series.6,7 More recent series evaluat- cystocele recurrence. ing traditional anterior colporrhaphy showed lower success The short-term results of using porcine dermal graft for rates of 42% to 57%.8,9 Biological and synthetic grafts for the cystocele repair raise significant concerns. Extrusion of the transabdominal and transvaginal treatment of pelvic organ porcine dermal graft through a dehiscence in the anterior prolapse and SUI may improve the success rates.9 Many vaginal epithelium occurred in 22% of the patients with materials have been tried, such as cadaveric fascia, porcine porcine dermis. It is possible that perioperative vaginal dermis, autologous fascia and various synthetic materials bleeding accumulated deep to the graft and could not drain with mixed results.9 Autologous grafts have fallen out of from the vagina because of the nonporous nature of the favor because they carry the risk of increased postoperative graft, creating hematoma and eventual infection. This infec- morbidity due to the additional incision site, postoperative tion in turn resulted in vaginal wall dehiscence, exposing the pain and increased operative time for graft harvesting. Syn- mesh materials and facilitating further infection, extrusion thetic materials and xenografts avoid these morbidities but and desiccation or sloughing of the graft. Two patients had cause others, such as infection, extrusion, erosion into the clinical evidence of severe porcine graft infection, which led lower genitourinary tract and pain at the graft site postop- to significant problems, including vaginal stenosis, dyspa- eratively. reunia, delayed resumption of sexual activity, persistent Porcine dermis has been used for diaphragmatic prosthe- vaginal discharge and recurrent cystocele. ses, dura replacement, burn treatment and other defect cor- In this study there was a high incidence of extruded mesh 10–12 rections. In a recent study Gomelsky et al examined the slings. The mesh sling may have been contributory to vagi- use of porcine dermis interposition graft for high grade cys- nal infections and, therefore, to graft extrusion. Sling extru- tocele.2 A total of 70 patients were followed an average of 24 sion also occurred in the absence of graft extrusion. There is months. Of the 77 patients 9 (12.9%) had recurrent cysto- certainly concern that the combination of mesh and porcine cele. Additionally, 65 patients had concomitant slings using dermis increases the risk of vaginal infections, which is autologous rectus fascia or porcine dermis with a 90% con- magnified by the frequency with which cystocele repair and tinence rate postoperatively.2 Graft related complications pubovaginal sling are done together. Our results favor the were not reported. Wheeler et al reviewed the records of patients who underwent transvaginal high uterosacral vault use of an alternate sling material, such as monofilament, suspension and cystocele repair using porcine dermis.13 Of large pore mesh, if graft interposition material is used for 36 patients 50% had recurrent stage II or greater using cystocele repair. Pelvic Organ Prolapse Quantification measurements. There is significant experience with synthetic mesh in vaginal reconstruction.14 Polypropylene mesh, a macro- CONCLUSIONS porous and monofilament graft is the most frequently used synthetic non absorbable mesh in reconstructive pelvic sur- Our short-term results of using nonporous porcine dermal gery.14 Reported success rates range from 75% to 100%.15–18 graft for cystocele repair raise significant concerns. A higher In two separate studies Julian15 and Nicata16 observed no recurrence rate as well as an increased local complication recurrences when using polypropylene mesh for cystocele rate was observed in patients who underwent repair with repair. However, Julian noted an erosion rate of 25%,15 porcine dermal graft compared to repair with polypropylene while no erosions were reported by Nicata.16 Flood et al or traditional repair. Randomized, controlled trials are nec- reviewed the charts of 142 women who underwent Marlex™ essary to identify the optimal interposition graft material. mesh augmentation for anterior colporrhaphy.17 They found no evidence of any cystoceles beyond stage 2 at approxi- APPENDIX mately 3 years with an erosion rate of 2%. Salvatore et al Baden-Walker Prolapse Classification reported the use of polypropylene mesh for cystocele repair and noted an erosion rate of 13% as well as increased over- Anatomical Grade Description 18 active bladder symptoms and dyspareunia. In a prospec- Grade I cystocele Bladder descent toward the introitus with strain tive study of polyglactin 910 mesh Sand et al noted a signif- Grade II cystocele Bladder to the introitus with strain icantly lower recurrence rate in the mesh group than in Grade III cystocele Bladder outside of the introitus with strain Grade IV cystocele Bladder outside of the introitus at rest controls (25% vs 43%).8 156 RESULTS OF CYSTOCELE REPAIR

17. Flood CG, Drutz HP and Waja L: Anterior colporrhaphy rein- Abbreviations and Acronyms forced with Marlex mesh for the treatment of cystoceles. Int SUI ϭ stress urinary incontinence Urogynecol J Pelvic Floor Dysfunct 1998; 9: 200. 18. Salvatore S, Soligo M, Meschia M, Luppino G, Piffarotti P and Arcari V: Prosthetic surgery for genital prolapse: functional REFERENCES outcome. Neurourol Urodyn 2002; 21: 296.

1. Leach GE, Zimmern PE and Ganabathi K: Formal cystocele EDITORIAL COMMENT repair with bladder neck suspension. In: Atlas of the Uro- logical Clinics of North America: Vaginal Surgery for the In this retrospective series of 3 techniques used to correct Urologist. Edited by MI Resnick and GE Leach. Philadel- cystocele there are some shortcomings, including study de- phia: WB Saunders Co 1994; pp 37–46. sign, short followup for a study spanning almost 6 years and 2. Gomelsky A, Rudy DC and Dmochowski RR: Porcine dermis a lack of validated questionnaires. Nonetheless, these au- interposition graft for repair of high grade anterior compartment defects with or without concomitant pelvic organ thors honestly report a negative experience with porcine prolapse procedures. J Urol 2004; 171: 1581. dermis. 3. Silva WA and Karram MM: Scientific basis for use of grafts The lessons to be learned are first that new is exciting but during vaginal reconstructive procedures. Curr Opin Obstet not always better in the short or long term.1 For the 56 Gynec 2005; 17: 519. patients who received porcine dermis this form of human 4. de Tayrac R, Gervaise A, Chaiveaud A and Fernandez H: experimentation turned into a disappointing experience for Tension-free polypropylene mesh for vaginal repair of an- many, although other series used the same material and terior vaginal wall prolapse. J Reprod Med 2005; 50: 75. seemingly encountered much fewer problems of extrusion 5. Baden WF and Walker TA: Surgical Repair of Vaginal Defects. and short-term failure rates. Philadelphia: JB Lippincott 1992. The second lesson is that our patients and our surgical 6. Porges RF and Smilen SW: Long-term analysis of the surgical management of pelvic support defects. Am J Obstet Gynecol community would be better served and protected by a more 1994; 171: 1518. rigorous initial assessment of new procedures, including 2 7. Walter S, Olesen KP, Hald T, Jensen HK and Pedersen PH: novel materials in the field of pelvic organ prolapse repair. Urodynamic evaluation after vaginal repair and colposus- Surgeries with the potential for long-term sequelae and pension. Br J Urol 1982; 54: 377. serious negative outcomes are regrettably subjected to none 8. Sand PK, Koduri S, Lobel RW, Winkler HA, Tomezsko J, of the demands placed on new medications before they are Culligan PJ et al: Prospective randomized trial of poly- released for public use. glactin 910 mesh to prevent recurrence of cystoceles and Traditional repair, ie anterior colporrhaphy, was met rectoceles. Am J Obstet Gynecol 2001; 184: 1357. with a 6% failure rate at a mean followup of 9 months. 9. Birch C and Fynes MM: The role of synthetic and biological Maybe this is the third lesson: start with traditional repairs prostheses in reconstructive pelvic floor surgery. Curr Opin Obstet Gynecol 2002; 14: 527. and consider newer and admittedly less known and tested 10. Dalla Vecchi L, Engum S, Kogon B, Jensen E, Davis M and therapies in well characterized patients who understand the Gosfeld J: Evaluation of small intestine submucosa and risks and uncertainties of mesh interposition. The vagina is acellular dermis as diaphragmatic prostheses. J Pediatr not like the abdominal wall and what works for one may not Surg 1999; 34: 167. be applicable to the other. Extreme caution has been recom- 11. Chaplin JM, Costantino PD, Wolpoe ME, Bederson JB, Griffey mended in this new domain by a number of authoritative ES and Zhang WX: Use of an acellular dermal allograft for groups.2,3 This series is yet another reminder that, as stated dural replacement: an experimental study. Neurosurgery by the authors, “Randomized, controlled trials are necessary 1999; 45: 320. to identify the optimal interposition graft material.” 12. Achauer BM, Bruce M, VanderKam VM, Celikoz B and Jacob- son DG: Augmentation of facial soft-tissue defects with Philippe E. Zimmern alloderm dermal graft. Ann Plast Surg 1998; 41: 503. Department of Urology 13. Wheeler TL, Richter HE, Duke AG, Burgio KL, Redden DT and University of Texas Southwestern Varner RE: Outcomes with porcine graft placement in the Medical Center at Dallas anterior vaginal compartment in patients who undergo high vaginal uterosacral suspension and cystocele repair. Dallas, Texas Am J Obstet Gynecol 2006; 194: 1486. 14. Cervigni M and Natale F: The use of synthetics in the treat- 1. Koch Y, Leininger T and Goldman H: Long-term results of the ment of pelvic organ prolapse. Curr Opin Urol 2001; 11: acellular human dermal allograft sling with transvaginal 429. bone anchors. J Pelvic Med Surg 2006; 12: 317. 15. Julian TM: Efficacy of Marlex mesh in the repair of severe, 2. Shull B and Karram M: Concerns regarding pelvic reconstruc- recurrent vaginal prolapse of the anterior midvaginal wall. tive surgery. Int Urogynecol J 2005; 16: 251. Am J Obstet Gynecol 1996; 175: 1472. 3. Maher C, Baessler K, Glazener C, Adams E and Hagen S: 16. Nicita G: A new operation for genitourinary prolapse. J Urol Surgical management of pelvic organ prolapse in women. 1998; 160: 741. Cochrane Library 2004; 4: 1. Urological Survey

INFECTION AND INFLAMMATION OF THE GENITOURINARY TRACT

Staphylococcal Secretory Inhibitor of Platelet Microbicidal Protein is Associated With Prostatitis Source I. B. Ivanov, V. A. Gritsenko and M. D. Kuzmin, Department of Human Microbiology, Institute of Cellular and Intracellular Symbiosis, Russian Academy of Sciences, Orenburg, Russia J Med Microbiol 2006; 55: 1645–1648. This study reports the detection of an extracellular staphylococcal product, designated secretory inhibitor of platelet microbicidal protein (SIPMP), that causes local inhibition of the bactericidal action of platelet microbicidal protein (PMP) in the fluid phase. Urethral isolates of Staphylococcus aureus (nϭ24) and coagulase-negative staphylococci (CNS) (nϭ47) from patients with or without chronic bacterial prostatitis (CBP) were tested. SIPMP production was tested by inhibition of PMP bioactivity against Bacillus subtilis and was expressed as percentage inhibition of PMP bactericidal activity. The PMP susceptibility of staphylococcal strains was determined by exposing bacterial cells to serial dilutions of PMP. Staphylococci from patients without CBP produced SIPMP at levels of 10.3ϩ/Ϫ1.2 and 13.25ϩ/Ϫ1.72 % for S. aureus and CNS, respectively. Strains isolated from men with CBP inhibited PMP-induced killing of B. subtilis by 23.38ϩ/Ϫ4.2%(PϽ0.05) and 23.69ϩ/Ϫ1.87 % (PϽ0.01) for S. aureus and CNS, respectively. SIPMP production correlated with staphylococcal resistance to PMP (r2ϭ0.6082 and 0.7264 for S. aureus and CNS, respectively). SIPMP represents a hitherto unrecognized determinant of staphylococcal pathogenicity. These results suggest that SIPMP production is associated with the CBP source. Data from this study may have significant implications for the understanding of the pathogenesis of CBP. Editorial Comment: If the findings of this study are confirmed, bacteria may be back in the running for a cause of “nonbacterial” prostatitis. These authors found that certain CNS produce a substance that inhibits a human produced antibacterial protein, PMP. Furthermore, CNS from men with prostatitis (defined by more than 10 white blood cells per high power field in expressed prostatic secretion; I.B.I., personal communication) produce more secretory inhibitors of PMP than CNS isolated from controls. Therefore, some CNS could be more pathogenic than others. This finding could definitely muddy the waters of previous studies showing no difference in isolation rates of CNS in prostatitis cases and controls, but equated all CNS isolates. Future larger studies in different populations with measurement of staphylococcal secretory inhibitor of PMP in CNS isolates from men with nonbacterial prostatitis will be of great interest. Richard E. Berger, M.D.

Catastrophizing and Pain-Contingent Rest Predict Patient Adjustment in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome D. A. Tripp, J. C. Nickel, Y. Wang, M. S. Litwin, M. McNaughton-Collins, J. R. Landis, R. B. Alexander, A. J. Schaeffer, M. P. O’Leary, M. A. Pontari, J. E. Fowler, Jr., L. M. Nyberg and J. W. Kusek; National Institutes of Health-Chronic Prostatitis Collaborative Research Network (NIH-CPCRN) Study Group, Department of Psychology, Anesthesiology and Urology, Queen’s University, Kingston, Ontario, Canada J Pain 2006; 7: 697–708. Cognitive/behavioral and environmental variables are signiﬁcant predictors of patient adjustment in chronic pain. Using a biopsychosocial template and selecting several pain-relevant constructs from physical, cognitive/behavioral, and environmental predictors, outcomes of pain and disability in chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) were explored. Men (n ϭ 253) from a North American multi- institutional NIH-funded Chronic Prostatitis Cohort Study in 6 US and 1 Canadian centers participated in a survey examining pain and disability. Measures included demographics, urinary symptoms, depression,

pain, disability, catastrophizing, control over pain, pain-contingent rest, social support, and solicitous responses from a significant other. Regressions showed that urinary symptoms (beta ϭ .20), depression (beta ϭ .24), and helplessness catastrophizing (beta ϭ .29) predicted overall pain. Further, affective pain was predicted by depression (beta ϭ .39) and helplessness catastrophizing (beta ϭ .44), whereas sensory pain was predicted by urinary symptoms (beta ϭ .25) and helplessness catastrophizing (beta ϭ .37). With regard to disability, urinary symptoms (beta ϭ .17), pain (beta ϭ .21), and pain-contingent rest (beta ϭ .33) were the predictors. These results suggest cognitive/behavioral variables (ie, catastrophizing, pain- contingent rest) may have significant impact on patient adjustment in CP/CPPS. Findings support the need for greater research of such pain-related variables in CP/CPPS. Perspective: This article explores predictors of patient adjustment in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Cognitive/behavioral variables of catastrophizing and pain-contingent rest respectively predicted greater pain and disability. Catastrophic helplessness was a prominent pain predictor. These findings inform clinicians and researchers on several new variables in CP/CPPS outcomes and suggest future research. Editorial Comment: Catastrophizing is the process by which people either magnify the negative or minimize the positive. They usually do both. Catastrophizing has been associated with decreased quality of life and disability associated with numerous pain syndromes. The trait has even been associated with shortening of life span. This type of thinking represents a serious roadblock to recovery, since the slightest setback is seen as catastrophic, and a reason to stop therapy and get off the sometimes long road to recovery. It is more often practiced by women than men, and is even seen in children. Cognitive therapy has been shown to decrease catastrophizing by making the patient more aware of this destructive pattern, and teaching ways to control unproductive thoughts and behaviors. In this article catastrophizing was a strong predictor of overall pain scores in men with CP/CPPS. Men and women who exhibit catastrophic thinking about their urological pain should be strongly encouraged to see a psychologist familiar with treating patients with pain. Many individuals are reluctant but I try to indicate that it may take a long time to control their pain, and in the meantime they can get help with coping with the pain and improving their life. Richard E. Berger, M.D.

IMAGING

Magnetic Resonance Urethrography in Comparison to Retrograde Urethrography in Diagnosis of Male Urethral Strictures: Is It Clinically Relevant? Y. Osman, M. A. El-Ghar, O. Mansour, H. Refaie and T. El-Diasty, Urology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt Eur Urol 2006; 50: 587–594.

Objective: To compare the clinical relevance of retrograde urethrography (RUG) and magnetic resonance (MR) urethrography in evaluating male urethral strictures. Methods: Between January and April 2004, 20 men were referred to our institute for management of urethral strictures. The patients were investigated by conventional RUG and multiformat MR urethrography. The patients were examined by urethroscopy under anesthesia to be followed by definitive endoscopic or open operative intervention. The radiologic data were compared by endoscopic as well as operative findings in all the patients. Results: Ten patients were managed by visual internal urethrotomy (VIU) and two by dilatation under anesthesia; two showed normal urethral caliber. Four patients required open urethral reconstructive procedures. Two patients underwent radical cystectomy and cutaneous diversion because of associated bladder or urethral malignancy. Although overall accuracy for diagnosis of urethral strictures was equal between both modalities (85%), MR urethrography provided extra clinical data in seven patients (35%). It was superior to RUG in judging the urethral stricture length in three patients, diagnosing a urethral tumor in one, detecting associated bladder mass in one, characterizing the site of urethra-rectal fistula in one, and accurately delineating the proximal urethra in the last patient. Unlike RUG, MR urethrography provided adequate information about the degree of spongiofibrosis in all patients. Conclusion: MR urethrography is a promising tool for defining male urethral strictures and can provide extra guidance for treatment planning that cannot be obtained with RUG. IMAGING 159

Editorial Comment: This study looks at 20 men with urethral strictures. The men underwent retrograde urethrography and magnetic resonance urethrography. Before the MR examination the patients were injected with a sterile gel into the urethra, with subsequent application of a soft clamp to the penile oriﬁce to prevent the gel from leaking out. High resolution T2-weighted images of the urethra and bladder were performed, and stricture length was measured. All patients underwent subsequent urethroscopy. Although this is a small study, it shows nice correlation between retrograde urethrography and MR urethrography. This technique is similar to sonourethrography, where sterile gel (or sterile saline) is injected into the urethra. This method may also provide important information on spongioﬁbrosis, which cannot be assessed on the retrograde urethrogram. Magnetic resonance urethrography should be considered an additional and promising technique complement- ing sonourethrography for evaluation of the male urethra. Cary Siegel, M.D. Urolithiasis/Endourology

Auricular Acupressure as a Treatment for Anxiety Before Extracorporeal Shock Wave Lithotripsy in the Elderly

Bruno Mora, Michele Iannuzzi, Thomas Lang, Barbara Steinlechner, Renate Barker, Michael Dobrovits, Christian Wimmer and Alexander Kober From the Departments of Anesthesia and Intensive Care (BM, TL, BS, RB, CW, AK) and Urology (MD), Medical University of Vienna, Vienna, Austria, and Department of Anesthesia and Intensive Care, University of Naples “Federico II” (MI), Naples, Italy

Purpose: Auricular acupuncture at the relaxation point has been shown to be effective treatment for anxiety. We hypothesized that auricular acupressure may decrease anxiety in elderly individuals who are transported by ambulance before receiving ESWL®. Materials and Methods: We enrolled 100 patients with renal calculi who were transported to the local hospital by special ambulance, accompanied by 2 paramedics. Paramedic 1 performed data collection, while paramedic 2 performed auricular acupressure in patients randomly assigned to a relaxation group and a sham treated group. Anxiety was measured using a visual analog scale score on a scale of 0 to 100 mm. Results: Each group consisted of 50 patients with similar demographic characteristics. The relaxation group had significantly decreased anxiety scores upon arrival at the hospital and lower anticipation of pain scores (mean Ϯ SD 57.6 Ϯ 21.8 to 15.4 Ϯ 9.8 and 35.7 Ϯ 29.7 to 9.5 Ϯ 4.1 mm VAS) than the sham treated group (55.5 Ϯ 25.9 to 49.8 Ϯ 28.9 and 37.7 Ϯ 24.1 to 33.8 Ϯ 25.2 mm VAS, respectively, 2-way repeated measure ANOVA each p ϭ 0.001). Estimated waiting times for treatment did not differ significantly between the 2 groups (5.0 Ϯ 2.5 and 5.5 Ϯ 2.95, respectively, repeated measures ANOVA p ϭ 0.83). The Post-Intervention Anxiety visual analog scale demonstrated the significant superiority of the true treatment group (19.5 Ϯ 5.9 and 66.8 Ϯ 27.9 mm VAS, respectively, p ϭ 0.001). Conclusions: Elderly patients who received auricular acupressure at specific relaxation points while being transported to the hospital were less anxious, anticipated less pain and were more optimistic about the outcome of treatment that they will receive than the sham treated group. These data prove that this is an effective treatment for anxiety that improves the patient overall perception of ESWL. Key Words: acupuncture; aged; aged, 80 and over; kidney calculi; ureteral calculi

n increasing number of procedures are being performed during transportation by ambulance are not permitted to as ambulatory outpatient surgery. Patients undergoing administer any medication.6 A outpatient surgery experience various degrees of fear In a recent study Wang reported that AA decreased and anxiety.1 The fact that all patients undergoing surgical anxiety in healthy volunteers and adults awaiting sur- procedures experience anxiety is well known and this may also gery.7 Acupuncture has also been used to treat chronic affect the outcome of the operation.2 In view of this fact there anxiety disorders.8 Eich et al noted that acupuncture is has been a shift in urological surgery from highly invasive able to signiﬁcantly decrease anxiety symptoms in pa- techniques toward minimally invasive and noninvasive proce- tients with minor depression as well as in those with 2 dures. In fact, recent machines for ESWL provide less power- generalized anxiety disorders.9 Roccia and Rogora proved 3 ful but more accurate shock waves. Elderly patients who have that the combination of body acupuncture and AA has a undergone ESWL are aware of the fact that the procedure is relaxing effect on patients with chronic anxiety disor- 4 painful despite analgesic medication. ders.10 Compared to body acupuncture the auricular ap- Elderly patients must be transported to outpatient sur- proach allows easy access to any stimulation point in the gery by ambulance cars or special vehicles for handicapped body and it also does not require the patient to undress. individuals, aided by paramedics. Elderly patients experi- Acupuncture includes several techniques, such as insert- ence signiﬁcant anxiety when faced with transportation by ing hair thin needles (acupuncture) or applying direct 5 ambulance. Several drugs can be administered to counter- pressure onto the acupuncture points (acupressure). De- act their anxiety but paramedics accompanying patients spite the paucity of direct comparisons between acupressure and other acupuncture techniques the application of pressure on so-called acupuncture points is a noninvasive Submitted for publication October 13, 2006. procedure and it can be performed by paramedics. Study received institutional review board approval. Based on these data we performed a prospective, random- For another article on a related topic see page 314. ized, double-blind study to test the hypothesis that AA may

0022-5347/07/1781-0160/0 160 Vol. 178, 160-164, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.019 AURICULAR ACUPRESSURE FOR ANXIETY BEFORE LITHOTRIPSY 161 decrease anxiety when elderly patients are transported by Patients remained seated while entering scores on the ambulance before receiving ESWL. VAS scale. After paramedic 1 obtained the baseline assessments paramedic 2 opened a sealed envelope that indicated MATERIALS AND METHODS the subject randomization to 1 or the other group and performed the intervention accordingly. After obtaining institutional review board approval and patient informed consent we enrolled 100 patients with renal Relaxation Group calculi. All patients had been transported to the local hospi- Subjects in this group received bilateral AA at a point of tal by special ambulance, accompanied by paramedics. No relaxation that was reported previously.7 The point is lo- patient was in pain during transportation. cated at the superior lateral wall of the triangular fossa Inclusion criteria were renal and urethral calculi, pa- (fig. 1). Acupressure was administered with a plastic ball 1 tients who previously underwent ESWL and recalled the mm in diameter, which was pressed on the relaxation point experience as a painful one, age between 65 and 90 years, and fixed with an opaque ear patch (figs. 2 to 4). The ear and patients with social insurance. Exclusion criteria were patch remained in position until the patient was delivered to lack of fluency in German, inability to provide informed the hospital. consent, neurological or psychiatric disorders, sedative intake for chronic psychological disorders, acute renal colic, a score of more than 0 on the VAS for pain, the intake of Sham Treated Group analgesic drugs within 48 hours before the investigation and The sham treated group received bilateral AA at a sham kidney stones larger than 2 cm. point, defined as a point with no relaxing or anxiolytic effect in acupuncture.8 For study purposes the sham acupuncture point was at the tip of the concha, a point that was reported Outcome Measures to cause homeostasis in the stomach (fig. 1). To administer The Pre-Intervention Visual Analog Scale for Anxiety is a acupressure a plastic ball 1 mm in diameter was pressed on self-assessment instrument used to rate the level of anxiety the sham point and fixed with an opaque ear patch that experienced by an individual. The scale consists of a 100 mm remained in position until the patient reached the hospital line that represents the extremes of symptoms on either end (figs. 2 to 4). of the continuum from 0—not anxious to 100—extremely After paramedic 1 left, paramedic 2 performed AA using anxious. All patients completed the scale under the super- ear patches. The patient was then transferred to the hand- vision of a paramedic. icapped transportation car. Paramedic 1 sat in the front seat of the car, while paramedic 2 remained with the patient in Anticipation Questionnaire the rear. The front and rear portions of the ambulance were This questionnaire consists of 4 questions about 1) subject separated by a rigid wall. Upon arrival at the hospital para- estimation of the waiting period for treatment, 2) antici- medic 1 reassessed patient parameters in the absence of pated pain during treatment, 3) the patient attitude toward paramedic 2. Paramedic 1 placed the completed data sheets the physicians and 4) treatment outcomes in relation to the in opaque envelopes and sealed them to ensure complete patient anticipation of medical treatment at the hospital. A blinding. After the ESWL procedure the urologist inquired 100 mm VAS was used to asses individual responses to each about the patient VAS score for anxiety and sent a letter to question. The VAS score was 0—maximal satisfaction to the office of the Red Cross secretary, where a clerk entered 100—thorough dissatisfaction. the data in a Windows® Access™ database. The entire pro- The Post-Intervention VAS for Anxiety is a self-assess- cedure was performed in blinded fashion. Neither the urol- ment instrument used to rate the level of anxiety experi- ogist nor clerk was aware of the type of acupressure that the enced by an individual. The scale consists of a 100 mm line patient received. The paramedics had no access to the com- that represents the extremes of symptoms on either end of puter. the continuum from 0—not anxious to 100—extremely anxious. Patients completed the scale under the supervision of a urologist.

Study Protocol Paramedics 1 (data collection) and 2 (treatment) were assigned to attend to patient at the patient residence. Patients were treated according to the guidelines of the Austrian Red Cross Ambulance Service. These guidelines are accepted as the basis for paramedical education in Austria, which ensures a speciﬁc standard of hospital transportation for dis- abled patients. Paramedic 2 obtained patient written informed consent and departed from the site. Paramedic 1 documented patient baseline demographic characteristics and hemodynamic parameters, including blood pressure and heart rate. The patient also completed the anxiety and anticipation questionnaires before acupressure. The ends of the VAS scales were randomized to prevent the handedness of the patient from confounding the results. FIG. 1. Intervention sites in relaxation and sham treated groups 162 AURICULAR ACUPRESSURE FOR ANXIETY BEFORE LITHOTRIPSY

FIG. 2. Plastic ball 1 mm in diameter used for acupressure

To minimize bias paramedic 2 was kept blinded as to whether a true or sham procedure was performed. Para- medic 2 was told that the aim of the study was to compare acupressure interventions using 2 points. None of the paramedics involved in the study had knowledge of or experience FIG. 4. Fixation of ball with patch with acupressure or similar treatments. To ensure that treatment was administered appropriately paramedic 2 was 2-way repeated measures ANOVA was used to analyze intensively trained by a physician experienced with acupres- changes in the behavioral and physiological anxiety level of sure and acupuncture at University Hospital of Vienna. patients at 2 time points, that is before acupressure and Great care was taken to ensure that treatment and data upon arrival at the hospital. Results are presented as the collection were performed in the presence of only 1 investi- mean Ϯ SD with significance considered at p Յ0.05. gator. The ambulance was designed such that paramedic 1 remained unaware of the AA intervention. To ensure effective blinding and accurate treatment execution a physician RESULTS not involved in data collection or treatment performed 10 A total of 100 patients were enrolled in the study. The audits on site of the methodology and data collection. relaxation group and the sham treated group consisted of 50 patients each. All enrolled patients completed the study. No Sample Size and Statistical Analysis patient was considered a dropout for technical or medical The a priori study protocol required a total sample size of 64 reasons. The patients had similar baseline characteristics in patients to detect a difference of 1 SD (effect size 1.0) with terms of age, gender, blood pressure, heart rate, belief in ANOVA at the ␣ level of 0.05 and a power of 80%. We acupuncture and all other outcome parameters (see table). included 100 patients because of the uncertain dropout rate Two-way repeated measures ANOVA to determine in trials out of hospital. After testing for normal distribution changes in anxiety showed that individuals who received acupressure at the relaxation point had significantly decreased anxiety scores upon arrival at the hospital than individuals who underwent sham intervention (57.6 Ϯ 21.8 to 15.4 Ϯ 9.8 vs 55.5 Ϯ 25.9 to 49.8 Ϯ 28.9 mm VAS, p ϭ 0.001). Thus, patients who received acupressure at the relaxation point had significantly lower anticipation of pain scores than patients who underwent sham intervention (35.7 Ϯ 29.7 to 9.5 Ϯ 4.1 vs 37.7 Ϯ 24.1 to 33.8 Ϯ 25.2 mm VAS, p ϭ 0.001). Furthermore, patients who received acupressure were significantly more optimistic about the treatment outcome for the illness than patients in the sham treated group (56.9 Ϯ 29.4 to 11.1 Ϯ 7.4 vs 55.0 Ϯ 29.5 to 51.5 Ϯ 25.5 mm VAS, p ϭ 0.001). In contrast, the estimation of waiting times for treatment did not differ significantly between the 2 groups (5.0 Ϯ 2.5 and 5.5 Ϯ 2.9, respectively, repeated measures ANOVA p ϭ 0.83), showing that waiting time was not a relevant reason for fear in this trial population. Similarly no difference was observed with regard to the

Baseline characteristics Acupressure Sham

Mean Ϯ SD age (year) 76.9 Ϯ 5 77.0 Ϯ 04 Mean Ϯ SD ht (cm) 175 Ϯ 11 178 Ϯ 11 Mean Ϯ SD wt (kg) 69 Ϯ 20 75 Ϯ 11 No. men/women 16/34 19/31 FIG. 3. Application of small plastic ball in relaxation (A) and sham treated (B) groups. Total of 50 patients per group. AURICULAR ACUPRESSURE FOR ANXIETY BEFORE LITHOTRIPSY 163 patient attitude toward the physicians (repeated measures into the blood.17 Furthermore, various neurotransmitters ANOVA p ϭ 0.53). There were also no significant changes in such as serotonin, norepinephrine and possibly ␥-aminobu- blood pressure or heart rate between or within the groups tyric acid are known to interrupt incoming stress signals in before and after intervention. The Post-Intervention Anxiety the central nervous system. VAS is a self-assessment instrument used to rate the level of AA is a useful measure for decreasing anxiety in the anxiety experienced by an individual. The scale was com- pre-interventional urological setting. The reasons are many. pleted by the patient under the supervision of a urologist. It 1) The equipment required is minimal. Any physician, revealed significant differences between the groups (19.5 Ϯ nurse, paramedic or emergency medical technician can ad- 5.9 vs 66.8 Ϯ 27.9 mm VAS, p ϭ 0.001), demonstrating the minister the treatment while elderly patients are being significant superiority of the true treatment group. transported to the hospital. 2) The period of training to learn a simple point is brief. Physicians and other health care DISCUSSION providers with no or minimal experience in traditional Chi- nese medicine can learn the technique in a few hours. 3) It is Elderly patients who received AA at specific relaxation an almost cost-free intervention. In view of the fact that points while being transported to the hospital were less anxiety is liable to cause major adverse physiological re- anxious, anticipated less pain and were more optimistic sponses an instantaneous decrease in anxiety before hospi- about the outcome of the treatment that they will receive tal admission, which probably decreases neurotransmitter than a sham treated group. release, is obviously beneficial in the elderly population and The pathogenesis of pain in ESWL is not fully known. in patients with a heart condition. AA is effective treatment Whether pain is due to cutaneous or to deep visceral afferent for anxiety and it may also decrease the overall cost of health stimulation is debatable. Ganapathy et al suggested that care by minimizing the complications associated with pre- pain in lithotripsy arises from the deeper visceral structures interventional stress.18 rather than from the skin.11 Pain is reportedly due to cavi- Several methods may be used to assess anxiety. Cur- tation mediated stimulation of nerve fibers. The intensity of rently STAI is considered the gold standard in the acute pain perceived during ESWL depends on the energy level of setting. The use of STAI was reported in more than 1,000 shock waves passing through the tissues. However, Loening peer reviewed medical publications.19 However, the STAI et al suggested that there is a cutaneous component to pain consists of 20 items and it may require approximately 10 induced by the lithotriptor.12 minutes to complete. Therefore, it is of limited use for re- Ambulatory surgical procedures are reported to be accom- search in a clinical care setting. Instead we used a VAS scale panied by stress due to various factors. The patient preop- to assess patient anxiety. The correlation coefficient r for erative anxiety level is associated with patient tolerance of VAS and STAI was reported to be 0.55 to 0.84.20 In the stress and fear of surgery.2 In addition to factors that concurrent study the use of VAS to assess anxiety was found to tribute to these phenomena, such as transportation by am- produce valid results. bulance or the pain of the procedure, prolonging total treatment time and the period of time during which patients CONCLUSIONS must maintain a relatively fixed position potentially increases their anxiety. However, it should be remembered AA proved to be an effective treatment for anxiety and it that pain might be an inaccurate indicator in elderly pa- improved the overall patient perception of ESWL. AA is easy tients with comorbidities such as arthritis and muscle com- to learn and it may greatly improve the quality of care for plaints.13 patients being transported to a urology department for an Elderly individuals who are about to receive a previously ESWL procedure. experienced painful ambulatory treatment obviously experience fear and anxiety. All of these factors join to produce increased sympathetic nervous system activity, which stim- Abbreviations and Acronyms ulates ventricular arrhythmias14 and increases the risk of mortality.15 AA ϭ auricular acupressure ϭ According to the law in several countries, including Aus- STAI State Trait Anxiety Inventory ϭ tria, only physicians may administer medication. In para- VAS visual analog scale medic based transportation systems anxiety decreasing medication may not be administered by a paramedic. Thus, REFERENCES the patient experiences significant anxiety while being driven to the hospital and may receive no medical treatment 1. Mackenzie JW: Daycase anaesthesia and anxiety. A study of for it. A nonpharmacological anxiolytic measure would be of anxiety profiles amongst patients attending a day bed unit. great use in this setting. We observed that AA is effective Anaesthesia 1989; 44: 437. treatment for stress and anxiety in these patients. The tech- 2. Brown SM: Quantitative measurement of anxiety in patients nique is easy to learn and can be administered by paramed- undergoing surgery for renal calculus disease. J Adv Nurs ics. 1990; 15: 962. 3. Parkin J, Keeley FX and Timoney AG: Analgesia for shock The mechanism underlying the efficacy of AA may be wave lithotripsy. J Urol 2002; 167: 1613. similar to that reported in the acupuncture literature. Stim- 4. Oh SJ, Ku JH, Lim DJ, Byun SS and Kim HH: Subjective pain ulating a specific point with a needle or with pressure acti- scale and the need for analgesia during shock wave litho- vates small myelinated nerve fibers that send impulses into tripsy. Urol Int 2005; 74: 54. 16 the spinal cord, midbrain, pituitary and hypothalamus, 5. Barker R, Kober A, Hoerauf K, Latzke D, Adel S, Kain ZN et al: causing a measurable amount of endorphins to be released Out-of-hospital auricular acupressure in elder patients 164 AURICULAR ACUPRESSURE FOR ANXIETY BEFORE LITHOTRIPSY

with hip fracture: a randomized double-blinded trial. Acad 17. Levine JD, Gormley J and Fields HL: Observations on the Emerg Med 2006; 13: 19. analgesic effects of needle puncture (acupuncture). Pain 6. Brismar B, Dahlgren BE and Larsson J: Ambulance utilization 1976; 2: 149. in Sweden: analysis of emergency ambulance missions in 18. Akca O, Melischek M, Scheck T, Hellwagner K, Arkilic CF, urban and rural areas. Ann Emerg Med 1984; 13: 1037. Kurz A et al: Postoperative pain and subcutaneous oxygen 7. Wang SM, Peloquin C and Kain ZN: The use of auricular tension. Lancet 1999; 354: 41. acupuncture to reduce preoperative anxiety. Anesth Analg 19. Tenenbaum G, Furst D and Weingarten G: A statistical reeval- 2001; 93: 1178. uation of the STAI anxiety questionnaire. J Clin Psychol 8. Wang SM and Kain ZN: Auricular acupuncture: a potential 1985; 41: 239. treatment for anxiety. Anesth Analg 2001; 92: 548. 20. Kindler CH, Harms C, Amsler F, Ihde-Scholl T and Scheidegger 9. Eich H, Agelink MW, Lehmann E, Lemmer W and Klieser E: D: The visual analog scale allows effective measurement of Acupuncture in patients with minor depressive episodes preoperative anxiety and detection of patients’ anesthetic con- and generalized anxiety. Results of an experimental study. cerns. Anesth Analg 2000; 90: 706. Fortschr Neurol Psychiatr 2000; 68: 137. 10. Roccia L and Rogora G: Acupuncture and relaxation. Minerva EDITORIAL COMMENT Med 1976; 67: 1918. 11. Ganapathy S, Razvi H, Moote C, Parkin J, Yee I, Gverzdys S et These authors examined the role of AA to decrease anxiety al: Eutectic mixture of local anaesthetics is not effective for before ESWL. Regardless of your view on nontraditional extracorporeal shock wave lithotripsy. Can J Anaesth 1996; medicine, it is hard to argue against this well done, prospec- 43: 1030. tive, blinded, randomized study, in whicha1mmacupres- 12. Loening S, Kramolowsky EV and Willoughby B: Use of local sure plastic ball applied to the upper ear could signiﬁcantly anesthesia for extracorporeal shock wave lithotripsy. J Urol decrease anxiety and the anticipation of pain in patients 1987; 137: 626. undergoing ESWL. Historically medical doctors have been 13. Medina HJ, Galvin EM, Dirckx M, Banwarie P, Ubben JF, skeptical of alternative forms of medical treatment. How- Zijlstra FJ et al: Remifentanil as a single drug for extra- ever, data such as these should encourage urologists to ex- corporeal shock wave lithotripsy: a comparison of infusion amine alternative forms of medicine to lessen the perioper- doses in terms of analgesic potency and side effects. Anesth ative anxiety and pain of all of their patients. Hospitals and Analg 2005; 101: 365. 14. Meredith IT, Broughton A, Jennings GL and Esler MD: Evi- medical schools are adding specialists who have medical dence of a selective increase in cardiac sympathetic activity degrees and training in alternative medicine. As urologists in patients with sustained ventricular arrhythmias. N Engl who pride ourselves in minimally invasive techniques and J Med 1991; 325: 618. rapid recovery, we should partner with these specialists to 15. Kawachi I, Colditz GA, Ascherio A, Rimm EB, Giovannucci E, see what role these techniques have for improving the care Stampfer MJ et al: Prospective study of phobic anxiety and of our patients. risk of coronary heart disease in men. Circulation 1994; 89: 1992. Robert B. Nadler 16. Hui KK, Liu J, Makris N, Gollub RL, Chen AJ, Moore CI et al: Section of Endourology, Laparoscopy and Stone Disease Acupuncture modulates the limbic system and subcortical Feinberg School of Medicine gray structures of the human brain: evidence from fMRI Northwestern University studies in normal subjects. Hum Brain Mapp 2000; 9: 13. Chicago, Illinois Percutaneous Nephrolithotripsy With the Patient in a Modiﬁed Supine Position

Elias Assad Chedid Neto, Anuar Ibrahim Mitre, Cristiano Mendes Gomes,* Marco Antonio Arap and Miguel Srougi From the Division of Urology, São Paulo University Medical School, São Paolo, Brazil

Purpose: The supine position has potential advantages over the prone position for percutaneous nephrolithotripsy but it is neglected by most urologists. We analyzed the efficacy and safety of percutaneous nephrolithotripsy with the patient in a modified supine position. Materials and Methods: In a prospective study 88 consecutive patients underwent percutaneous nephrolithotripsy in a modified supine position. Mean Ϯ SD stone size was 3.6 Ϯ 1.9 cm and 26 patients (29.5%) had complete staghorn stones. Ten patients (11.4%) also had ureteral stones and underwent concomitant ureteroscopy. Complications and success rates were analyzed. Results: The lower, middle and upper calix was the only access in 42 (47.7%), 10 (11.4%) and 5 patients (5.7%), respectively. Four patients (4.5%) had supracostal access. A single percutaneous nephrolithotripsy session was needed in 78 patients (88.6%), while 10 (11.4%) required 2 sessions. A total of 62 patients (70.5%) were stone-free. Five patients (5.7%) required blood transfusion. Postoperative complications included ureteral obstruction due to migration of stones in 3 cases (3.4%), serious bleeding requiring arterial embolization in 2 (2.3%) and prolonged fever in 4 (4.5%). The need for direct access to the upper pole and the need for concomitant ureteroscopy did not affect the success and complication rates of percutaneous nephrolithotripsy. The colon was never damaged and we had no cases of hydrothorax, kidney loss or sepsis. Conclusions: Percutaneous nephrolithotripsy with the patient in a modified supine position is effective and safe. It may be considered for most patients requiring percutaneous nephrolithotripsy, especially if concomitant ureteroscopy is planned. Key Words: kidney; kidney calculi; lithotripsy; nephrostomy, percutaneous; supine position

ercutaneous nephrolithotripsy is considered the treat- PATIENTS AND METHODS ment of choice for large kidney calculi based on supe- In this prospective study patients with an indication for P rior outcomes and acceptable low morbidity. Recent percutaneous nephrolithotripsy regardless of stone charac- advances in instrumentation and technique have improved teristics, or kidney anatomical or functional aspects under- the factors, including stone-free rates, increased treatment went surgery in a modified supine position. Patients with a efficiency and decreased morbidity, therefore, favoring solitary kidney or those requiring bilateral simultaneous PNL.1 PNL or supracostal access were also enrolled in this study. PNL is usually performed through a posterior access with Patients with concomitant ureteral calculi underwent PNL the patient prone. Lateral access with the patient supine in the original position described by Valdivia-Uria et al.4 was proposed by Valdivia-Uria et al, who suggested that it Exclusion criteria were patient age less than 18 years and might have several advantages, including ease of patient uncorrectable coagulopathy. Informed consent was obtained positioning, more patient comfort, the ability to perform from all patients before considering them for study. simultaneous PNL and ureteroscopic procedures, dependent From May 2002 to June 2005, 88 consecutive patients, Amplatz sheath drainage and better control of the airways including 58 women (65.9%) and 30 men (34.1%), with a during the procedure.2–4 mean Ϯ SD age of 43.5 Ϯ 13.3 years (range 19 to 76) under- Despite the potential advantages of the supine position went PNL in the supine position. Preoperative evaluation over the prone position for PNL this approach is neglected included clinical examination, routine laboratory investiga- by most urologists, mainly for fear of colon damage. We tions and radiological evaluation with plain abdominal x- evaluated the efficacy and safety of PNL with the patient in ray, ultrasonography, excretory urography or computerized a modified supine position for treating kidney stones. tomography. Mean stone diameter Ϯ SD was 3.6 Ϯ 1.9 cm (range 1.0 to 8.0). Of the patients 26 (29.5%) had complete staghorn Submitted for publication November 14, 2006. stones and 17 (19.3%) had stones smaller than 2 cm. Ten * Correspondence: Disciplina de Urologia, Hospital das Clinicas patients (11.4%) had concomitant ureteral stones and ure- da Faculdade de Medicina da Universidade de São Paulo, Ave. Dr. teroscopy was performed in association with PNL. Eneas Carvalho de Aguiar, 255, 7o andar, 05403-001 São Paulo-SP, Brasil (telephone: 55 11 3069-8080; FAX: 55 11 3064-7013; e-mail: Urinary tract infection was present in 10 patients (11.4%) [email protected]). preoperatively and it was treated with antibiotic according

0022-5347/07/1781-0165/0 165 Vol. 178, 165-168, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.056 166 MODIFIED SUPINE POSITION FOR PERCUTANEOUS NEPHROLITHOTRIPSY to urine culture sensitivity. As evaluated by serum creatinine, renal function was normal in 84 patients (95.4%) and decreased in 4 (4.6%). Table 1 shows patient demographic data and preoperative parameters. The patient received general anesthesia. A 7Fr ureteral catheter was inserted transurethrally with the patient in the lithotomy position. The patient was then placed in the modified supine position with the legs extended and the ipsilateral leg crossed over the contralateral leg. A cushion was placed below the ipsilateral flank to provide a 30-degree inclination (see figure). Patients with concomitant ureteral stones were maintained in the lithotomy position with a 30-degree flank inclination, which is the original Valdivia- Uria position.4 The ipsilateral arm was over the thorax and the contralateral arm was used for intravenous infusion. Percutaneous access was always created by 1 of a team of surgeons under fluoroscopic guidance. An 18 gauge needle was horizontally introduced through the flank in the posterior axillary line into the collecting system at the selected calix. We preferred to puncture the posterior calix. A 0.038- With patient in modified supine position ipsilateral leg is extended inch guidewire was passed through the needle and placed in and crosses over contralateral leg. the urinary tract. The nephrostomy tract was dilated with telescoping metal dilators and a 30Fr Amplatz sheath was positioned in the renal collecting system. Fluoroscopic con- during followup. The procedure was considered successful if trol was maintained perpendicular to the needle and dilators the patient was free of stones or had residual fragments during access maneuvers. Additional tracts were made ac- smaller than 5 mm in diameter on renal ultrasonography, cording to the stone burden and urinary tract anatomy with radiography or computerized tomography. Patients with the aim of complete stone clearance. The stone was disinte- larger residual fragments were candidates for additional grated using pneumatic or ultrasonic lithotripsy devices. PNL. Operative time, blood transfusion requirements, post- The procedure was finished after complete stone removal operative course, hospital stay and success rates were con- was confirmed fluoroscopically and endoscopically or it was sidered. interrupted when there was significant bleeding. Based on the hypothesis that direct access to the upper An 18Fr nephrostomy tube was left indwelling for 48 to calix with the patient supine may not be adequate we com- 72 hours. The ureteral catheter and a 16Fr Foley urethral pared patients who required puncture to the upper calix catheter were removed the following day. Patients with with those without the need for direct access to the upper multiple stones or a significant residual stone burden pole in terms of stone-free rates using the Fisher exact test. underwent second look nephroscopy 2 to 5 days after the The same test was used to assess the impact of concomitant initial procedure. In patients with small residual stones a ureteroscopy on the success and complication rates of PNL. Double-J® catheter was inserted antegrade and removed Data were processed using commercially available statisti- after ESWL®. cal software with p Ͻ0.05 considered significant. Patients were assessed with ultrasonography and antegrade pyelography on day 2 postoperatively to evaluate re- RESULTS sidual fragments and ureteral patency. The nephrostomy tube was removed if the ureter was patent and repeat PNL Mean operative time was 162.1 minutes (range 60 to 300) for residual stones was not necessary. Renal ultrasonogra- and mean hospital stay was 5.4 days (range 2 to 21). A total phy and plain abdominal x-ray were repeated after 4 weeks of 124 punctures were required in 88 patients. Kidney access was achieved with 1 puncture in 57 patients (64.8%), 2 punctures in 26 (29.6%) and 3 punctures in 5 (5.7%). Four patients had a supracostal tract. The lower, middle and TABLE 1. Preoperative parameters upper calix was the only access route in 42 (47.7%), 10 No. pts 88 (11.4%) and 5 patients (5.7%), respectively. Combined access No. men (%)/women 30 (34.1)/58 (65.9) via different calices was performed in the remaining pa- Mean Ϯ SD age (range) 43.5 Ϯ 13.3 (19–76) No. serum creatinine (%): tients. A single PNL session was needed in 78 cases (88.6%), Greater than 1.2 mg/dl 4 (4.6) while 10 (11.4%) required 2 sessions. 1.2 mg/dl or Less 84 (95.4) No. previous renal surgery (%) 55 (62.5) A total of 48 patients (54.6%) were completely stone-free No. cm stone diameter (%): and 14 (15.9%) had residual fragments smaller than 5 mm. 2 or Less 17 (19.3) In 26 patients (29.5%) residual fragments were treated with Greater than 2 71 (80.7) Mean Ϯ SD (range) 3.6 Ϯ 1.9 (1–8) ESWL on an outpatient basis 2 to 3 weeks after hospital No. stone location (%): discharge. Mean size of the residual fragments was 0.93 mm Renal pelvis 16 (18.2) (range 0.5 to 1.5). Residual stones were located in the lower Calices 29 (33) Staghorn 26 (29.5) calix in 16 patients (55.2%), in the middle calix in 4 (13.8%) Multiple 17 (19.3) and in the upper calix in 7 (24.1%). The remaining residual Concomitant ureteral stones 10 (11.4) stones were located in more than 1 calix. MODIFIED SUPINE POSITION FOR PERCUTANEOUS NEPHROLITHOTRIPSY 167

Of the 15 patients with stones located in the upper calix to the prone position during the procedure. Nevertheless, that required a direct access route 7 (46.7%) were stone-free, simultaneous PNL and ureteroscopic procedures can be 3 (20.0%) had residual fragments less than 5 mm and 5 done with the patient supine. Moreover, this position is more (33.3%) had residual fragments that required adjuvant comfortable for the patient, which might enable the use of treatment with ESWL. In comparison with patients without less intense anesthesia.4 Ventilatory difficulties may occur direct access to upper pole stones no differences were ob- while prone and control of the airways by the anesthesiolo- served in terms of stone clearance rates (p ϭ 0.761). gist is more demanding.3,5 Finally, dependent drainage of Ten patients (11.4%) underwent ureteroscopy in associa- the nephrostomy sheath with the patient supine may facil- tion with PNL. They did not differ from the other patients in itate the evacuation of stone fragments.4,6,7 terms of the stone-free rate, number of PNL sessions and In this series we introduced a modification to the original complications. position described by Valdivia-Uria et al.4 Unless concomi- Seven patients (8.0%) required blood transfusion. There tant ureteroscopy was planned the patient was placed su- were 2 cases (2.3%) of serious postoperative bleeding in pine with the legs extended and the ipsilateral leg crossed urine that occurred on days 3 and 4 postoperatively, and did over the contralateral let and a cushion below the ipsilateral not respond to conservative measures. They required renal flank to provide a 30-degree inclination. Extending and arteriography, which revealed arterial fistulas. These 2 pa- crossing the patient legs facilitates caliceal puncture and tients were successfully treated with arterial selective em- nephrostomy tract dilation, augmenting the distance from bolization. Serum creatinine after embolization was normal the lower rib to the iliac crest. Additionally, stretching the in each patient. tissues in this area of the abdominal wall avoids redundancy One patient with a ureteropelvic junction injury was suc- or folding of the tissue layers and further helps develop cessfully treated with a Double-J catheter. The colon was percutaneous access. We also believed that the modified never damaged and no case of pneumothorax or hydrothorax position enables more comfortable positioning of the assis- was observed. Postoperatively ureteral obstruction due to tant next to the surgeon. Finally, it is expected to decrease migrated stones was observed in 3 patients (3.4%), requiring potential complications associated with the lithotomy posi- ureteroscopic lithotripsy and Double-J stenting. Other com- tion.8–10 plications included hepatic decompensation in 1 patient Despite the potential advantages of the supine position it with hepatitis C virus infection after the second PNL ses- is neglected by the majority of urologists, perhaps due to sion, requiring 21 days of hospital stay. Additionally, 4 pa- lack of experience and fear that the supine position might tients (4.5%) had prolonged ileus and abdominal pain, which increase the risk of colonic injury. Although the procedure is was successfully treated conservatively. A total of 12 pa- performed with the patient supine, kidney access is achieved tients (13.6%) had fever, which lasted more than 24 hours in through the flank and the whole procedure is retroperito- 4. In all of these patients fever subsided without the need to neal. Our results reinforce those of other series showing the change antibiotics and sepsis did not develop. We noted no safety of this technique in terms of avoiding colonic inju- kidney loss or prolonged urinary leakage. Table 2 lists pa- ries.4 Additionally, our complication rates were similar to tient intraoperative data, success rates and complications. those in most other series. The need for blood transfusion was 8%, in contrast to an estimated 18% for contemporary DISCUSSION PNL series according to the American Urological Associa- tion guideline.1 We noted no acute kidney loss, pleural prob- PNL has been recommended as the treatment of choice for lems, prolonged urinary leakage or sepsis. Our most impor- 1 patients with staghorn calculi or large renal stones. The pro- tant complications were vascular injury in 2 cases (2.3%) cedure is usually performed with the patient prone with that required selective arterial embolization due to severe potential disadvantages compared to the supine position. urinary hemorrhage. Recent series with large populations Patient positioning is more demanding for the surgical team have demonstrated a 1.0% to 1.4% chance of requiring su- since there is a need for a position change from the lithotomy perselective embolization.11,12 Postoperative fever was observed in 12 patients (13.6%), similar to the rate in other reports.13–15 In all cases fever subsided without the need to TABLE 2. Operative data and outcomes change antibiotics and sepsis did not develop. Parameter Many urologists favor upper pole puncture with the patient prone because this approach provides a direct tract Mean Ϯ SD mins operative time (range) 162.1 Ϯ 49.3 (60–300) Mean Ϯ SD days hospitalization (range) 5.4 Ϯ 3.1 (2–21) down the renal pelvis and ureter. However, it may require No. access relative to 12th rib (%): supracostal punctures with their attendant risks.6,8–10 With Subcostal 84 (95.4) the patient supine most punctures are performed in the Supracostal 4 (4.5) No. second PNL session (%): lower and middle pole calices. No 78 (88.6) Our stone clearance rate of 70.5% is a little lower than Yes 10 (11.4) No. outcome (%): that reported in most contemporary PNL series, estimated Stone-free 62 (70.5) at 78%.1 We believe that this was secondary to the fact that Residual stones greater than 0.5 cm 26 (29.5) we did not routinely use a flexible nephroscope in our pa- No. complications (%): Blood transfusion 7 (8.0) tients because it was not available during most of the study Arterial fistula 2 (2.3) period. Furthermore, 88.6% of our patients were treated at a Fever 12 (13.6) single PNL session. No. punctures (%): 1 57 (64.8) In this series the upper calix was punctured in 15 pa- 2 26 (29.5) tients, including 4 who underwent supracostal puncture. 3 5 (5.7) The stone-free rate in this subgroup of patients was compa- 168 MODIFIED SUPINE POSITION FOR PERCUTANEOUS NEPHROLITHOTRIPSY rable to that in patients who did not require direct access to 9. Kubiak R, Wilcox DT, Spitz L and Kiely EM: Neurovascular the upper pole, indicating that access to the upper calices morbidity from the lithotomy position. J Pediatr Surg 1998; should not be considered an impediment to the use of the 33: 1808. supine position. 10. Mumtaz FH, Chew H and Gelister JS: Lower limb compart- Ten patients (11.4%) in our series underwent uretero- ment syndrome associated with the lithotomy position: con- scopic lithotripsy in association with PNL. Complication and cepts and perspectives for the urologist. BJU Int 2002; 90: stone-free rates were comparable to the rates in patients 792. 11. El-Nahas AR, Shokeir AA, El-Assmy AM, Mohsen T, Shoma who underwent PNL alone. The ability to perform the 2 AM, Eraky I et al: Post-percutaneous nephrolithotomy procedures without the need to change patient position is a extensive hemorrhage: a study of risk factors. J Urol 2007; major advantage of the supine position. 177: 576. 12. Srivastava A, Singh KJ, Suri A, Dubey D, Kumar A, Kapoor R CONCLUSIONS et al: Vascular complications after percutaneous nephrolithotomy: are there any predictive factors? Urology 2005; The lateral approach with the patient supine for percutane- 66: 38. ous nephrolithotripsy is safe and it provides several advan- 13. Meretyk S, Gofrit ON, Gafni O, Pode D, Shapiro A, Verstandig tages for the patient and urologist. It may be considered an A et al: Complete staghorn calculi: random prospective alternative to the conventional prone position for most pa- comparison between extracorporeal shock wave lithotripsy tients during percutaneous nephrolithotripsy. Patients re- monotherapy and combined with percutaneous nephrosto- quiring simultaneous nephrolithotripsy and ureteroscopic lithotomy. J Urol 1997; 157: 780. procedures are ideal candidates for this approach. 14. Roth RA and Beckmann CF: Complications of extracorporeal shock-wave lithotripsy and percutaneous nephrolithotomy. Urol Clin North Am 1988; 15: 155. 15. Osman M, Wendt-Nordahl G, Heger K, Michel MS, Alken P Abbreviations and Acronyms and Knoll T: Percutaneous nephrolithotomy with ultra- PNL ϭ percutaneous nephrolithotripsy sonography-guided renal access: experience from over 300 cases. BJU Int 2005; 96: 875.

REFERENCES EDITORIAL COMMENT

1. Preminger GM, Assimos DG, Lingeman JE, Nakada SY, Pearle These authors compare their results to those in studies that MS and Wolf JS Jr: Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recom- focused on staghorn calculi. With limitations in sample size mendations. J Urol 2005; 173: 1991. and lack of a control arm one cannot conclude equivalence in 2. Ali AA, Breslin DS, Hardman HD and Martin G: Unusual the risk of transfusion (8%) or arteriovenous fistula (2%). presentation and complication of the prone position for The ability to target renal access with the patient supine spinal surgery. J Clin Anesth 2003; 15: 471. through Brodel’s avascular plane and a posterior calix may 3. Raphael J, Rosenthal-Ganon T and Gozal Y: Emergency air- be best studied in a cadaveric model. way management with a laryngeal mask airway in a pa- Although no colonic injuries were noted, 5% of patients tient placed in the prone position. J Clin Anesth 2004; 16: experienced prolonged ileus, which is an uncommon compli- 560. 4. Valdivia-Uria JG, Valle GJ, Lopez Lopez JA, Villarroya RS, cation following prone PNL. This may account for the long Ambroj NC, Ramirez FM et al: Technique and complica- hospital stay of 5.4 days. Only 55% of patients were stone- tions of percutaneous nephroscopy: experience with 557 free, although postoperative success was determined by rel- patients in the supine position. J Urol 1998; 160: 1975. atively insensitive imaging modalities (KUB or ultrasound). 5. Cox RG, Ewen A and Bart BB: The prone position is associated What percent of residual fragments was in an anterior with a decrease in respiratory system compliance in calix? One would expect that lateral deflection of the rigid healthy anaesthetized infants. Paediatr Anaesth 2001; 11: nephroscope into an anterior calix would be hindered by the 291. 6. Clayman RV: Supine position is safe and effective for percuta- side of the bed. The resultant increased reliance on flexible neous nephrolithotomy. J Urol 2005; 174: 601. nephroscopy would limit endoscopic vision and intracorpo- 7. Ng MT, Sun WH, Cheng CW and Chan ES: Supine position real lithotripsy. is safe and effective for percutaneous nephrolithotomy. J Endourol 2004; 18: 469. Manoj Monga 8. Choudhari K, Choudhari Y and Fannin T: Acute lumbar inter- Department of Urologic Surgery vertebral disc prolapse: a complication of the lithotomy University of Minnesota position. Br J Obstet Gynaecol 2000; 107: 1519. Minneapolis, Minnesota Trauma/Reconstruction/Diversion

Application of Self-Expandable Metal Stents for Ureteroileal Anastomotic Strictures: Long-Term Results

Evangelos N. Liatsikos, George C. Kagadis, Dimitrios Karnabatidis, Konstantinos Katsanos, Zaﬁria Papathanassiou, Constantinos Constantinides, Petros Perimenis, George C. Nikiforidis, Jens-Uwe Stolzenburg and Dimitrios Siablis From the Departments of Urology (ENL, PP), Medical Physics (GCK, GCN) and Radiology (DK, KK, ZP, DS), University of Patras, School of Medicine, Patras and First Department of Urology, University of Athens Medical School, “Laikon” General Hospital (CC), Athens, Greece, and Department of Urology, University of Leipzig (JUS), Leipzig, Germany

Purpose: We report our long-term experience with the management of benign ureteroileal anastomotic strictures using self-expandable metal stents. Materials and Methods: A total of 16 male and 2 female patients with a mean Ϯ SD age of 72 Ϯ 7 years (range 66 to 78) with benign fibrotic strictures at the site of ureteroileal anastomosis underwent implantation of self-expandable metal stents with a nominal diameter of 6 to 8 mm. A total of 24 ureteroileal conduits were treated. The external nephrostomy tubes were removed after fluoroscopic validation of ureteral patency. Patients were followed with blood biochemistry, ultrasonography, urography and/or virtual endoscopy. Retrograde external-internal catheter insertion through the cutaneous stoma was performed in cases of recalcitrant stricture. Results: The technical success rate of ureteroileal stricture crossing and stenting was 100% (24 of 24 cases). Mean followup was 21 months (range 7 to 50). The clinical success rate during the immediate post-stenting period was 70.8% (17 of 24 cases). The 1 and 4-year primary patency rates were 37.8% and 22.7%, respectively. Secondary interventions included repeat balloon dilation in 15 ureters, of which 8 also underwent subsequent coaxial stent placement. The 1 and 4-year secondary patency rates were 64.8% and 56.7%, respectively. Except in 2 patients who died external-internal Double-J® catheters continued to be inserted retrograde in 6 ureteroileal conduits. They are periodically exchanged to prevent mucous inspissation and stent encrustation. Conclusions: Metal stents served as the definitive treatment for stricture in more than half of the cases, whereas in the remainder the stents allowed the uncomplicated and regular exchange of Double-J catheters in retrograde fashion. This combined, less invasive treatment for ureteroileal anastomotic strictures may help patients avoid surgical revision and preserve quality of life. Key Words: ureter, ureteral stricture, prostheses and implants, stents, urinary diversion

adical cystectomy and urinary diversion to an ileal cutting balloons and repetitive high pressure dilation with loop conduit represent the standard surgical tech- standard angioplasty balloons have been applied with moder- R nique for invasive transitional cell carcinoma of the ate success for treating stenosis since they are characterized by bladder. The most serious postoperative complication is late a high recurrence rate.3–5 In the era of rapidly evolving inter- development of a ureteroileal anastomotic stricture in 4% to ventional medicine and widespread clinical use of MSs the use 11% of the cases.1,2 The onset of such strictures is clinically of a permanent MS for ureteroileal anastomotic strictures has occult and ureteral obstruction may gradually progress and already been reported with promising results.6–9 jeopardize renal function. Open surgical revision with intra- Since 1996, we have been investigating the application of operative biopsy and ureteral reimplantation remains the MSs in the urinary tract and we have reported a small definitive treatment but it may prove technically demanding preliminary experience in the setting of ureteroileal stric- due to the formation of fibrotic adhesions and/or secondary tures.6,10,11 However, to our knowledge there are no litera- ischemia after previous surgery or even impaired healing ture data on the long-term outcome of these devices. Based due to radiotherapy. In addition, it carries a significant risk on our early favorable outcome6 we designed a prospective of postoperative morbidity.3 Nevertheless, many patients study investigating self-expandable MSs for ureteroileal are not eligible or even refuse to undergo a second operation. anastomotic strictures. We analyzed the long-term perfor- This was the impetus for the development of alternative, mance of the endoprosthesis in the ureteroileal conduit. minimally invasive strategies for the obliteration of ureteroileal strictures. Semirigid fascial dilators, electrocautery MATERIALS AND METHODS Patient Enrollment Submitted for publication December 19, 2006. Between January 1999 and June 2005, 16 male and 2 female * Correspondence: Department of Urology, University of Patras Medical School, Rio, Patras, 26 500 Greece (telephone: (01130-2610) patients with an ileal loop conduit and late postoperative 999386; FAX: (01130-2610) 993981; e-mail: [email protected]). stricture at the site of the ureteroileal anastomosis were

0022-5347/07/1781-0169/0 169 Vol. 178, 169-173, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.061 170 SELF-EXPANDABLE METAL STENTS AND URETEROILEAL ANASTOMOTIC STRICTURES treated at our institution. The underlying pathological condition for primary cystectomy and urinary diversion was transitional cell carcinoma in 16 male patients and uterine cervical carcinoma in 2 female patients. Bilateral ureteral ileostomy with 1 crossed-over ureter had been performed in all patients. The anastomoses were all end to side. Patients manifested symptoms of flank pain, urinary infection or hydronephrosis (12) or presented with compro- mised renal function with bilateral ureteroileal strictures (6). The mean Ϯ SD interval between ileal loop surgical construction and the diagnosis of anastomotic stricture was 15 Ϯ 9 months (range 6 to 40). Hydronephrosis was initially detected on transabdominal ultrasonography and the diagnosis was confirmed by excretory urography, which documented severe stenosis or complete obstruction of 1 or 2 ureteroileal anastomoses. The institutional review board ap- FIG.1.A, balloon predilation of bilateral ureteroileal anastomotic proved the protocol and all patients signed an informed strictures. B, final fluoroscopic image after bilateral deployment of 8 mm self-expandable MS. Note complete restoration of patency and consent form before the intervention. Eligibility criteria for trumpet configuration of left ureter proximal to inserted stent. study inclusion included at least 1 of remote metastatic disease, stricture relapse after surgical revision once, refusal to undergo surgical revision and associated systemic comorbidities with increased perioperative risk. Patients protruding approximately 0.5 cm within the conduit. This with stricture recalcitrant to repetitive balloon dilation were was an off label application and stent brands were chosen enrolled in the study, whereas patients with documented according to commercial availability without any specific carcinoma relapse and infiltration of the anastomotic site at preference criteria. In cases of highly resistant anastomotic biopsy were excluded. strictures, which may even induce waisting of the stent mesh and compromise stent integrity, final high pressure post-dilation was performed. Interventional Procedure After intravenous conscious sedation the patient was placed Patient Followup on the fluoroscopy table in an oblique supine position to After the intervention the patient was left with an external expose the respective lumbar fossa for percutaneous ne- capped nephrostomy tube for 48 hours to 1 week to examine phrostomy and concomitantly permit access to the cutane- ureteral patency on antegrade nephrostogram and assess ous stoma of the ileal loop. Initially percutaneous nephros- any periprocedural complications or early stent obstruction. tomy was performed using standard image guided A regular followup program with blood biochemistry, ultra- interventional techniques. Subsequently antegrade nephros- sonography and/or excretory urography was established for togram was done to identify the anastomotic stricture and prompt detection of any stricture recurrence. Patients were evaluate its exact location and length. If the patient was scheduled for followup 1, 3, 6 and 12 months after stent febrile and/or signs of urinary tract infection coexisted, the implantation and yearly thereafter. In exceptional cases patient was left on external nephrostomy drainage with computerized tomography at a late secretory phase was proper antibiotic therapy for 1 week. Otherwise transversal performed and virtual endoscopic images were produced. of the stricture, balloon dilation and implantation of a self- If recalcitrant obstructions due to excessive mucous se- expandable MS were done at the same session. cretion and/or urothelial hyperplasia occurred, repeat bal- Following percutaneous nephrostomy a 7Fr long sheath loon dilation up to 2 times and then coaxial overlapping was placed in the dilated ureter to facilitate the insertion of stenting only once were performed. In cases of eventual hydrophilic instruments and negotiate the stricture. Stric- failure an attempt was made to drain the kidney retrograde ture transversal was attempted with a combination of a through the cutaneous stoma by an external-internal 0.035-inch straight or angled hydrophilic guidewire and a nephro-uretero-ileal Double-J catheter, as described previ- 12 straight or angled 4Fr glide catheter. After crossing the ously. Briefly, an external-internal nephro-uretero-ileal stricture the hydrophilic guidewire was advanced into the Double-J catheter was inserted retrograde through the cu- ileal loop, preferably out of the cutaneous stoma. It was taneous stoma up to the renal pelvis with an over the wire subsequently exchanged for a rigid 0.035-inch Amplatz technique and with its outer port draining in the stoma bag. guidewire to secure luminal passage during balloon dilation Regular exchanges of the external-internal catheter at and ureteral stent placement. 3-month intervals were performed, likewise obviating the Dilation of the fibrotic anastomotic ureteroileal strictures need for repeat percutaneous nephrostomies and favoring involved a 2-step procedure. The stricture was predilated patient comfort. with 6 to 7 mm wide high pressure angioplasty balloons up to 30 atm. After fluoroscopy revealed ureteral continuity a Statistical Analysis self-expandable MS was inserted at the level of the anasto- Technical success was defined as successful transversal and mosis to fully restore and secure ureteral patency. A stan- stenting of the ureteroileal strictures. Clinical success was dard vascular self-expandable MS witha6to8mmnominal defined as the depiction of an unobstructed stent and a diameter and a length of 4 to 10 cm was applied (fig. 1). The patent ureteroileal conduit at the post-procedural nephros- distal part of the stent was positioned in the ileal conduit, togram with nondeteriorating renal function. Life table SELF-EXPANDABLE METAL STENTS AND URETEROILEAL ANASTOMOTIC STRICTURES 171 analysis was performed to analyze ureteroileal patency and a Kaplan-Meier curve was constructed to illustrate the success rate for restoring luminal ureteral patency with time. Primary patency was defined as successful abolishment of the stricture after stent implantation without any additional intervention, while secondary patency also included any repeat ballooning or even coaxial stent placement. Cases that eventually required an external-internal Double-J catheter were considered unsuccessful. All statistical studies were performed with Prism® for Windows™, version 4.00.

RESULTS A total of 24 severely stenosed ureteroileal conduits were treated in 16 males and 2 females with a mean age of 72 Ϯ 7 years (range 66 to 78). Bilateral strictures were treated in 6 patients. Strictures were focally located at the anastomotic site and they were 3 to 8 cm long. Of the strictures 12 were located in the right and left ureter, respectively. The technical success rate of transversal and stenting of the ureteroileal strictures was 100% (24 of 24 cases). Total operative time was less than 1 hour per ureter. No major complications occurred and the post-stenting hospitalization period never exceeded 3 days. Minor complications included 3 cases of transient febrile septicemia immediately after stricture ballooning and stent placement, which were pri- FIG. 3. Bilateral retrograde insertion of external-internal Double-J catheters after failure of ureteral full metal jacket to achieve ade- marily treated with intravenous isotonic fluids and para- quate renal decompression. Such catheters are regularly exchanged cetamol infusion. The implanted stents were Wallstent®, through cutaneous stoma by applying easy and rapid over wire Protégé®, Memotherm (Bard, Karlsruhe, Germany) and si- technique. nus stents. Mean followup was 21 months (range 7 to 50). All patients avoided surgical revision of the anastomotic site with The clinical success rate during the immediate post- satisfactory preservation of renal function. At the last fol- stenting period was 70.8% (17 of 24 cases). The 1 and 4-year lowup visit 16 ureteroileal stents were still patent without primary patency rates were 37.8% with 10 patients at risk any signs of hydronephrosis (fig. 2). Two patients died of and 22.7% with 3 at risk, respectively. Secondary interven- remote metastatic disease, while external-internal Double-J tions included repeat balloon dilation in 15 ureters, of which catheters were still inserted through the stoma in the re- 8 also underwent subsequent coaxial stent placement. When maining ureteroileal segments. Except for the 2 deaths pa- primary patency was achieved, there was no need for further tency in the 6 remaining ureteroileal conduits is maintained manipulations and renal function was stable. Imaging re- with internal-external Double-J catheters, which are peri- vealed amelioration of the obstructive phenomena. odically exchanged in retrograde fashion every 3 months to In cases of secondary patency the trigger point for sec- avoid mucous inspissation and stent encrustation (fig. 3). ondary intervention was pelvicaliceal system dilatation and/or renal function deterioration, ie bilateral obstruction. Patients with external-internal nephro-uretero-ileal Double-J catheters periodically experienced mild flank pain, which was managed by analgesic treatment. Mucolytic agents were administered in 2 cases in which mucous inspissation was identified with successful treatment in 1. There was no evidence of encrustation, infection or migration of the stents during followup evaluation. The 1 and 4-year secondary patency rates were 83.3% with 14 patients at risk and 56.7% with 4 at risk, respectively (fig. 4). As demonstrated by the Kaplan-Meier curve, most recurrent strictures developed in the early post-interventional period during the first 6 months. Secondary patency was significantly higher than primary patency (log rank test p ϭ 0.0396).

DISCUSSION FIG.2. A, baseline image shows left ureteroileal anastomotic stricture. B and C, followup urography 1 month after successful obliter- Ureteroileal anastomotic strictures represent a serious post- ation of stricture with implantation of 2 overlapping metal stents reveals ureteral peristalsis and trumpet conﬁguration proximal to operative complication that may lead to gradual and silent implanted stents. loss of renal function and are characterized by a high recur- 172 SELF-EXPANDABLE METAL STENTS AND URETEROILEAL ANASTOMOTIC STRICTURES

implanted in the ureter to achieve an optimum balance between sufficient restoration of the ureteral lumen and the induction of hyperplastic narrowing. As shown by the patency curve, most relapsing strictures occurred early after stent placement (fig. 5). This is in accordance with endoscopic findings that urothelial hyperplasia usually regresses 4 to 6 weeks after stent insertion.18 Retrograde kidney drainage with external-internal nephro-uretero-ileal Double-J catheters represents an attractive alternative if the patient is not a surgical candidate and endoluminal techniques eventually fail.12,19 In this way infectious and uncomfortable external nephrostomy tubes are avoided. In addition, the previously inserted MS may serve as an outer support sheath precluding extraluminal strangulation and easing the periodic exchange of catheters. Encrustation, which complicates metal and plastic stents,

FIG. 4. Kaplan-Meier survival curves show primary and secondary has a multifactorial etiology, such as urolithiasis, recurrent patency with time (log rank test p ϭ 0.0396). urinary infections and biofilm formation. Moreover, patients with a ureteroileal conduit are especially prone to mucous inspissation and recurrent infections. Arguably on grounds rence rate.3,5 Percutaneous or endoscopic approaches have of ureteral narrowing due to an acute hyperplastic response recently evolved with acceptable long-term success rates after stent placement mucous inspissation may gradually for restoring and maintaining ureteral patency. Balloon contribute to complete obstruction of the anastomotic site dilation and incisional endoureterotomy have documented and compromise renal function. Hence, a regular clinical 16% to 37% and 35% to 63% long-term patency rates, surveillance program is mandatory in these patients to respectively.3,5,13,14 promptly diagnose and re-treat any relapse of anastomotic Motivated by the popular and successful implementation obstruction. of MSs in the cardiovascular and gastrointestinal systems, None of these patients underwent endoureterotomy. Nev- several groups have used them to treat urinary tract ob- ertheless, endoureterotomy could fit in as an additional struction, such as benign prostatic hyperplasia, urethral treatment proposal before attempting MS insertion. Like- strictures, benign and malignant ureteral blockage, and de- wise, we advocate MSs as the ultimate treatment of choice trusor-sphincter dysenergia.11,15 A few reports describe the since the presence of an MS might complicate open surgical promising short-term performance of MSs for ureteroileal repair. A small number of stents of each brand were im- anastomotic strictures.6–9 To our knowledge this is the first planted. Hence, no definite, statistically significant conclu- study to provide long-term followup data on minimally in- sions could be drawn on whether the type of stent may affect vasive, fluoroscopic insertion of self-expandable MSs for be- the patency rate. Ureteroscopy was not regularly performed nign fibrotic anastomotic strictures after ureteroileal uri- and, thus, it was not included in our algorithm. However, we nary diversion. previously noted urothelial hyperplasia in the stented ure- MSs succeeded in definitively treating more than 50% of teral lumen.20 Considering that most failures occur in the obstructions at a mean surveillance period of 21 months, early post-interventional period due to acute urothelial hy- thus, obviating the need for technically demanding and perplastic response, application of the newly developed drug highly morbid surgical revision procedures. These results eluting stents, which might improve early clinical success compare favorably to those in mentioned studies and stress and primary patency, seems to be an attractive future per- the upcoming value of MSs in the lower urinary tract. The spective. Preclinical animal data on paclitaxel eluting stents interventional procedure had a high technical success rate in the ureter are encouraging20 and further investigation in for restoring ureteral patency, short operative time and min- human clinical trials will be intriguing. imal periprocedural complications. Early urothelial hyperplasia is the Achilles heel of ureteral MSs and it leads to progressive luminal loss and relapse of obstruction. Experimental studies have elucidated that mechanical trauma to the epithelium, lamina propria and muscular layers, which is caused by irritative pressure of the stent against the ureteral wall and is aggravated by concomitant ureteral peristalsis, is the primary determinant of urothelial hyperplasia.16 The cumulative effect of these stress factors damages the ureteral wall layers and results in reactive hyperplasia, which ends in aperistaltic ureteral segments since the severely damaged muscle layer of the ureter can no longer function properly.16 The grade of urothelial hyperplasia seems to proportionally depend on the degree of ureteral over stretching and the force exerted FIG. 5. Computerized tomography virtual endoscopy. A, patent 17 stented ureteral lumen. B, circumferential ureteral stenosis in stent on the ureteral wall by the stent. In our experience MSs due to severe early urothelial hyperplasia during month 1 after with a nominal diameter of no more than 8 mm should be stent implantation. SELF-EXPANDABLE METAL STENTS AND URETEROILEAL ANASTOMOTIC STRICTURES 173

CONCLUSIONS 8. Rapp DE, Laven BA, Steinberg GD and Gerber GS: Percuta- neous placement of permanent metal stents for treatment Percutaneous insertion of self-expandable MSs in ﬁbrotic of ureteroenteric anastomotic strictures. J Endourol 2004; anastomotic strictures following ureteroileal urinary diver- 18: 677. sion shows encouraging long-term outcomes with minimal 9. Sanders R, Bissada NK and Bielsky S: Ureteroenteric anasto- comorbidities and complications. Unlike surgical interven- motic strictures: treatment with Palmaz permanent in- tion, the method is less invasive, rapid and well tolerated, dwelling stents. J Urol 1993; 150: 469. and it does not require prolonged hospitalization. In cases of 10. Barbalias GA, Liatsikos EN, Kalogeropoulou C, Karnabatidis failure combined strategies with external-internal Double-J D and Siablis D: Metallic stents in gynecologic cancer: an catheters inserted retrograde may help avoid open surgical approach to treat extrinsic ureteral obstruction. Eur Urol revision and attain quality of life in properly selected pa- 2000; 38: 35. tients. 11. Barbalias GA, Siablis D, Liatsikos EN, Karnabatidis D, Yarmenitis S, Bouropoulos K et al: Metal stents: a new treatment of malignant ureteral obstruction. J Urol 1997; 158: 54. Abbreviations and Acronyms 12. Tal R, Bachar GN, Baniel J and Belenky A: External-internal MS ϭ metal stent nephro-uretero-ileal stents in patients with an ileal conduit: long-term results. Urology 2004; 63: 438. 13. Kramolowsky EV, Clayman RV and Weyman PJ: Endourologi- REFERENCES cal management of ureteroileal anastomotic strictures: is it effective? J Urol 1987; 137: 390. 1. Frazier HA, Robertson JE and Paulson DF: Complications of 14. Wolf JS Jr, Elashry OM and Clayman RV: Long-term results of radical cystectomy and urinary diversion: a retrospective endoureterotomy for benign ureteral and ureteroenteric review of 675 cases in 2 decades. J Urol 1992; 148: 1401. strictures. J Urol 1997; 158: 759. 2. Sullivan JW, Grabstald H and Whitmore WF Jr: Complica- 15. Milroy EJ, Chapple CR, Cooper JE, Eldin A, Wallsten H, tions of ureteroileal conduit with radical cystectomy: review Seddon AM et al: A new treatment for urethral strictures. of 336 cases. J Urol 1980; 124: 797. Lancet 1988; 1: 1424. 3. Cornud F, Chretien Y, Helenon O, Casanova JM, Correas JM, 16. Soria F, Sun F, Duran E, Sanchez FM and Uson J: Metallic Bonnel D et al: Percutaneous incision of stenotic uroenteric ureteral stents versus endoureterotomy as a therapeutic anastomoses with a cutting balloon catheter: long-term re- approach for experimental ureteral stricture. J Vasc Interv sults. Radiology 2000; 214: 358. Radiol 2005; 16: 521. 4. Meretyk S, Clayman RV, Kavoussi LR, Kramolowsky EV and Picus DD: Endourological treatment of ureteroenteric anasto- 17. Thijssen AM, Millward SF and Mai KT: Ureteral response to motic strictures: long-term followup. J Urol 1991; 145: 723. the placement of metallic stents: an animal model. J Urol 5. Shapiro MJ, Banner MP, Amendola MA, Gordon RL, Pollack 1994; 151: 268. HM and Wein AJ: Balloon catheter dilation of ureteroen- 18. Wakui M, Takeuchi S, Isioka J, Iwabuchi K and Morimoto S: teric strictures: long-term results. Radiology 1988; 168: Metallic stents for malignant and benign ureteric obstruc- 385. tion. BJU Int 2000; 85: 227. 6. Barbalias GA, Liatsikos EN, Karnabatidis D, Yarmenitis S 19. Drake MJ and Cowan NC: Fluoroscopy guided retrograde ure- and Siablis D: Ureteroileal anastomotic strictures: an inno- teral stent insertion in patients with a ureteroileal urinary vative approach with metallic stents. J Urol 1998; 160: conduit: method and results. J Urol 2002; 167: 2049. 1270. 20. Liatsikos EN, Karnabatidis D, Kagadis GC, Rokkas K, Con- 7. Gort HB, Mali WP, van Waes PF and Kloet AG: Metallic stantinides C, Christeas N et al: Application of paclitaxel- self-expandable stenting of a ureteroileal stricture. AJR eluting metal mesh stents within the pig ureter: an exper- Am J Roentgenol 1990; 155: 422. imental study. Eur Urol 2007; 51: 217. Urological Survey

TRAUMA, AND GENITAL AND URETHRAL RECONSTRUCTION

Tissue Expansion in Management of Failed Phallic Reconstruction: Initial Report of Clinical Series R. Mathews, C. P. Nelson, J. P. Gearhart and C. A. Vander Kolk, Division of Pediatric Urology, Johns Hopkins School of Medicine, Baltimore, Maryland Urology 2005; 66: 180–184. Objectives: To report the first significant experience with the use of tissue expanders in phallic reconstruction. Patients who have undergone multiple failed surgical procedures for repair of hypospadias or epispadias often have minimal residual skin available for additional reconstructive efforts. Although a variety of graft options exist, local skin expansion can provide pigment and texture-matched skin for reconstructive procedures. Methods: We reviewed our experience with tissue expansion in patients after multiple failed phallic reconstructive efforts. A total of 18 males (mean age 13.2 years) with an underlying diagnosis of exstrophy/epispadias (n ϭ 9), hypospadias (n ϭ 7), partial androgen insensitivity syndrome (n ϭ 1), and congenital adrenal hyperplasia (n ϭ 1) had penile tissue expanders placed and inflated during a 6-week period. The expanders were removed at penile reconstruction. Results: Tissue expanders were placed in 18 patients and successfully inflated in 17 patients. Good surgical results requiring no additional procedures were obtained in 8 (47%) of the 17 patients. Two patients subsequently underwent repeated tissue expansion; one of these patients had a good outcome after two expansions and supplemental pedicle graft, and the other had persistent fistulas and required a forearm graft. The implants were replaced because of extrusion in 3 patients and removed for malfunction, erosion, or infection in 1 patient each. Conclusions: The use of tissue expansion provides a useful option for reconstruction in patients with minimal or scarred skin after multiple failed prior phallic reconstructions and offers certain benefits over the transfer of free grafts. The availability of smaller tissue expanders makes this technique feasible even for young children. Editorial Comment: Many patients with hypospadias or epispadias have minimal local skin for penile coverage and urethral reconstruction. In this series of 18 such patients undergoing reoperation tissue expanders safely provided pigment and texture matched skin for genital reconstruction. Allen F. Morey, M.D.

Management of Complications After Hypospadias Repair C. L. Snyder, A. Evangelidis, G. Hansen, S. D. St. Peter, D. J. Ostlie, J. M. Gatti, G. K. Gittes, R. J. Sharp and J. P. Murphy, Department of Surgery, Children’s Mercy Hospital, Kansas City, Missouri Urology 2005; 65: 782–785. Objectives: To review our experience with hypospadias complications (seen after 10%–15% of repairs) and to identify factors influencing outcome. Methods: We reviewed the available medical records of 113 patients who underwent repeat operation for hypospadias complications. Of the 113 patients, 40% had undergone the initial repair at our institution (internal referral); 60% had undergone the initial repair elsewhere before referral (external referral). The variables potentially affecting outcome were reviewed, including the severity of the defect, concomitant disease, age at the initial operation and revisions, type of complications and treatment, and the number of revisions. Outcomes were compared on the basis of specialty and experience. Results: Isolated hypospadias was present in 81% and other genitourinary abnormalities in 10%. External referral patients were older at the first revision (7.3 versus 4.2 years, P ϭ 0.027). Compli- cations included fistula (73%), stricture (12%), breakdown of repair (10%), and diverticulum formation (11%). Successful revision was independent of the initial defect. The first, second, and third revision was successful in 77%, 64%, and 67% of patients, respectively. The cumulative success rate was 77%, 92%, and 97% after each respective repair attempt. The success of the repair was independent of the patient’s age at the initial operation/revision and of the interval from the initial repair to reoperation. Internal referral and external referral patients had similar results. Specific experience with the repair of hypospadias complica-

0022-5347/07/1781-0174/0 174 Vol. 178, 174-177, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.084 TRAUMA, AND GENITAL AND URETHRAL RECONSTRUCTION 175 tions correlated with a successful outcome (P Ͻ0.001). Conclusions: Complications after hypospadias repairs are common, with ﬁstula accounting for approximately 75%. The outcome in our series was independent of hypospadias severity, patient age at repair, number of revisions, stent use, and referral status. Repairs performed by an experienced pediatric urologist were associated with improved outcomes (P Ͻ0.001). Editorial Comment: This analysis of 113 reoperative hypospadias cases shows that nearly three quarters initially involved a mid shaft or proximal defect, compared to the typical distribution of 75% involving distal hypospadias. Clearly, these data indicate that these complex cases constitute a higher risk group. Fistula was by far the most common complication (73%), with stricture, breakdown of repair and diverticulum formation all occurring much less frequently (about 10%). We have similarly noted in a series of penile skin ﬂap urethroplasty cases that the risk of extravasation is directly proportional to the length of the repair.1 Allen F. Morey, M.D.

1. Hick EJ and Morey AF: Initial experience with ﬁbrin sealant in pendulous urethral reconstruction. Is early catheter removal possible? J Urol 2004; 171: 1547.

Conservative Management of Priapism in Acute Spinal Cord Injury S. A. Gordon, K. H. Stage, K. E. Tansey and Y. Lotan, Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas Urology 2005; 65: 1195–1197.

Objectives: To perform a retrospective chart review of priapism as a complication of spinal cord injury and review the management and follow-up. Priapism is a known complication of acute spinal cord injury, but little has been written concerning the management of this condition. Methods: A retrospective chart review (1992 through 2002) was performed for all patients with a diagnosis of priapism. Of these patients, 6 had priapism in the setting of acute spinal cord injury without pelvic trauma. We reviewed the management of the priapism in these cases, and follow-up was attempted in each case. Results: Of the 6 patients with spinal cord injury-related priapism, 4 had spinal cord injury located at C5-C7, 1 at C5-C6, and 1 at T12. The prolonged erections were managed conservatively in 4 patients and irrigated with intracorporeal phenylephrine in 2. All patients with corporal blood gas measurement (n ϭ 4) had nonischemic priapism. All 4 patients who underwent no intervention had the priapism resolve within 5 hours. Four patients (two treated conservatively and two who underwent irrigation) had recurrent episodes during the same admission that resolved spontaneously. Long-term outcomes were obtained by telephone from all 6 patients. Of the 6 patients, 5 had maintained spontaneous erections to date (range 3 to 10 years). Conclusions: The results of our study have shown that priapism related to acute spinal cord injury is nonischemic and may be managed conservatively because of the high likelihood of resolution. Corporal blood gas measurement is important because the results can guide further management decisions. Our results suggest that conservative management of priapism related to spinal cord injury has a low rate of causing long-term erectile dysfunction. Editorial Comment: This study analyzes long-term outcomes in 6 patients in whom priapism developed as a result of acute spinal cord injury. Corporeal blood gas measurement uniformly demonstrated nonischemic status, and conservative treatment yielded spontaneous resolution within 5 hours and preservation of spontaneous erections at 3 to 10 years later in all patients. Recurrent episodes developed in most men during the same hospitalization but all resolved spontaneously within 4 hours. As the authors remind us, current American Urological Associ- ation guidelines recommend that the initial management of nonischemic priapism be observation,1 and phenylephrine irrigation has no role in this setting. Allen F. Morey, M.D.

1. Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF et al: Members of the Erectile Dysfunction Guideline Update Panel; American Urological Association: American Urological Association guideline on the management of priapism. J Urol 2003; 170: 1318. 176 DIAGNOSTIC UROLOGY, URINARY DIVERSION AND PERIOPERATIVE CARE High-Flow Priapism: Colour-Doppler Ultrasound-Guided Supraselective Embolization Therapy G. Bartsch, Jr., R. Kuefer, O. Engel and B. G. Volkmer, Department of Urology, Faculty of Medicine, University of Ulm, Ulm, Germany World J Urol 2004; 22: 368–370. High flow priapism is mainly caused by traumatic arteriocavernous fistulas. The standard therapy is a transcatheter embolization of the fistula. This study analyzes the combined approach of arteriography and color Doppler ultrasound during the embolization procedure. During the arteriography procedure, a perineal color Doppler ultrasound examination of the fistula was performed to achieve an optimal positioning of the catheter tip in the fistula with a minimum of radiation exposure. To visualize the correct localization, ultrasound contrast medium or saline solution was injected through the catheter. The flow-pattern of the contrast medium allowed evaluation of the successful occlusion of the fistula and preservation of the unaffected penile arteries. In six patients (unilateral fistula: three, bilateral fistulas: three) with a posttraumatic high-flow priapism, this technique was performed for embolization of the fistulas. A total of nine embolization sessions were performed. Only one case required a second session due to dislocation of a microcoil. In all cases, the priapism disappeared immediately after the final session while erectile function was restored within 4 weeks after embolization. The combined approach of x-ray and ultrasound imaging facilitates the supraselective embolization of the arteriocavernous fistula, leading to an optimal success rate, while reducing the radiation exposure and the applied dose of contrast medium. Editorial Comment: High flow priapism typically occurs due to laceration of internal pudendal artery branches after blunt pelvic, perineal or penile trauma. In this study supraselective transfemoral, transarterial embolization of the lacerated artery was combined with perineal color Doppler ultrasound imaging. Diluted ultrasound contrast medium was injected to distinguish the nonpulsatile fistula flow pattern into the cavernous body versus intact (pulsatile) penile arteries. In this series of 6 cases all fistulas were localized in the perineal part of the cavernous bodies near the bulbar urethra, and all were successfully embolized. Allen F. Morey, M.D.

DIAGNOSTIC UROLOGY, URINARY DIVERSION AND PERIOPERATIVE CARE

Continent Cutaneous Urinary Diversion: Long-Term Follow-Up of More Than 800 Patients With Ileocecal Reservoirs C. Wiesner, R. Bonﬁg, R. Stein, E. W. Gerharz, S. Pahernik, H. Riedmiller and J. W. Thuroff, Department of Urology, Johannes Gutenberg University Medical School, Mainz, Germany World J Urol 2006; 24: 315–318.

We report the clinical outcome of more than 800 patients, who underwent continent cutaneous urinary diversion with an ileocecal reservoir (Mainz-pouch I) in two urological tertiary referral centers at a mean follow-up of 7.6 years. Complications related to the continence mechanism (intussuscepted ileal nipple vs. submucosally embedded in situ appendix) and the antirefluxive uretero-intestinal anastomosis (submucosal tunnel vs. serosa-lined extramural tunnel) were recorded retrospectively. Stomal stenosis was observed in 23.5% of the patients with appendix stoma and in 15.3% of the patients with intussuscepted ileal nipple. The incidence of calculi was 10.8% in reservoirs with intussuscepted ileal nipple and 5.6% in reservoirs with appendix stoma. Eleven patients (eight with appendix, three with ileal nipple) required reoperation because of ischemic degeneration of the continence mechanism. The overall continence rate (day and night) was 92.8%. Anastomotic strictures of the afferent limb occurred in 6.5% of renal units (RUs) with a submucosal tunnel and in 5.0% of RUs with a serosa-lined extramural tunnel. Continent cutaneous urinary diversion with an ileocecal pouch is a highly satisfactory and safe option for patients, in whom orthotopic urinary diversion is impossible or contraindicated. Editorial Comment: The authors present long-term followup data on their experience with Mainz pouch I ileocecal diversions. With a mean followup of 7.6 years and more than 800 patients in their series they provide a detailed retrospective analysis of the benefits and risks of this type of continent urinary diversion. Attention is given to the modifications of the technique, with DIAGNOSTIC UROLOGY, URINARY DIVERSION AND PERIOPERATIVE CARE 177 comparison of the relative complications of the various continence mechanisms used, as well as the type of stoma. Richard K. Babayan, M.D.

Using Peplau’s Theory of Interpersonal Relations to Guide the Education of Patients Undergoing Urinary Diversion K. Marchese, Women’s Pelvic Medicine Center, Loyola University Medical Center, Maywood, Illinois Urol Nurs 2006; 26: 363–370. Patients diagnosed with bladder cancer may require a urinary diversion to maximize their health care outcomes. These patients, faced with sudden changes in their health status, develop complex unmet needs that can be addressed by a planned program of education. Peplau’s theory of interpersonal relations offers a framework for patient teaching that emphasizes the importance of the nurse-patient relationship. This therapeutic relationship enables the nurse to provide the patient with the information needed to understand the diagnosis, cooperate in the treatment plan, facilitate postoperative recovery, and return to a state of independence with quality of life. Editorial Comment: This is an interesting nursing perspective on perioperative treatment of patients undergoing urinary diversion, with techniques outlined to aid nurses in facilitating postoperative recovery and teaching patients how to cope with the implications of various forms of post-cystectomy urinary diversion. Richard K. Babayan, M.D. Voiding Dysfunction

Malignant Ureteral Obstruction: Outcomes After Intervention. Have Things Changed?

Lih-Ming Wong, Laurence K. Cleeve,* Alvin D. Milner and Alexander G. Pitman From the Division of Surgical Oncology, Urology (LMW, LKC), Centre for Biostatistics and Clinical Trials (ADM), Peter MacCallum Cancer Centre, East Melbourne, and Department of Medical Imaging, St. Vincent’s Hospital Melbourne (AGP), Victoria, Australia

Purpose: We reviewed the clinical outcome for patients who underwent decompression of malignant ureteral obstruction by analyzing potential prognostic factors, technical success, complication rates and days spent in hospital. Materials and Methods: Retrospective analysis of 102 patients who underwent decompression for malignant ureteral obstruction from 1991 to 2003 was performed. Data on overall survival, prognostic factors, technical failure, complications and days of hospitalization after decompression were examined. Results: Median overall survival was 6.8 months (95% CI 4.8–9.3) and the overall survival rate at 12 months was 29% (95% CI 21%–39%). Univariate analyses found inferior overall survival associated with patients having metastases (p ϭ 0.041), undergoing nephrostomy (p ϭ 0.046), prior treatment for cancer (p ϭ 0.024) and diagnosis of malignant ureteral obstruction in previously established malignancy (p ϭ 0.043). After multivariate analysis poor prognostic factors were presence of metastases (p ϭ 0.020) and diagnosis of malignant ureteral obstruction in previously established malignancy (p ϭ 0.039). Unfavorable cohorts with 3 or 4 unfavorable baseline risk factors had an inferior overall survival (p ϭ 0.008) with 12-month overall survival rates of 12% to 19%. Initial decompression of malignant ureteral obstruction failed in 6% of patients (95% CI 2%–12%) and complications were experienced by 53% (95% CI 43%–63%). Patients were more likely to experience a complication if they had therapy after decompression (p ϭ 0.03). The median percentage of their remaining lifetime spent in hospital was 17.4% (range 0.21% to 100%). Conclusions: The overall survival of patients with malignant ureteral obstruction remains poor. Prognostic factors for decreased overall survival and prolonged hospital stay have been identiﬁed. Although the technical success of decompression has improved the subsequent complication rate is still high. Key Words: ureteral obstruction, decompression, prognosis, quality of life

alignant ureteral obstruction is an ominous event identifies those prognostic factors which predict an unfavor- usually associated with advanced, often incurable able outcome despite procedural success. Therefore, it M disease. It can present with urosepsis, renal failure should aid the clinician treating the patient with MUO in and localized pain, or be diagnosed during staging or eval- the difficult task of outcome prognostication. uation of impaired renal function. Causes include extrinsic tumor compression, retroperitoneal lymphadenopathy or di- PATIENTS AND METHODS rect tumor invasion. Open nephrostomy for MUO with its significant compli- Peter MacCallum Cancer Center is a tertiary referral center cation rate (45%)1 and perioperative mortality rate (25%)2 with multidisciplinary oncology facilities. Patients were iden- was phased out in the 1970s. Percutaneous nephrostomy or tified from the hospital database under the procedure codes for retrograde cystoscopic stenting have matured in the last 20 RS and PCN performed between 1991 and 2003. The hospital years. PCN in particular reports high technical success rates Clinical Research and Ethics Committee approved the study. with low morbidity and mortality.3–5 Insertion is performed From this group all patients with a diagnosis of malignancy with the intention of prolonging a life of dignified quality. (based on histology) and radiological evidence of ureteral ob- Despite these technical advances there is little evidence in struction (diagnosed by computerized tomography, ultrasound, the literature to suggest improvement in patient outcomes. or retrograde or antegrade diagnostic study) were included. This study analyzes outcome data including survival, Patients were excluded from analysis if ureteral obstruction technical success, complication rates and time spent in hos- was due to benign disease (eg calculus) or RS or PCN were pital following attempted decompression of MUO. It then performed for a nonobstructive indication (eg urinary diversion away from fistula). By definition patients who had a diagnosis of MUO but who did not proceed to PCN or RS were not Submitted for publication October 26, 2006. captured. Demographic and clinical data were collected on case Study received Clinical Research and Ethics Committee approval. record forms from the medical histories and followup data * Correspondence: Department of Urology/Surgery, Peter MacCal- lum Cancer Centre, Locked Bag 1, A’Beckett St., Victoria 8006 obtained from the Victorian Cancer Registry and referring Australia (telephone: ϩ613 9419 1668; FAX: ϩ613 9416 3034; doctors/hospitals. Followup continued until February 25, 2005. e-mail: [email protected]). Radiological AS, RS or PCN were performed according to See Editorial on page 12. standard techniques by consultant urologists and radiolo-

0022-5347/07/1781-0178/0 178 Vol. 178, 178-183, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.026 MALIGNANT URETERAL OBSTRUCTION OUTCOMES 179 gists or under their direct supervision. The choice of which vanced Statistics 11.0.1). The removal and entry levels of procedure to attempt first was dictated by patient factors significance were 0.05 and 0.01, respectively. Patients with (fitness for anesthesia, bladder tumor obviating RS) and by unknown values of any prognostic factor were excluded from institutional factors (availability of theater and interven- multivariate analysis. The Kaplan-Meier estimate of me- tional radiology suite facilities). Antegrade stenting followed dian potential followup was computed.6 PCN when feasible. Technical failure of the initial procedure The rate of technical failure of the initial procedure was means urinary decompression was not achieved in that pa- calculated as the percentage of all patients with the 95% CI tient. Thus, a patient with bilateral obstruction who has calculated using the exact binomial distribution (StatXact® decompression of at least 1 side is considered to have treat- 6.0). The proportion of all patients experiencing at least 1 ment success. For each patient all complications related to postoperative complication was calculated together with the the procedure were documented. 95% CI. The 2-sided Fisher exact test or chi-square test was The primary outcome measure was OS. The postulated used to compare complication rates in prognostic factor sub- predictors of poorer OS included patient age, gender, cancer groups (StatXact 6.0). type, presence of metastases, extent of urinary obstruction, The percentage of patient remaining lifetime spent in presence of symptoms, creatinine level before initial decom- hospital following the initial procedure was computed for all pression, type of initial procedure, de novo diagnosis of malig- patients who had died by the study closeout date and were nancy, and if therapy (chemotherapy, radiation therapy or not lost to followup. Summary statistics were calculated and surgery) was given before or after ureteral decompression. the Mann-Whitney test (2 groups) or Kruskal-Wallis test Secondary end points included complications requiring (more than 2 groups) was used to compare percentages be- readmission to hospital, technical failure rates for PCN/RS, tween the prognostic factor subgroups (S-plus 2000). No number of days spent in hospital following decompression adjustments were made for multiple comparisons and all (as a proportion of patient remaining lifetime), and outcome p values were 2-sided. of PCN/RS (eg conversion of PCN to internal AS, removal of PCN/stent). Our calculations did not include day admissions RESULTS for routine change of stents or chemotherapy. A total of 102 patients (45 men, 57 women) underwent Statistical Analysis decompression. Median patient age at MUO diagnosis was OS was measured from the date of the initial MUO procedure 62 years (range 31 to 86). At presentation 68% of patients to the date of death from any cause. The Kaplan-Meier product had bilateral obstruction, 59% of patients had known me- limit method was used to estimate OS, with censoring of sur- tastases and 69% had symptoms of obstruction. PCN was vival times at the closeout date for patients still alive or the the more common initial procedure (75%). date of last contact for those patients lost to followup (S-plus® The median time for MUO to develop from diagnosis of 2000). The Brookmeyer-Crowley method was used to estimate primary malignancy was 11 months (range 0 to 345). There the 95% CIs for median survival times, and the 95% CIs for the were 16 patients (16%) who had MUO at the first presenta- proportion of patients surviving at particular times was esti- tion of cancer (de novo diagnosis7) whereas MUO developed mated using the logit transformation. Assessment of potential in 86 patients (84%) with previously diagnosed cancer. The prognostic factors with respect to OS was made using the median time between diagnosis of MUO and decompression Mantel-Cox log rank test and Cox proportional hazards regres- was 1 day (range 0 to 564). A full summary of patient sion (S-plus 2000, SPSS® Advanced Statistics 11.0.1). characteristics is shown in tables 1 and 2. Multivariate analysis to identify independent prognostic Median OS was estimated at 6.8 months (95% CI 4.8– factors was performed using Cox proportional hazards re- 9.3), and the OS rate at 6 and 12 months was estimated at gression and the stepwise backward procedure (SPSS Ad- 56% (95% CI 46%–65%) and 29% (95% CI 21%–39%), re-

TABLE 1. Univariate Kaplan-Meier analysis of predictors of poor overall survival—prognostic factors showing signiﬁcant difference Cox Regression Relative Hazard Rate Estimated Median p Value (Mantel-Cox No. OS (mos) HR 95% CI log rank test)

All pts 102 6.8 Metastases: Yes 60 6.7 1.56 (1.01–2.41) No 42 7.0 1.00 (reference) 0.041 Prior therapy (omitting 2 pts with missing data): Yes 77 6.5 1.80 (1.07–3.00) No 23 14.6 1.00 (reference) 0.024 Newly diagnosed malignancy:* No 86 6.5 1.83 (1.01–3.31) Yes 16 16.0 1.00 (reference) 0.043 Preop creatinine (mmol/l): Greater than 40 39 4.5 1.45 (0.94–2.23) 40 or Less 63 7.9 1.00 (reference) 0.088 Initial procedure: Nephrostomy 77 6.5 1.66 (1.00–2.76) Stent 25 9.2 1.00 (reference) 0.046 * Time between diagnosis of malignancy and MUO is 0 days for newly diagnosed patients. 180 MALIGNANT URETERAL OBSTRUCTION OUTCOMES

TABLE 2. Univariate Kaplan-Meier analysis of predictors of poor overall survival—prognostic factors showing no signiﬁcant difference Cox Regression Relative Hazard Rate Estimated Median p Value (Mantel-Cox No. OS (mos) HR 95% CI log rank test)

All pts 102 6.8 Age group: 65 or Younger 64 6.8 1.00 (reference) Older than 65 38 6.8 1.03 (0.67–1.56) 0.906 Gender: Male 45 4.5 1.18 (0.78–1.79) Female 57 8.5 1.00 (reference) 0.426 Ca group: Gastrointestinal 21 4.5 1.15 (0.63–2.10) Gynecological 32 7.8 1.19 (0.70–2.01) Urological 30 7.0 1.00 (reference) Other* 19 6.4 1.47 (0.80–2.71) 0.660 Extent of obstruction (omitting 2 pts with missing data): Unilat 32 8.5 1.00 (reference) Bilat 68 6.1 1.14 (0.74–1.77) 0.554 Symptoms at presentation (omitting 3 pts with missing data): No 31 9.3 1.00 (reference) Yes 68 5.1 1.30 (0.83–2.05) 0.257 Creatinine before decompression (mmol/l): Normal (less than 0.14) 27 7.9 1.00 (reference) Abnormal (0.14 or greater) 75 6.7 1.00 (0.62–1.59) 0.986 Subsequent therapy (omitting 2 pts with missing data): No 30 2.4 1.37 (0.86–2.16) Yes 70 7.9 1.00 (reference) 0.180 * Lymphoma (5), breast (5), sarcoma (3), lung, melanoma, hemangiopericytoma, pseudomyxoma, SCC (unknown primary), mucinous appendiceal carcinoma. spectively (fig. 1). Of the 102 patients included in this anal- (p ϭ 0.041), prior therapy (p ϭ 0.024), diagnosis of MUO in ysis 93 (91%) died before the closeout date, 2 were lost to previously established malignancy (p ϭ 0.043) and creati- followup and 7 were still alive at the closeout date. The 7 nine greater than 40 mmol/l (p ϭ 0.088) (table 1). Creatinine patients still alive all had decompression internalized with levels were originally collected as continuous data but anal- stents. The median potential followup of patients was esti- ysis revealed a level of more than 0.40 mmol/l to be most mated at 46 months (95% CI 32–108). The longest survival associated with inferior OS. Patients who then underwent time observed was 3,299 days. Thus, we postulate the ure- PCN had worse OS (p ϭ 0.046). Multivariate analysis re- teral obstruction in this patient may be from radiotherapy vealed independent prognostic factors for inferior OS were related retroperitoneal fibrosis. presence of metastases (p ϭ 0.020) and diagnosis of MUO in previously established malignancy (p ϭ 0.039) (fig. 2). Prognostic Factors for OS Patients were divided into 4 risk groups according to The effect of each prognostic factor on OS was examined the number of baseline unfavorable univariate OS prog- independently with univariate analysis. Inferior OS was nostic factors. There were 18 patients with 4 unfavorable associated with baseline factors of presence of metastases factors, 43 patients had 3, 21 had 2, and 16 patients had 1 or zero. Five patients were excluded from analysis because they had 1 or more factors missing. OS differed significantly among the 4 risk groups (p ϭ 0.011) with the 12-month OS rate ranged from 63% (95% CI 38%–82%) for the cohort of patients having 1 or zero unfavorable factors to 12% (95% CI 3%–38%) for the cohort of patients having all 4 (fig. 3).

Technical Failure The initial procedure was unable to decompress 5 patients (4 RS, 1 PCN), thus resulting in a 5% failure rate (95% CI 2%–12%). It was successful in 96 patients (94%) and data were not available for 1 patient. Failure rates for PCN and RS were 1% (1 of 76) and 16% (4 of 25), respectively. Three patients in whom RS initially failed went on to undergo successful PCN insertion.

Outcome After Primary Procedure PCN was removed in 8 of 77 patients when obstruction was relieved by chemotherapy or radiotherapy. Internalization by FIG. 1. Kaplan-Meier curve of overall survival from date of initial procedure for MUO. Dotted lines indicate 95% conﬁdence intervals. AS was attempted in 37 of 77 patients who had PCN. The Patients with censored times are shown by tick marks. remaining patients (32) were too unwell or died before AS. AS MALIGNANT URETERAL OBSTRUCTION OUTCOMES 181

FIG. 2. Kaplan-Meier curves of independent prognostic factors for overall survival on multivariate analysis including newly (solid line) and previously (dotted line) diagnosed malignancy (A) and absence (solid line) or presence (broken line) of metastases (B). Patients with censored times are shown by tick marks. resulted in successful internalization in 21 of 37 (57%), defined embolization and wound dehiscence after laparotomy with as the patient no longer being dependent on a covering PCN. RS insertion. Infection (not including patients with infection Primary RS was performed in 25 patients and 8 died secondary to stent/tube blockage) and blockage were the before the time to change the stent. Two patients with TCC most common complications (table 3). bladder involving the ureteral orifices were able to have Of the 54 patients experiencing a complication, 36 (67%) stents removed after response to therapy. Five patients had had 1, 14 (26%) had 2 and 4 (7%) had more than 2 compli- stents inserted together with laparotomy for tumor resec- cations. The complication rate was significantly higher for tion. Of the 5 patients 2 had surgery abandoned due to patients who had postoperative therapy for cancer (61% vs unresectable disease and the other 3 all had tumor recur- 37% for no therapy, p ϭ 0.03). There was no significant rence. Eight patients had 2 or more changes of stent (AS and difference in complication rates between primary PCN (53%, RS). The median number of stent changes in this group was 40 of 76) and RS cases (56%, 14 of 25) (p ϭ 0.82). 4.5 (range 2 to 13) with 3 patients still alive and having regular stent changes. Data after the primary procedure Duration of Hospital Stay were not available for 3 patients. A total of 90 patients with required available data died by the study closeout date. Their overall median remaining Complications lifetime spent in hospital was 17.4% (range 0.2% to 100%). A total of 54 patients (53%, 95% CI 43%–63%) had at least Six patients spent all of their remaining life as hospital 1 complication associated with the initial or subsequent inpatients. Prolonged hospital stay was associated with pa- procedure. Significant complications occurred in 2 patients tients who presented with symptoms (p ϭ 0.012), who had (2%) consisting of arterial hemorrhage after RS requiring no postoperative therapy for their cancer (p ϭ 0.01) and had a PCN as the initial procedure (p ϭ 0.043).

DISCUSSION We have examined many aspects of clinical outcome in MUO before and after decompression. To our knowledge this study is the second largest in the literature (at 102, Shekarriz et al with 103)8 and reviews a broad scope of clinical outcomes. Our followup (median 46 months) is the longest to be presented. Furthermore, with only 2 patients lost and 90% deceased by closeout date it represents the most complete data set to be analyzed.

TABLE 3. Complications by primary procedure type No. PCN No. Retrograde Stent Totals

Infection 27 5 32 Blockage 19 8 27 Hemorrhage 2 2 4 Other* 7 2 9 FIG. 3. Kaplan-Meier curves of risk groups for overall survival. Patients with censored times are shown by tick marks. Solid line * Dislodgement (3), signiﬁcant bleeding and abdominal wound dehiscence represents 0 or 1, dotted line 2, dash/dot line 3 and dashed line 4 (1), pain (1), stricture (1), nephrostomy leak (1), collecting system leak after unfavorable factors. PCN (1) and stent fracture (1). 182 MALIGNANT URETERAL OBSTRUCTION OUTCOMES

TABLE 4. Literature review of survival data References Survival Data (range) No. Pts

Current study Median survival 6.8 mos (204 days, 4.8–9.3 mos), 6-mo survival rate 56% (46%–65%) 102 (retrospective) Shekarriz et al8 Median survival 112 days (1–600) 103 (retrospective) Harrington et al9 Median survival 133 days, 6-mo survival rate 40% 42 (prospective) Donat and Russo11 Median survival 6.8 mos (0.5–46.1), 12-mo survival rate 55% 78 (retrospective) Wilson et al7 Median survival 87 days (12–814) 32 (retrospective) Lau et al10 Median survival 26 wks (182 days), 2-yr survival rate 30% 77 (retrospective) Other series reviewed consisted of smaller numbers and were restricted to particular types of cancer or nephrostomy only (Gasparini et al with 22 patients, mean survival 526 days; Chiou et al with 37 patients, median survival 21 months).16,17

Our study shows that survival in our patient group (de- leading to blockage. The incidence of blockage of stents and spite successful decompression) is poor. Literature review of PCN was similar (32%, 8 of 25 and 25%, 19 of 77). the larger studies in the last 10 years show little change in It is difficult to differentiate whether these complications OS (table 4).7–11 Adverse prognostic OS factors identified by are due to disease progression or intervention. The potential our study, presence of metastases (p ϭ 0.029) and diagnosis negative impact on QOL from intervention, such as pain from of MUO in previously established malignancy (p ϭ 0.044), stent/nephrostomy placement, ongoing irritation and infection have not formerly been established. Furthermore, we believe treated by a local doctor were not assessed in this study. the identification of adverse risk factors from our univariate analysis, and the associated poor survival for patients hav- Days in Hospital ing 3 or 4 of these factors (fig. 3), will be particularly helpful Days spent in hospital as a proportion of OS as a simple for clinicians in discussing prognosis and the benefit of MUO measure of QOL has been reported in several previous stud- treatment with patients. ies.7–9 Our results were similar (table 4). Formal QOL anal- The literature reports malignancy that is unresectable or ysis is difficult to perform retrospectively. Shekarriz et al unsuitable for chemotherapy,12 gastric, pancreatic11 and en- used a modified Karnofsky performance scale retrospec- docrine resistant prostate cancers,13 and requiring hemodi- tively, and demonstrated a difference in performance be- alysis before the procedure13 as statistically significant pre- tween known disseminated metastases and locally advanced dictors of worse survival. Availability of further treatment, or local metastatic disease (p ϭ 0.03) in patients who under- while not demonstrated statistically,7,9,10 still remains a went decompression.8 Ideally a randomized trial involving commonly proposed reason for decompression. Our study application of a formal QOL tool to patients with MUO indirectly confirms this with inferior OS on univariate anal- having or not having decompression would be performed. ysis associated with diagnosis of MUO in a previously estab- However, it is difficult ethically to refuse decompression if a lished malignancy and with the presence of prior therapy. patient or the family requests it to be performed.

Technical Failure The failure rate of primary RS placement has been reported CONCLUSIONS as high (range 37% to 51%,8 79%14) and even higher in It is important to predict clinical outcome because this will patients with prostate or bladder carcinomas (55%).11 Tech- decide plans for treatment after undergoing decompression. nical success rates for PCN vary between 96% and 100%.3–5 We have identiﬁed adverse prognostic factors for clinical Our failures with primary RS placement (16%, 4 of 25) all outcomes after decompression in MUO. Our results suggest occurred in patients with prostate (2) or bladder (2) carcino- there is minimal beneﬁt in OS after decompression in pa- mas. Our results support primary PCN in prostate or blad- tients with metastases, diagnosis of MUO in a preexisting der carcinomas.14 However, it should be noted that RS is malignancy or with 3 to 4 unfavorable risk factors. Improve- often attempted during the initial resection/diagnostic pro- ments in technical success rates have not been matched by cedure and, thus, failure does not necessarily represent an progress in complication rates or hospital stay. This new extra procedure. Our conversion rate for PCN to AS (57%) is prognostic information can be incorporated by clinicians in similar to other reported studies (34.4%,2 58%15). their treatment of patients with MUO.

Complications Our complication rate (53%) was in concordance with previous series (68.3%,8 50%11) and reﬂects the gravity of the Abbreviations and Acronyms disease despite advancements in insertion technique. There AS ϭ antegrade stent was no procedural mortality. Major complication rates for MUO ϭ malignant ureteral obstruction PCN reported in a group of 6 studies (total 1,602 nephros- OS ϭ overall survival ϭ tomies) varied between 3.1% and 7.7% (this highest rate was PCN percutaneous nephrostomy ϭ in nondilated collecting systems5).3–5 QOL quality of life RS ϭ retrograde stent The complication rate was signiﬁcantly higher for patients who had postoperative treatment for cancer (p ϭ 0.03). The immunosuppression associated with chemotherapy pre- REFERENCES disposes to infection. Dehydration from the nausea, vomiting and anorexia associated with chemoradiotherapy exac- 1. Holden S, McPhee M and Grabstald H: The rationale of uri- erbates the crystallization of solutes in the foreign stent nary diversion in cancer patients. J Urol 1979; 121: 19. MALIGNANT URETERAL OBSTRUCTION OUTCOMES 183

2. Brin EN, Schiff M and Weiss RM: Palliative urinary diversion 15. Zadra J, Jewett MAS, Keresteci AG, Rankin JT, St Louis E, for pelvic malignancy. J Urol 1979; 113: 610. Grey RR et al: Nonoperative urinary diversion for malig- 3. Radecka E and Magnusson A: Complications associated with nant ureteral obstruction. Cancer 1987; 60: 1353. percutaneous nephrostomies. A retrospective study. Acta 16. Gasparini M, Carroll P and Stoller M: Palliative percutaneous Radiol 2004; 45: 184. and endoscopic urinary diversion for malignant ureteral 4. Wah TM, Weston MJ and Irving HC: Percutaneous nephros- obstruction. Urology 1991; 38: 408. tomy insertion: outcome data from a prospective multi- 17. Chiou RK, Chang WY and Horan JJ: Ureteral obstruction operator study at a UK training centre. Clin Radiol 2004; associated with prostate cancer: the outcome after percuta- 59: 255. neous nephrostomy. J Urol 1990; 143: 957. 5. Patel U and Hussain FF: Percutaneous nephrostomy of nondilated renal collecting systems with ﬂuoroscopic guidance: technique and results. Radiology 2004; 233: 226. 6. Altman DG, De Stavola BL, Love SB and Stepniewska KA: EDITORIAL COMMENT Review of survival analyses published in cancer journals. Br J Cancer 1995; 72: 511. This series describes a somewhat heterogeneous group of 7. Wilson JR, Urwin GH and Stower MJ: The role of percutane- 102 patients with malignant ureteral obstruction, 68% of ous nephrostomy in malignant ureteric obstruction. Ann R which was bilateral. Of the patients 61% had urological or Coll Surg Engl 2005; 87: 21. gynecological malignancies. Complications were found in 8. Shekarriz B, Shekarriz H, Upadhyay J, Banerjee M, Becker H, Pontes JE et al: Outcome of palliative urinary diversion in 53% of patients, most commonly infection or stent block- the treatment of advanced malignancies. Cancer 1999; 85: age, but there were also 2 patients with hemorrhage. 998. Diversion via nephrostomy is often required in true pelvic 9. Harrington K, Pandha H, Kelly H, Lambert HE, Jackson JE malignancies and tended to be more successful in this and Waxman J: Palliation of obstructive nephropathy due series, but can have a greater impact on quality of life if to malignancy. Br J Urol 1995; 76: 101. external drainage is required. This experience echoes that 10. Lau M, Temperley DE, Mehta S, Johnson RJ, Barnard RJ and Clarke NW: Urinary tract obstruction and nephrostomy of Donat and Russo (reference 14 in article) and highlights drainage in pelvic malignant disease. Br J Urol 1995; 76: some of the major concerns with decompression proce- 565. dures in this population. These patients have only limited 11. Donat SM and Russo P: Ureteral decompression in advanced survival and the required procedures can have an adverse nonurologic malignancies. Ann Surg Oncol 1996; 3: 393. effect on quality of life. Median survival in both series was 12. Little B, Ho KJ, Gawley S and Young M: Use of nephrostomy identical at only 6.8 months. Decompression for malig- tubes in ureteric obstruction from incurable malignancy. nant ureteral obstruction should not be a knee-jerk re- Int J Clin Pract 2003; 57: 180. 13. Romero FR, Broglio M, Pires SR, Roca RF, Guibu IA and Perez sponse and should only be pursued after thoughtful coun- MD: Indications for percutaneous nephrostomy in patients seling. with obstructive uropathy due to malignant urogenital neo- Steven C. Campbell plasias. Int Braz J Urol 2005; 31: 117. 14. Chitale SV, Scott-Barrett S, Ho E and Burgess NA: The man- Section of Urologic Oncology agement of ureteric obstruction secondary to malignant Cleveland Clinic Foundation pelvic disease. Clin Radiol 2002; 57: 1118. Cleveland, Ohio Nitrous Oxide Inhalation to Improve Patient Acceptance and Reduce Procedure Related Pain of Flexible Cystoscopy for Men Younger Than 55 Years

J. G. Calleary,*,† J. Masood, R. Van-Mallaerts and J. M. Barua From the Department of Urology, Directorate of Special Surgery, Harold Wood Hospital, Essex, United Kingdom

Purpose: Flexible cystoscopy in men younger than 55 years is painful despite the current best standard anesthesia (20 ml 2% lidocaine gel 15 minutes before endoscopy). The anesthetic value of lidocaine gel is debated and led us to seek an alternative. Nitrous oxide is a well established analgesic and anxiolytic agent, and it significantly reduces pain associated with transrectal ultrasound guided prostate biopsy. We studied its use in flexible cystoscopy in men younger than 55 years. Materials and Methods: A total of 61 patients were prospectively randomized to receive air (31) or Entonox® (30). Both groups had 3 minutes of gas via a breath activated facemask (either Entonox or air) before endoscopy. The gel control group was comprised of 8 patients who underwent cystoscopy after instillation of lidocaine gel. The air and Entonox groups had lidocaine gel as per best standard. Vital signs were recorded before, during and after cystoscopy. Patients completed a visual analog score for gel insertion and cystoscopy. Results: There were no statistically significant differences between the groups in terms of baseline characteristics. Pain scores for cystoscopy (p Ͻ0.001) and intraoperative pulse rate (p ϭ 0.008) were significantly less with Entonox. Side effects were transient and seen more often with Entonox (p Ͻ0.05). More of the air group would require more analgesia (p ϭ 0.001) or a general anesthetic (p ϭ 0.011) if undergoing repeat cystoscopy. Conclusions: Nitrous oxide inhalation significantly reduces cystoscopy related pain without significant complications. We propose that Entonox should be the anesthetic agent of choice for men younger than 55 years. Key Words: nitrous oxide, lidocaine, pain measurement, cystoscopy

lexible cystoscopy is an integral part of the evaluation urethral (ie striated) sphincter. Anatomically, the Pudendal of hematuria. In addition to its diagnostic role, it is nerve supplies the striated sphincter and indirect evidence F also required for followup in transitional cell carci- for the urethral sphincter being the most painful point of noma of the bladder. Given a quoted prevalence of micro- urethral instrumentation comes from George and Dixon who scopic hematuria in a United States male population of have shown that the sensation of pain associated with ure- between 1% and 16% this translates into a potentially large thral catheterization is inhibited by bilateral pudendal number of procedures.1 There is an increasing body of liter- nerve block.7 The implication of these observations is that ature showing that diagnostic procedures in urology (eg an alternative to lidocaine, and possibly a nontopical agent, transrectal ultrasound guided prostate biopsy) are painful is required for optimal anesthesia in flexible cystoscopy. and require more analgesia than previously administered.2 Entonox (50% nitrous oxide and oxygen) is a safe and We believe flexible cystoscopy in younger men to be one of rapidly effective agent used for anesthesia/analgesia and these procedures. Despite the optimal use of periurethral anxiolysis in obstetrics,8 emergency departments9 and in lidocaine, flexible cystoscopy in males is a painful proce- dental practice throughout the world.10 It has been shown to dure.3–5 This seems to be especially true for males younger be effective for the relief of pain associated with transrectal than 55 years. The current best evidence practice is for 20 ml ultrasound guided prostatic biopsies.2 Therefore, we per- 2% lidocaine gel instilled 15 minutes before cystoscopy.3 formed this randomized blinded controlled trial to assess its However, recent work suggests lidocaine gel to be no better efficacy in relieving pain in flexible cystoscopy for men than lubricating gel.5,6 younger than 55 years. The most painful part of urethral instrumentation is said to occur when the instrument passes through the external PATIENTS AND METHODS Following approval for the study from the regional ethics Submitted for publication November 17, 2006. committee, the records of all men 55 years old or younger Study received regional ethics committee approval. listed for flexible cystoscopy were screened for exclusion * Correspondence: #6 Willow Cottages, Lodge Lane, Bicknacre, criteria. These were lidocaine allergy, concurrent use of anti- Chelmsford, Essex CM3 4HJ, United Kingdom (e-mail: johngcall@ aol.com). inflammatory medications, neurological disease impairing † Financial interest and/or other relationship with UK HIFU/ pain perception, requirement for a secondary procedure or a Misonix. history of significant cardiac or cardiopulmonary disease. See Editorial on page 14. Those without exclusion criteria were invited by mail to

0022-5347/07/1781-0184/0 184 Vol. 178, 184-188, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.036 NITROUS OXIDE INHALATION TO REDUCE PAIN OF FLEXIBLE CYSTOSCOPY 185 participate in the study. On the day of the procedure fully informed consent was obtained. Those who consented were prospectively randomized to an air or Entonox treatment group. Randomization was performed by the prepared card in envelope method and it was not possible to see the card through the envelope. The remaining 8 men formed a control group for gel insertion and cystoscopy was performed immediately after instillation of lidocaine gel. In line with best evidence practice the Entonox and air groups received 20 ml 2% lidocaine gel (Instillagel®, Farco- Pharma GmbH, Cologne, Germany) 15 minutes before endoscopy. A penile clamp held the gel in the urethra during this time. All gel insertions took less than 5 seconds and were performed by nonendoscopy suite personnel before FIG. 1. Visual analog scores for gel insertion and cystoscopy. There blinding. was no significant difference between groups for gel insertion. The air group received air via a breath activated demand Scores were significantly reduced in Entonox group (ANOVA valve mask for 3 minutes before and during endoscopy. The p Ͻ0.0001) compared to air and placebo groups. No significant treatment group received Entonox via an identical demand difference between placebo and air groups (Tukey’s test). valve mask for the same time period. The gel control group did not use the mask. The endoscopist and assisting nurse Entonox group (Anova F ϭ 15.145). This was also the case were blinded as to the randomization. with verbal score results (p Ͻ0.001, Anova F ϭ 14.661). Not For the purposes of the study pulse rate and oxygen unexpectedly, the mean pulse rates 15 minutes after cystos- saturation were measured before, during, immediately after copy, were reduced in all 3 groups, but not significantly so. and 15 minutes after completion of the cystoscopy. The in- There was a significant reduction in intraoperative pulse traoperative measurement coincided with intubation of the rate (p ϭ 0.008, Anova F ϭ 5.346) in the Entonox group external sphincter. Blood pressure before, immediately after compared to the air group. There were too few in the gel and 15 minutes after cystoscopy was also recorded. control group for subgroup analysis. Table 2 shows the pulse During the 15-minute period after cystoscopy patients rates at the sampling times in the groups. The lack of an were asked to complete a questionnaire which included an increase in pulse rate during cystoscopy in the Entonox assessment of pain response to gel insertion and cystoscopy. group is indirect evidence of its analgesic/anxiolytic proper- Pain perception was recorded using a standard visual analog ties. score and verbal score. There were no significant differences in blood pressure A single operator performed all procedures using readings or oxygen saturation readings between groups. The Olympus® instruments. Cystoscopy was performed to mimic main side effects noted by this patient cohort were light- standard United Kingdom practice as much as possible. headedness, pins and needles and mask related discomfort. All Verbal contact between the patient, the endoscopist and/or these were transient and resolved before discharge (table 3). the nurse during flexible cystoscopy was kept to a minimum They occurred more often in the Entonox group (p Ͻ0.05). in an effort to maintain the blinding. Statistical analysis There were no serious adverse events associated with was performed using SSPS®. Significance was assumed for Entonox use. The study was not designed to assess any a p value of less than 0.05. longer-term effects but our own experience and also that of others would suggest that for short exposure times, the risk RESULTS In total 69 men were recruited into the study. A total of 30 TABLE 2. Pulse rates in the 3 groups before, during were randomized to the Entonox group and 31 to the air and after the procedure group. There were no statistical differences between the groups in terms of age, diagnosis or pain scores for gel No. Pts Mean SD SE Min Max insertion (table 1 and fig. 1). The visual analog scores for Preop: cystoscopy (p Ͻ0.001) were significantly decreased in the Air 31 82.29 17.207 3.090 46 139 Entonox 30 78.83 14.849 2.711 58 112 Placebo 2 85.00 18.385 13.000 72 98 Overall 63 80.73 15.981 2.013 46 139 Intraop: Air 28 88.32 15.804 2.987 51 120 TABLE 1. Age and indication/diagnosis of the cohort Entonox 26 76.81 11.200 2.197 54 98 Placebo 1 67.00 67 67 Air Entonox Placebo Overall 55 82.49 14.852 2.003 51 120 Mean pt age (ϮSD) 43.84 (9) 45.1 (10.08) 47.38 (10.37) Immediately postop: No. indication/diagnosis: Air 31 82.13 16.225 2.914 51 128 Hematuria 9 7 3 Entonox 30 78.27 10.932 1.996 54 97 Obstruction 8 6 1 Placebo 2 78.50 14.849 10.500 68 89 Lower urinary tract symptoms 10 13 2 Overall 63 80.17 13.806 1.739 51 128 Urinary tract infection 3 2 0 15 Mins postop: Transitional cell carcinoma 12 2 Air 31 74.65 12.901 2.317 39 99 followup Entonox 30 72.03 11.944 2.181 56 100 Placebo 1 65.00 65 65 Total 31 30 8 Overall 62 73.23 12.349 1.568 39 100 186 NITROUS OXIDE INHALATION TO REDUCE PAIN OF FLEXIBLE CYSTOSCOPY

TABLE 3. Patient reported sensations after cystoscopy No. Gel No. Air (%) No. Entonox (%) Control (%)

None 27 (87) 17 (57) 2 (25) Form not ﬁlled out 2 (6) 1 (3) 6 (75) Urinary frequency 1 — — Mask discomfort — 1 — Light-headed 1 6 (20) — Tingling — 4 (13) — Slight numbness — 1 — Dizziness — 1 — Very happy — 1 — Dissociated from world — 1 — Total 31 33* 8 * One patient had mask related discomfort and tingling, and commented on being “dissociated from the world” immediately after the procedure, but was feeling perfectly normal on leaving 20 minutes later. A second patient FIG. 3. Patient desire (percentage of sample) for greater analgesia complained of light-headedness and tingling. All Entonox related side before repeat procedure. Using chi-square test there is signiﬁcant effects had ceased by discharge home. difference between Entonox and other 2 groups (p ϭ 0.001).

dwell times of 15, 10 and 10 minutes, respectively, before of serious adverse events is minimal. Figure 2 illustrates the cystoscopy. Such dwell times are not commonly used. The preferences for repetition of cystoscopy with 10 of the air results of McFarlane et al suggest that dwell time is not group and 1 of the Entonox group saying they would not important because they noted no difference with dwell times have the cystoscopy repeated under the same conditions of 15 minutes.5 In a group undergoing followup flexible (chi-square test p ϭ 0.011). Figure 3 illustrates that 14 of the cystoscopy, Herr and Schneider noted no difference between air group vs 4 of the Entonox group would have preferred the lidocaine and lubricant gel groups with a dwell time of more preoperative analgesia (chi-square test p ϭ 0.001). A 10 to 15 minutes.6 This lack of benefit may be due to the significantly greater proportion of the air group indicated a older age of this group or their reduced anxiety as they had preference for a general anesthetic (chi-square test p ϭ all undergone flexible cystoscopy in the past. No consensus 0.011) for any subsequent cystoscopy. has been agreed concerning the effect of gel temperature on pain. There is only 1 article in the English language litera- DISCUSSION ture dealing with rate of gel delivery and it showed significantly greater pain scores in patients with a delivery time of There is an increasing body of evidence showing that peri- 13 urethral lidocaine gel is at best of no benefit5,6 and at worst, 2 vs 10 seconds. causes more pain when compared to plain lubricant.11 Pos- Anxiety is also postulated as a major cause of pain felt during cystoscopy. Goldfischer et al demonstrated this for sible reasons for this lack of effect include difficulty in iden- 14 tifying the optimal regimen and conditions for use of topical outpatient rigid cystoscopy. Choong et al showed second procedures to be less painful than first, presumably due to lidocaine, the need to overcome patient anxiety and the need 3 to adequately anesthetize the sphincter. a reduction in anxiety due to increased familiarity. This may explain the low pain scores recorded by Herr and With regard to lidocaine administration, potential vari- 6 ables include the timing of cystoscopy post gel instillation (ie Schneider. These were all older patients who underwent the dwell time), the rate of gel delivery or the temperature of previous cystoscopy by the same operator and with whom the gel. A dwell time of at least 10 minutes, slow instillation dialogue was maintained throughout. Periurethral lidocaine and a gel temperature of 4C have all been suggested as ways does little for this component of urethral pain. Pain in younger males has been demonstrated to be of improving the analgesic effect of lidocaine. The work of 3 12 Choong,3 Holmes4 and Brekkan et al12 suggested minimum worse. Choong et al and Brekkan et al showed a significant increase in pain scores in those less than 55 years. Khan13 and Holmes et al4 disagree. Holmes et al found no link, although their study had few patients younger than 55. Khan et al looked at pain from gel insertion and found no difference between those older or younger than 60.13 Our pain scores are higher than those of Choong et al (2.1 after dwell time of 25 minutes vs 5 after dwell time of 15 minutes) but our gel insertion pain scores are similar to those recorded by Khan et al for gel insertion in a population from the same geographic region. As far as we are aware, ours is the only study to exclusively examine pain in men younger than 55 years. Therefore, these pain scores may represent the actuality of the pain experienced in men younger than 55. They also reflect our attempt to mimic the clinical situation as much as possible and in part may relate to the attempt to keep the operator and nurse blinded to the ran- FIG. 2. Patient attitude (percentage of sample) to repeat cystoscopy in same manner. Using chi-square test there is significant differ- domization by the lack of verbal reassurance to the patient, ence between Entonox and other 2 groups (p ϭ 0.011). which they would normally supply. NITROUS OXIDE INHALATION TO REDUCE PAIN OF FLEXIBLE CYSTOSCOPY 187

The ideal agent for flexible cystoscopy in younger men agent. These psychomotor tests are designed to detect drug would overcome these 3 major problems. Nitrous oxide is induced impairment of driving ability. Their results show no such an agent because of its analgesic, anxiolytic and am- significant difference between scores of those who did or did nesic properties. The combination of anxiolysis and analge- not receive Entonox. Based on this study they concluded sia is probably responsible for the lower pain scores and that the use of Entonox would not impair driving skills. We lower intraoperative pulse rates seen in the Entonox group monitored vital signs and oxygen saturations during the in this study. Nitrous oxide has been in clinical use for more study but the guidelines issued by the American Society of than a hundred years. It is highly effective in reducing Anesthesiologists Task Force indicate that less than 50% anxiety as has been shown in many dental publications15 nitrous oxide and oxygen mixture constitutes minimal seda- and is commonly used in pediatric16 and emergency depart- tion and thus minimal risk.20 This implies little monitoring is ments.9 In all these applications it has been shown to be safe required. Clinical evidence for this is provided by Frampton and effective. Its effects are dependant on the concentration et al who demonstrated that little added care was required inhaled and at the 50% concentration these are mainly an- using Entonox in a pediatric emergency setting.9 algesia and anxiolysis with a smaller degree of amnesia. Carbajal has demonstrated analgesia within 3 minutes of inhalation with complete or partial relief of pain in 75% to CONCLUSIONS 80%. The effect wears off in less than 4 minutes by excretion This study and others have shown flexible cystoscopy in men 16 from the lungs. younger than 55 years to be painful. The increased pulse The mechanisms behind the analgesic and antinocicep- rate in the air group as the endoscope passed through the 17 tive effects of nitrous oxide are becoming clearer. The external sphincter suggests that this is the most painful part evidence suggests that the trigger is release of opioid peptide of the procedure and, thus, should be the target of analgesic from the periaqueductal gray matter leading to activation of agents. Therefore, the place of periurethral lidocaine as sole descending inhibitory pathways, which are thought to be anesthesia for flexible cystoscopy in younger males must be predominantly noradrenergic. Activation of the descending questioned. In our cohort Entonox with its anxiolytic and inhibitory pathways results in modulation of nociceptive analgesic effects significantly improved the pain experience impulses. for younger males. The increased analgesia was achieved at Nitrous oxide is a colorless and odorless gas although to no cost to the patient and avoided the use of a general some it has a faint sweet smell. Its major adverse effect of anesthetic, which would otherwise have been necessary for light-headedness is transient and said to be not unpleasant. these men. With the application of well established stan- Its use as an analgesic in concentrations up to 50% is asso- dards of care this reduction in pain as a consequence of ciated with no significant cardiovascular changes. Nitrous Entonox is achieved without increased risk to endoscopy oxide may cause some slight cardiac depression but this is of suite staff. Therefore, we propose that Entonox is the agent little clinical concern in the majority of patients but for this of choice for flexible cystoscopy in men younger than 55 years. reason it should be used with care in those with significant cardiac failure and in those with chronic obstructive pulmonary disease.2 These conditions are not commonly seen in REFERENCES males younger than 55 years. 1. Woolhandler S, Pels RJ, Bor DH, Himmelstein DU and There have been some concerns regarding the use of Lawrence RS: Dipstick urinalysis screening of asymptom- nitrous oxide in relation to prolonged administration to pa- atic adults for urinary tract disorders. I. Hematuria and tients or chronic exposure of staff. Symptoms from exposure proteinuria. JAMA 1989; 262: 1214. to nitrous oxide are time and dose related. According to 2. Masood J, Shah N, Lane T, Andrews H, Simpson P and Barua Weimann there is little evidence to support the earlier re- JM: Nitrous oxide (Entonox) inhalation and tolerance of ported reduction in fertility or the development of cancer.18 transrectal ultrasound guided prostate biopsy: a double- Early hematopoietic changes require 6 hours of continuous blind randomized controlled trial. J Urol 2002; 168: 116. exposure to sedative concentrations of nitrous oxide while 3. Choong S, Whitfield HN, Meganathan V, Nathan MS, Razack measurable change in granulocytes needed 2 or more weeks A and Gleeson M: A prospective, randomized, double-blind of continuous exposure. The mechanism relates to the inter- study comparing lignocaine gel and plain lubricating gel in relieving pain during flexible cystoscopy. Br J Urol 1997; ference of the action of vitamin B .18 These risks are mainly 12 80: 69. associated with the use of continuous flow nitrous oxide 4. Holmes M, Stewart J and Rice M: Flexible cystoscopy: is the rather than the demand valve system and are significantly volume and content of the urethral gel critical? J Endourol reduced by gas scavenging systems. In dental practice there 2001; 15: 855. are guidelines for minimizing exposure to nitrous oxide 5. McFarlane N, Denstedt J, Ganapathy S and Razvi H: Random- which when implemented reduce staff exposure to accepted ized trial of 10ml and 20ml of 2% intraurethral lidocaine levels.10 The low exposure from use in flexible cystoscopy gel and placebo in men undergoing flexible cystoscopy. would not be expected to cause any adverse hematological J Endourol 2001; 15: 541. effects. 6. Herr HW and Schneider M: Outpatient flexible cystoscopy in Flexible cystoscopy is a day case office procedure. One of men: a randomized study of patient tolerance. J Urol 2001; 165: 1971. the questions raised about the use of nitrous oxide whether 7. George NJR and Dixon JS: Normal sensation of the lower patients could drive themselves home. We did not address urinary tract. In: Sensory Disorders of the Bladder and this particular issue but can comment on it with studies by Urethra. Edited by NJR George and JA Gosling. Berlin: 19 Martin et al. Martin et al performed complex psychomotor Springer-Verlag 1986; pp 7–16. testing on a group of 40 men and women undergoing flexible 8. Lawler K: Entonox: too useful to be limited to childbirth? Prof sigmoidoscopy with either Entonox or air as the analgesic Care Mother Child 1995; 5: 19. 188 NITROUS OXIDE INHALATION TO REDUCE PAIN OF FLEXIBLE CYSTOSCOPY

9. Frampton A, Browne GJ, Lam LT, Cooper MG and Lane LG: EDITORIAL COMMENT Nurse administered relative analgesia using high concentration nitrous oxide to facilitate minor procedures in chil- Intravenous nitrous oxide is a sedative-analgesic that may dren in an emergency department. Emerg Med J 2003; 20: relieve anxiety and discomfort during diagnostic procedures. 410. Inhaled N2O has shown promise in providing sedation for 10. Howard WR: Nitrous oxide in the dental environment: assess- atrial flutter ablation1,2 and flexible bronchoscopy.3 Its sed- ing the risk, reducing the exposure. J Am Dent Assoc 1997; ative properties and ability to reduce anxiety may be bene- 128: 356. 11. Ho KJ, Thompson TJ, O’Brien A, Young MR and McCleane G: ficial for patients who undergo diagnostic cystoscopy, and Lignocaine gel: does it cause urethral pain rather than the authors have clearly shown that in this article. However, prevent it? Eur Urol 2003; 43: 194. side effects can limit efficacy. Effects such as dizziness, 12. Brekkan E, Ehrnebo M, Malmström PU, Norlén BJ and headache and light-headedness suggest the need for postop- Wirbrant A: A controlled study of low and high volume erative monitoring. Administration by mask may not only anesthetic jelly as a lubricant and pain reliever during induce anxiety for patients but may also increase procedure cystoscopy. J Urol 1991; 146: 24. related costs. Finally, it would be interesting to learn 13. Khan MA, Beyzade B, Tau W, Virdi JS and Potluri BS: Effect of the rate of delivery of lidocaine gel on patient discomfort whether second procedures appear to be less painful than perception prior to performing flexible cystoscopy. Urol Int first procedures as a result of a reduction in patient anxiety.

2002; 68: 164. This may also decrease N2O requirements in future proce- 14. Goldfischer ER, Cromie WJ, Karrison TG, Naszkiewicz L and dures, as would be the case for patients who need periodic Gerber GS: Randomized, prospective, double-blind study of surveillance cystoscopy. the effects on pain perception of lidocaine jelly versus plain lubricant during outpatient rigid cystoscopy. J Urol 1997; Stanley Zaslau 157: 90. 15. Zacny JP, Hurst RJ, Graham L and Janiszewski DJ: Preoper- Division of Urology ative dental anxiety and mood changes during nitrous oxide West Virginia University School of Medicine inhalation. J Am Dent Assoc 2002; 133: 82. Morgantown, West Virginia 16. Carbajal R: Analgesia using a (50/50) mixture of nitrous oxide/ oxygen in children. Arch Pediatr 1999; 6: 578. 1. Laurent G, Bertaux G, Martel A, Fraison M, Fromentin S, 17. Fujinaga M and Maze M: Neurobiology of nitrous oxide- Gonzalez S et al: A randomized clinical trial of continuous flow induced antinociceptive effects. Mol Neurobiol 2002; 25: nitrous oxide and nalbuphine infusion for sedation of patients 167. during radiofrequency atrial flutter ablation. Pacing Clin 18. Weimann J: Toxicity of nitrous oxide. Best Pract Res Clin Electrophysiol 2006; 29: 351. Anaesthesiol 2003; 17: 47. 19. Martin JP, Sexton BF, Saunders BP and Atkin WS: Inhaled 2. Ujhelyi M, Hoyt RH, Burns K, Fishman RS, Musley S and patient-administered nitrous oxide/oxygen mixture does Silverman MH: Nitrous oxide sedation reduces discomfort not impair driving ability when used as analgesia during caused by atrial defibrillation shocks. Pacing Clin Electro- screening flexible sigmoidoscopy. Gastrointest Endosc 2000; physiol 2004; 27: 485. 51: 701. 3. Atassi K, Mangiapan G, Fuhrman C, Lasry S, Onody P and 20. American Society of Anesthesiologists Task Force on Sedation Housset B: Prefixed equimolar nitrous oxide and oxygen and Analgesia by Non-Anesthiologists: Practice guidelines mixture reduces discomfort during flexible bronchoscopy in for sedation and analgesia by non-anesthesiologists. Anes- adult patients: a randomized, controlled, double-blind trial. thesiology 2002; 96: 1004. Chest 2005; 128: 863. Urethral and Bladder Current Perception Thresholds: Normative Data in Women

Kimberly Kenton,* Jennifer Simmons, Mary Pat FitzGerald,† Lior Lowenstein and Linda Brubaker‡ From the Division of Female Pelvic Medicine and Reconstructive Surgery, Departments of Urology and Obstetrics and Gynecology, Loyola University Medical Center, Chicago, Illinois

Purpose: Given increased evidence of sensory dysfunction in lower urinary tract pathology, we determined normative current perception threshold values in the lower urinary tract of asymptomatic women. Materials and Methods: After receiving institutional review board approval women without lower urinary tract symptoms underwent current perception threshold testing of the urethra and bladder using a Neurometer® constant current stimulator. Current perception threshold values were determined at 3 frequencies, including 2,000 Hz (corresponding to A-␤ fibers), 250 Hz (corresponding to A-␦ fibers) and 5 Hz (corresponding to C fibers). Results: A total of 48 women with a mean age of 38 years (range 23 to 67) underwent current perception threshold testing. Normative values were established for the urethra and bladder at 2,000, 250 and 5 Hz. Median urethral current perception thresholds at 2,000, 250 and 5 Hz were 1.2 (IQR 0.76–1.5), 0.45 (IQR 0.33–0.56) and 0.11 mA (IQR 0.07–0.24), respectively. Median bladder current perception thresholds at 2,000, 250 and 5 Hz were 4.1 (IQR 2.0–6.3), 2.3 (IQR 0.87–5.5) and 1.4 mA (IQR 0.22–2.9), respectively. Urethral and bladder current perception thresholds increased significantly with subject age at all 3 frequencies (p Ͻ0.0005). Prior pelvic surgery was associated with an increased bladder current perception threshold at all 3 frequencies (p Ͻ0.005) but not with the urethral current perception threshold. Conclusions: We report urethral and bladder current perception thresholds for a large sample of asymptomatic women. These reference values may help elucidate changes in afferent nerve function in women with lower urinary tract dysfunction. Key Words: bladder, urethra, sensory thresholds, female, electric stimulation

nimal data first introduced the role of afferent neural asymptomatic controls and did not find a significant corre- pathways in regulating LUT function,1–3 which has lation between perception thresholds with the 2 types of A been supported by empirical treatments with neuro- stimuli.11 They hypothesized that the waveforms may stim- modulation and neurotoxins.4–6 Increasing evidence sug- ulate different afferent neural pathways or alternatively the gests that alterations in afferent signaling in the LUT may lack of correlation may have been due to differing mecha- have a crucial role in various LUT disorders, including over- nisms of neural activation by the waveforms. More recently active bladder and incontinence after urological proce- CPT testing has been done using different frequency sine 2,7–9 dures. Afferent signals from the urinary tract are con- wave stimuli to selectively depolarize different sized afferent ducted by A-␦ and C fibers in pelvic, hypogastric and nerve fibers by differences in their membrane ion concentra- pudendal nerves, which follow sympathetic and parasympa- tions. Three major types of afferent neurons can be com- 1 ␦ thetic pathways. Normally A- fibers are activated by in- pared clinically, including large, myelinated A-␤ fibers, creased tension in the bladder wall, while C fibers are not smaller, myelinated A-␦ fibers and unmyelinated C fibers. typically activated but begin to fire spontaneously in certain Despite the increasing use of CPT testing in subjects with pathological states and increase firing with bladder disten- LUT pathology and the recommendation of the American 10 tion. Association of Electrodiagnostic Medicine that future re- Several investigators reported the feasibility of quantita- search should establish reference values for CPT testing in tive sensory testing in the LUT using CPT testing.11–14 well characterized populations17 little normative data exist Initial studies used square wave electrical stimuli, which using this technology in the urinary tract. Although a min- are unable to differentiate fiber types.15,16 De Laet et al imum of 20 subjects is the bare minimum for validating a compared sine and square wave stimuli in the LUT of new electrodiagnostic test,18 there are 10 urethral12 and 10 bladder11 published reference values for CPT testing in women without LUT symptoms. Ukimura et al provided Submitted for publication November 6, 2006. results in 9 healthy volunteers but did not specify gender,9 Study received institutional review board approval. * Financial interest and/or other relationship with Allergan and limiting the ability to generalize these data. We established Pfizer. a set of normative data for CPT testing in the bladder and † Financial interest and/or other relationship with Pfizer, Aller- urethra of a representative population of women without gan and Medtronic. ‡ Financial interest and/or other relationship with Allergan, LUT symptoms to which values in symptomatic patients can Pfizer and QMed. then be compared.

0022-5347/07/1781-0189/0 189 Vol. 178, 189-192, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.032 190 URETHRAL AND BLADDER CURRENT PERCEPTION THRESHOLDS

MATERIALS AND METHODS groups. We used all 2-sided tests with p Ͻ0.05 considered significant. After obtaining institutional review board approval women 20 through 80 years old were recruited at our institution. Consented participants completed the Medical Epidemio- RESULTS logic and Social Aspects of Aging urinary incontinence ques- A total of 48 women underwent CPT testing. Participants 19 tionnaire and were queried about bothersome urinary had a mean age of 38 years (range 23 to 67), a mean body symptoms, and medical and surgical history. This analysis mass index of 26 kg/m2 (range 19 to 40) and a median was limited to women who responded that they were never vaginal parity of 1 child (range 0 to 4). Of the women 36 or rarely bothered by any Medical Epidemiologic and Social (78%) were premenopausal and 32 (68%) had undergone Aspects of Aging item and they did not report any bother- prior pelvic surgery. All subjects had normal, symmetric some urinary symptoms. Participants underwent dipstick patellar and Achilles reflexes. urinalysis and a directed physical examination, including Most women perceived the stimuli at all frequencies. One neurological evaluation with bulbocavernosus and lower ex- woman did not perceive stimuli in the bladder or urethra at tremity deep tendon reflexes. We excluded women in whom 5 Hz. Table 1 lists the results of CPT testing in the bladder the dipstick test was positive for leukocytes, nitrites or blood and urethra at all 3 frequencies. Median bladder CPT was and those who had a known history of neurological disor- significantly higher than urethral CPT at all 3 frequencies. ders. Bladder and urethral CPT at all frequencies increased sig- CPT testing of the urethra and bladder was performed in nificantly with age (p Ͻ0.0005). Bladder CPT at all 3 fre- 12 standardized fashion using a Neurometer CPT device. The quencies was significantly higher in women who underwent Neurometer is a constant current stimulator capable of de- prior pelvic surgery (table 2). Urethral CPT was not differ- livering sine wave stimuli at 3 frequencies, including 2,000, ent in women with and without pelvic surgery (p Ͼ0.32). 250 and 5 Hz. Testing was done with participants in the Vaginally parous women had higher median urethral CPT dorsal lithotomy position. Bladder testing at all 3 frequen- at 2,000 Hz than nulliparous women (1.5 mA, IQR 1.0–2.3 cies followed urethral testing at these 3 frequencies. Ring vs 1.0 mA, IQR 0.71–1.4, p ϭ 0.02). Bladder and urethral electrodes, consisting of 2 pieces of platinum wire wound CPT at other frequencies did not differ by parity (p Ͼ0.11). around a thin cylinder and coated with plastic, were positioned 1 cm distal to the balloon on a 14Fr Foley catheter and placed in the bladder of participants. The catheters were DISCUSSION left open, keeping the bladder decompressed during the en- Measurement of LUT sensation is a developing science with- tire test. out an established gold standard. Clinically sensation is typically estimated subjectively during filling cystometry. However, as increasing data implicate afferent neuropathy Urethral CPT Testing 4,6,7 The Foley balloon was inflated and gently positioned at the in disorders of LUT dysfunction, the search for an objec- urethrovesical junction. The urethral electrode was con- tive, quantifiable method to determine LUT sensation inten- nected to the Neurometer and testing was initiated at 2,000 sifies. Current perception threshold testing offers a feasible, valid, objective measure for quantifying subjective sensa- Hz. Stimulus intensity was gradually increased until the 9,11,12 participant first perceived it and then it was decreased until tion. it was no longer perceptible. CPT measurements were es- To our knowledge our results provide the first normative tablished semi-automatically using a forced choice para- CPT data on a large, clinically relevant population of women digm, in which randomly chosen pairs of stimuli were pre- without urinary tract symptoms. Like most electrodiagnos- sented as A or B with a brief rest period until a consistent tic tests, CPT testing depends on normative data for its perception threshold was attained. The process was then interpretation. No matter how well a neurophysiological test repeated at 250 and 5 Hz. is performed, it cannot be interpreted meaningfully without a valid body of normative data with which to compare studies. Although prior studies demonstrated the feasibility of Bladder CPT Testing CPT testing, the number of women studied was insufficient After determining the final urethral CPT measurement the to establish normal values. Early studies suggest differences Foley balloon was deflated and the catheter was advanced in bladder CPT in neurologically abnormal subjects com- into the bladder. The bladder was emptied and the catheter pared to that in a small, poorly characterized group of 8 remained open to drain for the procedure. Impedance was controls.9,11,12 Therefore, establishing normative data on a measured using a Nicolet Viking™ IVp electrodiagnostic well characterized population of adequate size is fundamen- instrument to ensure that the electrode was in contact with the bladder mucosa and the catheter was securely held in place. The electrode was reconnected to the Neurometer and bladder CPT measurements were determined at all 3 fre- TABLE 1. Urethral and bladder CPTs quencies, as described for the urethra. All participants were Median mA (IQR) given a single dose of 100 mg nitrofurantoin to minimize the risk of urinary tract infection from catheterization. CPT (Hz) Urethra Bladder SPSS®, version 13 was used for statistical management 2,000 1.2 (0.76–1.5) 4.1 (2.0–6.3) and analysis. The Mann-Whitney test was used to compare 250 0.45 (0.33–0.56) 2.3 (0.87–5.5) 5 0.11 (0.07–0.24) 1.4 (0.22–2.9) CPT measurements between independent groups and the Ͻ Wilcoxon signed rank test was used to compare related Wilcoxon signed rank test p 0.0005. URETHRAL AND BLADDER CURRENT PERCEPTION THRESHOLDS 191

in women with and without LUT dysfunction, and link these TABLE 2. Bladder CPTs by prior pelvic surgery differences with histological findings and other measures of Median Prior Pelvic Surgery neuromuscular function. (IQR) p Value Yes No (Mann-Whitney test) CONCLUSIONS No. pts 20 34 CPT (Hz): Our data provide normative CPT values for the bladder and 2,000 2.9 (1.2–4.0) 4.8 (3.2–8.5) 0.005 urethra of women with which to compare women with LUT 250 1.1 (0.47–2.2) 3.5 (1.1–7.2) 0.003 disorders. Future studies should control for the demon- 5 0.65 (0.09–1.3) 2.1 (0.44–3.3) 0.003 strated effects of aging, vaginal parity and prior pelvic surgery. The relationship of these objective sensory measures to symptoms and urodynamic findings may allow clinician re- tal to understanding altered sensation in women with LUT searchers to further develop hypotheses on the etiology of disorders. specific pelvic floor disorders. Bladder and urethra sensory thresholds in this population were increased (became less sensitive) with increasing age. This is consistent with CPT measurements in the fascial and limb nerves, which show a similar increase with Abbreviations and Acronyms aging. Altered CPT values can be associated with neuropa- CPT ϭ current perception threshold thy. Increased CPT measures (hypoesthesia) reflect the loss LUT ϭ lower urinary tract of sensory nerve function, while abnormally low CPT measures (hyperesthesia) reflect inflamed or irritated nerves. REFERENCES Therefore, the increased CPT values (or decreased sensation) that we found throughout the urinary tract with aging 1. De Groat WC: Nervous control of the urinary bladder of the cat. are not surprising and they are consistent with age related Brain Res 1975; 87: 201. neuromuscular decreases elsewhere in the body. 2. de Groat WC: A neurologic basis for the overactive bladder. The selective decrease in urethral sensation associated Urology 1997; 50: 36. with vaginal parity suggests that parity associated neuro- 3. DeGroat WC and Saum WR: Synaptic transmission in parasympathetic ganglia in the urinary bladder of the cat. muscular changes in the urethra are not limited to motor J Physiol 1976; 256: 137. functions. Previously investigators noted motor neuropathy 4. Fowler CJ, Beck RO, Gerrard S, Betts CD and Fowler CG: in the urethra after vaginal childbirth and with stress uri- Intravesical capsaicin for treatment of detrusor hyper- nary incontinence. More recently investigators reported that reflexia. J Neurol Neurosurg Psychiatry 1994; 57: 169. modulating urethral afferents affects bladder activity, sug- 5. Wyndaele JJ, Michielsen D and Van Dromme S: Influence of gesting that a reflex may be involved in some detrusor over- sacral neuromodulation on electrosensation of the lower activity in stress incontinent women.20,21 The characteriza- urinary tract. J Urol 2000; 163: 221. tion of urethral afferent innervation in health and disease 6. Yokoyama T, Nozaki K, Fujita O, Nose H, Inoue M and Kumon H: warrants further investigation. Role of C afferent fibers and monitoring of intravesical The increased sensory threshold in the bladder of women resiniferatoxin therapy for patients with idiopathic detrusor overactivity. J Urol 2004; 172: 596. who underwent prior pelvic surgery suggests that this pop- 7. Brehmer M and Nilsson BY: Elevation of sensory thresholds in ulation has some loss of sensory nerve function. It is intrigu- the prostatic urethra after microwave thermotherapy. BJU ing whether the decreased sensation is associated with an Int 2000; 86: 427. underlying pelvic floor nerve disorder that resulted in the 8. John H, Sullivan MP, Bangerter U, Hauri D and Yalla SV: need for pelvic surgery or whether pelvic surgery disrupted Effect of radical prostatectomy on sensory threshold and the fine sensory nerve fibers. It seems more likely that the pressure transmission. J Urol 2000; 163: 1761. increased sensory threshold is related to the prior surgical 9. Ukimura O, Ushijima S, Honjo H, Iwata T, Suzuki KNH, intervention, although this finding requires further evalua- Okihara K et al: Neuroselective current perception thresh- tion. old evaluation of bladder mucosal sensory function. Eur Several limitations of our data include more variability in Urol 2004; 45: 70. 10. Fall M, Lindstrom S and Mazieres L: A bladder-to-bladder bladder CPT measurements than actually existed due to our cooling reflex in the cat. J Physiol 1990; 427: 281. technique. While we ensured electrode contact with the 11. De Laet K, De Wachter S and Wyndaele JJ: Current percep- bladder mucosa using impedance testing, we did not char- tion thresholds in the lower urinary tract: Sine- and acterize the precise electrode location in the bladder. De square-wave currents studied in young healthy volun- Wachter and Wyndaele reported that sensory thresholds in teers. Neurourol Urodyn 2005; 24: 261. the bladder using square wave stimuli varied with electrode 12. Kenton K, Fuller E and Benson JT: Current perception thresh- position in the bladder.15 In addition, while other investiga- old evaluation of the female urethra. Int Urogynecol J Pel- tors noted good reproducibility in the LUT using square vic Floor Dysfunct 2003; 14: 133. wave stimuli, they were unable to report reproducibility 13. Kinn AC and Nilsson BY: Urethral sensitivity in incontinent data for sine wave stimuli due to a lack of data in symptom- women. Eur Urol 2005; 48: 116. 14. Wyndaele JJ, Van Eetvelde B and Callens D: Comparison in atic or diseased women.11 Future studies using sine wave young healthy volunteers of 3 different parameters of con- stimuli in women with LUT problems are needed to deter- stant current stimulation used to determine sensory mine clinically important differences in CPT measures. thresholds in the lower urinary tract. J Urol 1996; 156: To our knowledge the clinical meaning of differences in 1415. sensory thresholds, as measured by the CPT technique, is 15. De Wachter S and Wyndaele JJ: Can the sensory threshold not known. Further research is necessary to compare CPTs toward electrical stimulation be used to quantify the sub- 192 URETHRAL AND BLADDER CURRENT PERCEPTION THRESHOLDS

jective perception of bladder filling? A study in young semi-objective measurements of sensory function in the healthy volunteers. Urology 2001; 57: 655. LUT. With the same equipment normative data in a healthy 16. Wyndaele JJ: Study on the correlation between subjective percep- population were published recently in different parts of the tion of bladder filling and the sensory threshold towards electri- LUT and compared with CPTs obtained with the more fre- cal stimulation in the lower urinary tract. J Urol 1992; 147: 1582. 17. Technology review: the Neurometer Current Perception quently used square wave impulses (reference 11 in article). Threshold (CPT). AAEM Equipment and Computer Com- Although sinusoidal current is said to be neuroselective, this mittee. American Association of Electrodiagnostic Medi- must be confirmed in the LUT. CPTs at 5, 250 and 2000 Hz cine. Muscle Nerve 1999; 22: 523. can probably not be used as a semi-objective measurement of 18. Dorfman LJ and Robinson LR: AAEM minimonograph #47: the bladder filling sensation because no correlation was normative data in electrodiagnostic medicine. Muscle found between CPTs and the cystometric sensation of filling Nerve 1997; 20: 4. (reference 11 in article). Electrosensation must be done in a 19. Herzog AR, Diokno AC, Brown MB, Normolle DP and Brock BM: Two-year incidence, remission, and change patterns of standardized way, considering bladder fullness, rectal full- 1 urinary incontinence in noninstitutionalized older adults. ness, electrode positioning, etc (reference 16 in article). J Gerontol 1990; 45: M67. Only then may comparisons among studies and centers be- 20. Geirsson G and Fall M: Reflex interaction between the proxi- come possible. mal urethra and the bladder. A clinical experimental study. Scand J Urol Nephrol 1999; 33: 24. 21. Jung SY, Fraser MO, Ozawa H, Yokoyama O, Yoshiyama M, De Groat WC et al: Urethral afferent nerve activity affects Jean-Jacques Wyndaele the micturition reflex; implication for the relationship be- University Antwerpen tween stress incontinence and detrusor instability. J Urol Antwerp, Belgium 1999; 162: 204.

EDITORIAL COMMENT 1. De Wachter S and Wyndaele JJ: Quest for standardisation of electrical sensory testing in the lower urinary tract: the These authors used sinusoidal currents at different frequen- inﬂuence of technique related factors on bladder electrical cies of the Neurometer equipment to continue the search for thresholds. Neurourol Urodyn 2003; 22: 118. The Volume at Which Women Leak First on Urodynamic Testing is Not Associated With Quality of Life, Measures of Urethral Integrity or Surgical Failure

Lior Lowenstein,*,† Yashika Dooley,‡ Kimberly Kenton,§ Leslie Rickey,‡ Mary Pat FitzGerald,ʈ Elizabeth Mueller¶ and Linda Brubaker** From the Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, and Department of Urology, Loyola University Medical Center, Maywood, Illinois

Purpose: We determined if the bladder volume at which urodynamic stress incontinence is first detected is related to preoperative quality of life, urethral sphincter assessment or surgical outcome in women undergoing continence surgery. Materials and Methods: Charts of consecutive women who underwent a sling or Burch procedure were reviewed. Preoperative and postoperative assessment included the Incontinence Impact Questionnaire and Urogenital Distress Inven- tory. Urodynamic stress incontinence volume is the bladder volume at which urodynamic stress incontinence was first detected. Women were divided into 4 groups according to urodynamic stress incontinence volume, and compared with respect to maximum urethral closure pressure, Valsalva leak point pressure, Incontinence Impact Questionnaire and Urogenital Distress Inventory. Urodynamic stress incontinence persistence was evaluated only in patients who had sling surgery. Results: A total of 168 women were recruited for the study. Urodynamic stress incontinence volume was 100 ml for 31% of women, 200 ml for 17%, 300 ml for 17% and 400 ml or greater for 35%. Baseline and postoperative Urogenital Distress Inventory, Incontinence Impact Questionnaire, maximal urethral closure pressure and Valsalva leak point pressure did not differ by urodynamic stress incontinence volume. Among the 116 patients who had the sling procedure, urodynamic stress incontinence persistence did not differ by urodynamic stress incontinence volume (p ϭ 0.72). Conclusions: Women who demonstrate urodynamic stress incontinence at lower bladder volumes do not report greater bother from incontinence than women who leak at higher volumes, suggesting leakage severity on urodynamics is not an adequate reflection of incontinence related quality of life. Key Words: urodynamics; urinary incontinence, stress; quality of life; suburethral slings

reoperative urodynamic evaluation is common in assumed to be associated with worse incontinence severity women undergoing stress incontinence surgery. Uro- and possibly worse surgical outcome. This observation is P dynamic observations have been used to conﬁrm the also used to direct selection of surgical treatment. Women diagnosis of stress incontinence by observing transurethral with urinary loss at a lower bladder volume are usually urine loss at the moment of increased abdominal pressure in treated with some form of sling. The purpose of this analysis the absence of a detrusor contraction (USI).1 In addition to was to determine if bladder volume was related to validated this general diagnostic ﬁnding, urodynamic criteria are also quality of life measures, urethral sphincter assessments and used to inform surgical decision making. Factors such as low standardized surgical outcome measures in women with MUCP have been associated with poor surgical results.2,3 In urodynamic stress incontinence, and whether USI volume our practice a low bladder volume at the time of USI is often could predict failure following rectus fascial sling.

METHODS AND MATERIALS Submitted for publication November 6, 2006. After obtaining Institutional Review Board approval, we Study received Institutional Review Board approval. * Correspondence: Division of Female Pelvic Surgery and Recon- reviewed charts of consecutive new patients who underwent structive Surgery, 2160 South First Ave., Maywood, Illinois 60153 urodynamic testing before a continence procedure at Loyola (telephone: 708-216-2170; FAX: 708-216-2171; e-mail: llowenstein@ University’s Urogynecology Center in 2000. All women un- lumc.edu). † Financial interest and/or other relationship with Pfizer Inc. derwent standardized multichannel urodynamic testing ‡ Nothing to disclose. (model 1106, Life-Tech, Inc., Houston, Texas) in a birthing § Financial interest and/or other relationship with Allergan and chair reclined at 45 degrees. Stage III and IV prolapse was Pfizer. ʈ Financial interest and/or other relationship with Pfizer Inc., Allergan and Medtronic. ¶ Financial interest and/or other relationship with Allergan. ** Financial interest and/or other relationship with Global Advi- Editor’s Note: This article is the fourth of 5 published sory Board, Eli Lilly, Yamanouchi, Novartis, Allergan, Pfizer and in this issue for which category 1 CME credits can be QMed. earned. Instructions for obtaining credits are given For another article on a related topic see page 326. with the questions on pages 358 and 359.

0022-5347/07/1781-0193/0 193 Vol. 178, 193-196, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.031 194 URODYNAMIC STRESS INCONTINENCE VOLUME AND QUALITY OF LIFE MEASURES

400 ml or greater for 60 (35%). Median MUCP was 28 cm TABLE 1. Quality of life measures by USI volume H2O (range 0 to 180). Median Score (range) At baseline median IIQ and UDI scores did not differ by Before Before After After USI volume group or whether the patient had undergone a USI Vol (ml) IIQ-7 UDI-6 UDI-6 IIQ-7 previous continence procedure (p ϭ 0.68 and p ϭ 0.55, re- 100 43 (0–86) 61 (17–94) 17 (0–78) 5 (0–76) spectively) (table 1). Median MUCP and VLPP did not differ 200 24 (0–90) 39 (17–75) 14 (0–28) 5 (0–71) significantly by USI volume group (p ϭ 0.14 and p ϭ 0.31, 300 29 (0–100) 44 (0–83) 11 (0–83) 0 (0–71) 400 or Greater 31 (0–90) 50 (11–100) 17 (0–61) 2 (0–71) respectively). In addition, neither MUCP nor VLPP were cor- p Value* 0.64 0.11 0.36 0.57 related with baseline UDI and IIQ scores (p ϭ 0.34, p ϭ 0.44 ϭ ϭ * Kruskal-Wallis test. and p 0.88, p 0.19, respectively). A total of 52 (31%) women had a Burch colposuspension and 116 (69%) had a fascial sling procedure based on clinical reduced with procto swabs or the examiner’s hand through- counseling and patient preference. As expected based on our out the study. A 7Fr microtip catheter (Millar Instruments, clinical practice there were significant differences between Houston, Texas) was placed in the vagina or rectum to the Burch and sling groups. The sling group had a lower USI record abdominal pressure, and a 7Fr dual microtip catheter volume, lower median MUCP, and higher total scores on IIQ with infusion port (Millar Instruments) was placed with the and UDI before surgery (table 2). distal transducer in the bladder and the proximal trans- Of the patients 87% completed the standardized postop- ducer in the mid urethra facing the 9 o’clock position to erative assessment 3 months following surgery. Persistent record vesical pressure and urethral pressure, respectively. USI was detected in 27% of patients and this rate was not True detrusor pressure and urethral closure pressure were significantly different by surgical group (Burch 29% vs sling electronically subtracted and recorded throughout the 26%, p ϭ 0.52). Postoperative UDI and IIQ scores did not study. We performed retrograde cystometry with room tem- differ by preoperative USI volume group among patients perature saline at 80 ml per minute. At each 100 ml interval who had the sling procedure (table 3). patients were assessed for USI during 3 consecutive Val- Women with persistent USI did not leak at lower volumes salva and cough maneuvers. Urodynamic stress inconti- on preoperative urodynamic evaluation compared to women nence volume was defined as the lowest bladder volume at with resolved USI (267 Ϯ 159 ml vs 307 Ϯ 192 ml, respec- which the patient demonstrated USI rounded to the nearest tively, p ϭ 0.49). Likewise, the percentage of women with 100 ml interval. Maximum urethral closure pressures were persistent USI did not differ by USI volume group (table 3). obtained at MCC using a profilometer that was withdrawn at a rate of 1 mm per second. VLPP was determined as the DISCUSSION lowest abdominal pressure at which the patient leaked at MCC. All terminology conforms to the standards recom- USI volume is not associated with decreased quality of life or mended by the International Continence Society.1 decreased MUCP and VLPP in patients undergoing Burch Women with USI who desired surgical correction under- colposuspension or rectus fascial sling. USI volume is also went a Tanagho modification Burch colposuspension4 using not associated with increased surgical failure in patients permanent suture or a rectus fascial sling5 based on clinical undergoing rectus fascial sling surgery. Previous investiga- counseling. Demographic data, history, and the short forms tors have reported that a positive empty supine stress test is associated with intrinsic sphincter deficiency as defined by of the Incontinence Impact Questionnaire and the Urinary 6–8 Distress Inventory were recorded. low MUCP or VLPP. These prior studies are consistent All patients underwent a standardized postoperative as- with current anecdotal clinical care, suggesting that urine sessment 3 months after surgery including repeat IIQ and leakage at a low bladder volume may be associated with UDI, as well as a standardized standing cystometrogram. more severe sphincter disease. However, quality of life and Persistent USI was determined if a patient lost even 1 drop surgical outcomes data are not provided in those reports. of urine with repetitive cough or Valsalva. Many incontinence treatment providers intuitively tend SPSS® for Windows version 13 was used for data manage- to believe that USI at lower bladder volumes is associated ment and statistical analysis. The Kruskal-Wallis and the with easier leakage, more severe sphincter dysfunction and Mann-Whitney tests were used to compare independent a higher rate of surgical failure. Clearly we shared this belief groups with respect to noncategorical variables, and the chi- as reflected by our surgical practice of using slings prefer- square test of association was used to compare independent entially in that group of patients. However, our data indicate groups with respect to percentages. A significance level of 0.05 that a low preoperative USI volume is not associated with was used for all statistical tests. No 1-sided tests were done.

RESULTS TABLE 2. Baseline differences between burch and sling groups A total of 168 women with a mean age of 60 years (range Mean Ϯ SD 34 to 89) and median vaginal parity of 2 children (range 0 Burch Sling p Value* to 9) were included in this study. The majority (94%) was USI vol (ml) 357 Ϯ 167 256 Ϯ 168 Ͻ0.00 of white race. There were 28 women (17%) who had un- Ϯ Ϯ Ͻ MUCP (cm H2O) 53 32 28 21 0.00 Ϯ Ϯ Ͻ dergone prior continence surgery. Median IIQ and UDI VLPP (cm H2O) 64 35 48 28 0.04 Ϯ Ϯ Ͻ scores at baseline were 38 (range 0 to 100) and 56 (range UDI-6 total score 45 23 56 20 0.02 IIQ-7 total score 28 Ϯ 24 41 Ϯ 27 Ͻ0.02 0 to 100), respectively. USI volume was 100 ml for 52 (31%) women, 200 ml for 28 (17%), 300 ml for 28 (17%) and * Mann-Whitney test. URODYNAMIC STRESS INCONTINENCE VOLUME AND QUALITY OF LIFE MEASURES 195

We included patients who had Burch and fascial sling TABLE 3. Postoperative assessment of patients with autologous fascial sling repair by preoperative USI volume group procedures in this report despite the statistically different baseline UDI and IIQ scores because in both groups it was Median Score Median Score MI USI Vol After IIQ After UDI % Persistent demonstrated that there was no relationship between base- (No. pts) (range) (range) USI line QOL measures and USI volume leakage. The consistent, standardized preoperative and postoperative assessments 100 (34) 5 (0–76) 19 (0–78) 27 200 (23) 7 (0–71) 17 (6–28) 19 with minimal loss of followup are strengths of this study. 300 (21) 4 (0–33) 22 (0–61) 19 The generalizability of the study is somewhat limited be- 400 or Greater (30) 5 (0–71) 17 (0–68) 29 p Value 0.20* 0.28* 0.72† cause the population was predominantly white. We also did not include patients undergoing a mid urethral sling proce- * Kruskal-Wallis test. † Chi-square test. dure. decreased condition specific quality of life or persistent in- CONCLUSIONS continence 3 months following rectus fascial sling. Increasing evidence suggests there is an important dissoci- Urodynamic testing for USI is highly variable and the ation between urodynamic findings and patient condition specific volume for USI detection is not standardized. There specific quality of life.12 Triage of stress incontinence proce- appears to be no rationale for USI testing at multiple vol- dures is at best an imperfect science and urgently requires umes or any preferential volume for USI testing. The lack of additional investigation. Each aspect of the preoperative difference in preoperative QOL scoring at varied USI vol- urodynamic evaluation for women with stress incontinence umes suggests the need for additional measures to capture should be stringently evaluated to determine its role in the the impact of incontinence on quality of life. Another possi- patient reported outcome of surgical intervention for stress bility is that bother in women is not affected by the bladder incontinence. capacity at which incontinence occurs but by the incontinence in itself. Traditional urodynamic observations such as USI volume are poorly related to patient daily activities, which are likely to include adaptive behaviors to minimize Abbreviations and Acronyms leakage. IIQ ϭ Incontinence Impact Questionnaire The range of MUCP values may be too limited to detect MCC ϭ maximum cystometric capacity meaningful differences in sphincteric health. Furthermore, MUCP ϭ maximal urethral closure pressure differences in MUCP and VLPP might be related to the fact QOL ϭ quality of life that these were not measured at the same bladder volume in UDI ϭ Urogenital Distress Inventory ϭ all patients but at MCC. The use of urethral pressure has USI urodynamic stress incontinence ϭ known limitations as a static measure of sphincteric func- VLPP Valsalva leak point pressure tion.9 This may explain the lack of differences among USI volume groups despite the association with surgical failure as reported by other investigators.2 A recent study of the REFERENCES correlations of Valsalva and cough leak point pressure and 1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U QOL in women undergoing sling surgery demonstrated that et al: The standardisation of terminology of lower urinary leak point pressure is not correlated with stress urine incon- tract function: report from the Standardisation Sub-com- tinence severity as evaluated by the short form of the UDI mittee of the International Continence Society. Neurourol 10 and IIQ. These results support our finding regarding the Urodyn 2002; 21: 167. lack of association between urethral closure pressure and 2. Bowen LW, Sand PK, Ostergard DR and Franti CE: Unsuc- Valsalva leak point pressure with QOL measures. These cessful Burch retropubic urethropexy: a case-controlled findings may be due to the lack of accuracy of QOL and/or urodynamic study. Am J Obstet Gynecol 1989; 160: 452. urodynamic findings in measuring incontinence severity. 3. Sand PK, Bowen LW, Panganiban R and Ostergard DR: The In our study there were baseline differences in the Burch low pressure urethra as a factor in failed retropubic urethropexy. Obstet Gynecol 1987; 69: 399. and sling groups, making it difficult to determine if quality 4. Tanagho EA: Colpocystourethropexy: the way we do it. J Urol of life differences after surgery were related to the surgical 1976; 116: 751. procedure. In addition, there were too few patients in the 5. Brubaker L: Suburethral Sling Procedure: Operative Tech- Burch group to compare USI volume groups with respect to niques in Gynecologic Surgery. Philadelphia: WB Saunders postoperative QOL measures and USI persistence. There- Co 1997; vol 2, pp 31–34. fore, we limited our assessment of postoperative QOL and 6. Hsu TH, Rackley RR and Appell RA: The supine stress test: a USI persistence to patients who had sling surgery. Our simple method to detect intrinsic urethral sphincter dys- results regarding the absent correlation between USI vol- function. J Urol 1999; 162: 460. ume and postoperative QOL could not be generalized to 7. Lobel RW and Sand PK: The empty supine stress test as a other types of surgery except for autologous fascial sling. predictor of intrinsic urethral sphincter dysfunction. Obstet Gynecol 1996; 88: 128. The study is not designed to compare the success rate of 8. McLennan MT and Bent AE: Supine empty stress test as a Burch colposuspension vs rectus fascial sling surgery. Large predictor of low valsalva leak point pressure. Neurourol randomized surgical trials like the Stress Incontinence Sur- Urodyn 1998; 17: 121. gical Treatment Efficacy Trial (SISTEr), which compares 9. Kenton K, Fitzgerald MP and Brubaker L: Striated urethral Burch urethropexy to rectus fascial sling, will likely address sphincter activity does not alter urethral pressure during this issue.11 filling cystometry. Am J Obstet Gynecol 2005; 192: 55. 196 URODYNAMIC STRESS INCONTINENCE VOLUME AND QUALITY OF LIFE MEASURES

10. Chen C, Paraiso MR, Kleeman S, Walters MD, Karram M and 11. Tennstedt S: Design of the Stress Incontinence Surgical Treat- Barber MD: Does leak point pressure correlate with incon- ment Efﬁcacy Trial (SISTEr). Urology 2005; 66: 1213. tinence severity or bother in women undergoing surgery for 12. Elkadry EA, Kenton KS, FitzGerald MP, Shott S and urodynamic stress incontinence? Presented at 27th Annual Brubaker L: Patient-selected goals: a new perspective Scientiﬁc Meeting of the American Urogynecologic Society, on surgical outcome. Am J Obstet Gynecol 2003; 189: Palm Springs, California, October 19–21, 2006. 1551. Sacral Neuromodulation for Nonobstructive Urinary Retention—Is Success Predictable?

Meidee Goh* and Ananias C. Diokno†,‡ From the Department of Urology, William Beaumont Hospital, Royal Oak, Michigan

Purpose: We investigated whether there are factors which can predict successful stage II (permanent) sacral nerve stimulator (InterStim®) implantation for patients with nonobstructive urinary retention. Materials and Methods: We retrospectively reviewed our sacral neuromodulation database from January 1, 1999 to January 1, 2006. A total of 29 patients were referred to the William Beaumont Hospital Department of Urology for nonobstructive urinary retention. All patients completed a 3-day voiding log followed by test stimulation. Patients underwent test stimulation for a 2-week trial period. Those who experienced 50% improvement in void volume and/or catheterization frequency subsequently underwent permanent implantation. We reviewed patient charts with respect to age, sex, duration of retention, underlying diagnosis for retention and voiding ability. Results: Of the 29 patients 15 were men and 14 were women. Mean patient age was 58.8 Ϯ 16 years (range 18 to 82). The mean age of the men in the study was 55.5 Ϯ 18 years while the mean age of the women was 62.3 Ϯ 14 years. Although all the patients performed intermittent self-catheterization 18 were able to void (more than 50 cc per void). The remaining 11 patients had minimal (50 cc or less) or no ability to void. Of the 18 patients who were able to void 12 (67%) underwent successful permanent implantation. However, voiding improved after test stimulation in only 2 of the 11 patients (18%) who had been unable to void. This difference was statistically signiﬁcant (p ϭ 0.02) and suggests that pre-implantation ability to void can predict success of test stimulation. Conclusions: Patient ability to void predicts success of ﬁrst stage test stimulation. Although we would still offer a trial of sacral neuromodulation to those with nonobstructive urinary retention and the inability to void, this study would allow better counseling regarding the likelihood of successful outcome. Key Words: treatment outcome, prognosis, urinary retention, electric stimulation

acral neuromodulation was approved in 1997 by the sphincter activity) may have a more successful outcome.5 Food and Drug Administration for the treatment of None of these studies suggest why some treatment is suc- S urinary urge incontinence, urinary urgency-frequency cessful in some patients and not in others. We hope to and nonobstructive urinary retention.1 In 1998 Shaker and identify factors which may influence success during first Hassouna reported their successful experience of sacral neu- stage sacral neuromodulation testing. romodulation in 20 patients with idiopathic nonobstructive chronic urinary retention.2 However, not all patients with nonobstructive urinary retention are treated successfully MATERIALS AND METHODS during initial test stimulation. In a multicenter prospective trial by Jonas et al treatment was successful in only 38% of A retrospective review of our database from January 1, 1999 patients following first stage testing.3 Koldewijn et al dem- to January 1, 2006 was performed. During this period 29 onstrated similar outcomes with perfect results in 38% of patients with nonobstructive urinary retention underwent patients with bladder underactivity and moderate/slight re- first stage sacral neuromodulation (InterStim) testing. sults in an additional 21%.4 Other studies suggest that There were 15 males and 14 females who underwent testing. Ϯ sacral neuromodulation in young women with Fowler’s syn- The mean age of the patients was 58.8 16 years (range 18 Ϯ drome (urinary retention secondary to abnormal striated to 82). The mean age of the men in the study was 55.5 18 years while the mean age of the women was 62.3 Ϯ 14 years. Of the women 29% (4 of 14) and of the men 47% (7 of 15) Submitted for publication November 29, 2006. were unable to void or voided less than 50 cc. Study received Investigational Review Board approval. Baseline evaluation included a 3-day voiding diary and * Financial interest and/or other relationship with United Medical urodynamic testing. Due to the tertiary referral nature of System. † Correspondence: Department of Urology, M.O.B. Suite 438, Wil- the practice, patients had undergone urodynamic testing to liam Beaumont Hospital, 3535 W. 13 Mile Rd., Royal Oak, Michigan confirm the diagnosis at William Beaumont Hospital or 48073 (telephone: 248-551-0387; FAX: 248-551-8107; e-mail: adiokno@ through their referring urologist. Of the 29 patients 7 un- beaumont.edu). ‡ Financial interest and/or other relationship with Medtronic Inc., derwent InterStim first stage testing through the percuta- Ortho Urology, McNeil Pharmaceuticals, Eli Lilly, Advanced Uro- neous approach. The remaining 22 patients underwent logic Devices, Allergan, GSK and Life-Tech. staged InterStim implantation. The patients completed a For another article on a related topic see page 320. 2-week voiding log following the test implantation. Those

0022-5347/07/1781-0197/0 197 Vol. 178, 197-199, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.058 198 SACRAL NEUROMODULATION FOR NONOBSTRUCTIVE URINARY RETENTION who experienced a 50% reduction in catheterization fre- TABLE 2. Gender distribution of first stage implants quency or 50% improvement in voided volume were offered permanent implantation. Of all the patients 14 (48%) sub- No. Female (%) No. Male (%) sequently underwent second stage (permanent) InterStim Failed first stage testing 6 (42.9) 9 (60.0) implantation following initial testing. We reviewed the pa- Successful first stage testing 8 (57.1) 6 (40.0) tient records and voiding logs for factors which may influ- Total 14 (100) 15 (100) ence the outcome of first stage testing. p ϭ 0.36. Descriptive statistics were presented as mean Ϯ SD. The independent samples t test was used to analyze duration of retention and age at implantation. The chi-square test was used to analyze gender and voiding function before implant. nary retention is not well understood. Many have suggested Statistical significance was considered at p Յ0.05. inhibition of the guarding reflex as the operative mechanism. The spinally mediated guarding reflex results in contraction of the urinary sphincter to prevent urinary inconti- RESULTS nence when a sudden increase in intravesical pressure Mean duration of urinary retention was 5.9 Ϯ 5.1 years occurs. An overactive guarding reflex is postulated to have a (range 0.5 to 25). The majority of patients were diagnosed role in the development of nonobstructive urinary retention. with idiopathic urinary retention or detrusor sphincter dys- Sacral neuromodulation interrupts the excitatory outflow to synergia (table 1). Baseline urodynamic evaluation of the the sphincter, interfering with the guarding reflex and, thus, 3,6 patients confirmed the absence of an obstructive etiology for facilitating voiding. the retention. Data from DasGupta and Fowler suggest that this 7 Of the 29 patients who underwent InterStim testing mechanism may be incorrect. They studied 30 women through a percutaneous or staged approach, 14 experienced with retention before and after sacral neuromodulation at least 50% improvement in voided volume and/or post-void with sphincter electromyography. They found that the elec- residual to qualify for permanent implantation. Patient age tromyographically abnormality present before implantation at implantation did not have a role in success or failure. The was unchanged following implantation. A slight increase in mean age of those treated successfully was 57.9 Ϯ 19.4 years detrusor contractility was noted, and they postulated that while the mean age of those not treated successfully was this increase in contractility was sufficient to overcome the 59.7 Ϯ 13.9 years (p ϭ 0.77). The gender of the recipient also increased sphincter activity and result in voiding. did not have a role in determining success (table 2). Our data support these findings. We found that those who However, duration of retention and the ability to void are able to void some despite having urinary retention are (more than 50 cc) were associated with an increased rate of more likely to have treatment success with neuromodula- success of first stage testing. Of the 18 patients in the study tion. Only 18% of those who were minimally able/unable to who were able to void (more than 50 cc) 12 (67%) went on to void were successfully treated with first stage testing while undergo permanent implantation, while only 2 of the 11 67% of those who were able to void (more than 50 cc) had a (11%) who were unable to void or voided minimally (50 cc or successful outcome. This may suggest that those with some less) went on to undergo permanent implantation. This dif- preserved detrusor function may benefit more from neuro- ference in voiding ability was statistically significant (p ϭ 0.02) modulation through an augmentation mechanism. (table 3). In the patients who underwent permanent implan- The finding that patients with successful first stage neu- tation, the duration of retention (mean 8.2 Ϯ 6.1 years) was romodulation testing had longer duration of retention may significantly longer than those who did not undergo implan- allow better stabilization of voiding dysfunction and thus, an tation (mean 3.6 Ϯ 2.4 years) (t ϭ 2.73, p ϭ 0.01). improved outcome. Alternatively the patients may seek intervention later since they hope that the ability to void will DISCUSSION continue to improve with time, while those unable to void are more frustrated with the situation and may be more Sacral neuromodulation has been used in the setting of likely to seek earlier treatment. nonobstructive urinary retention. Success has been best in While we would still offer neuromodulation to patients the situation of young women with Fowler’s syndrome.5 The with nonobstructive urinary retention who were unable to mechanism of how sacral neuromodulation remedies uri- void, we would counsel them that the likelihood of success may be decreased. This study is limited by its retrospective nature and the small number of study patients. Data from Scheepens et al suggest that success of neuromodulation in TABLE 1. Primary diagnosis associated with voiding dysfunction patients with urinary retention is an on/off phenomenon.8 No. (%)

Detrusor sphincter dyssynergia/detrusor hyperactivity 8 (26) with impaired contractility Idiopathic urinary retention 7 (24) TABLE 3. Voiding ability Atonic bladder 3 (10) Spinal cord injury 3 (10) No. Void More Fowler’s syndrome 2 (7) No. No Void (%) Than 50 cc (%) Autonomic failure (variant of Shy-Dragers) 1 (3) Bladder rupture 1 (3) Failed ﬁrst stage testing 9 (81.8) 6 (33.3) Hinman’s syndrome 1 (3) Successful ﬁrst stage testing 2 (18.2) 12 (66.7) Multiple sclerosis 1 (3) Total 11 (100) 18 (100) Transverse myelitis 1 (3) Pelvic pain 1 (3) p ϭ 0.02. SACRAL NEUROMODULATION FOR NONOBSTRUCTIVE URINARY RETENTION 199

Neuromodulation was either effective or not in this subpopu- EDITORIAL COMMENT lation of this study. They also suggest that long-term efficacy results may be better in patients with urinary retention. We The authors retrospectively reviewed their 7-year experi- look forward to a prospective study of patients with reten- ence with InterStim for nonobstructive urinary retention in tion in the future, including urodynamic testing before and 29 patients. Ability to void more than 50 cc was the only after the procedure. factor associated with positive clinical response during test stimulation (stage 1). This finding could help urologists better counsel patients. However, there are several weaknesses CONCLUSIONS in the study. Urodynamic data, which were collected on all The ability to void predicts outcome of sacral neuromodula- patients, were not analyzed. Data from before and after test tion in patients with nonobstructive urinary retention. stimulation (volume voided, post-void residual, number of Those who were able to void at least 50 cc were more likely catheterizations required, etc) were not presented. Post-bat- to benefit from neuromodulation than patients who were tery implantation data (post-stage 2) were not presented and unable to void or voided less than 50 cc. These results may thus, we do not have any idea about the long-term success of allow better counseling of prospective patients. InterStim in these patients. Finally, the patient population is a hodgepodge of diagnoses making it difficult to hypothesize a consistent mechanism of action for this therapy. De- trusor sphincter dyssynergia is not associated with detrusor REFERENCES hyperactivity with impaired contractility. Furthermore, de- 1. Pettit PD, Thompson JR and Chen AH: Sacral neuromodula- trusor sphincter dyssynergia results in bladder outlet ob- tion: new applications in the treatment of female pelvic floor struction and, thus, probably should not be considered a dysfunction. Curr Opin Obstet Gynecol 2002; 14: 521. form of nonobstructive retention. 2. Shaker HS and Hassouna M: Sacral root neuromodulation in idiopathic nonobstructive chronic urinary retention. J Urol Toby C. Chai 1998; 159: 1476. Division of Urology 3. Jonas U, Fowler CJ, Chancellor MB, Elhilali MM, Fall M, University of Maryland School of Medicine Gajewski JB et al: Efficacy of sacral nerve stimulation for Baltimore, Maryland urinary retention: results 18 months after implantation. J Urol 2001; 165: 15. 4. Koldewijn EL, Rosier PFWM, Meuleman EJH, Koster AM, Debruyne FMJ and van Kerrebroeck PEV: Predictors of success with neuromodulation in lower urinary tract dysfunction: results of trial stimulation in 100 patients. J Urol 1994; REPLY BY AUTHORS 152: 2071. 5. Swinn MJ, Kitchen ND, Goodwin RJ and Fowler CJ: Sacral neuromodulation for women with Fowler’s syndrome. Eur We agree that our study does not lend to the understanding Urol 2000; 38: 439. of why InterStim works, which to date has not been eluci- 6. Leng WW and Chancellor MB: How sacral nerve stimulation dated despite intensive studies by previous investigators. neuromodulation works. Urol Clin North Am 2005; 32: 11. Rather, the main message of our report is the positive out- 7. DasGupta R and Fowler CJ: Urodynamic study of women in come following a first stage InterStim implant in patients urinary retention treated with sacral neuromodulation. J Urol 2004; 171: 1161. with chronic nonobstructive urinary retention, including 8. Scheepens WA, Jongen MM, Nieman FH, de Bie RA, Weil EH those with functional obstruction such as detrusor-sphincter and van Kerrebroeck PE: Predictive factors for sacral neuro- dyssynergia, and those without anatomic obstruction, such modulation in chronic lower urinary tract dysfunction. Urol- as BPH or bladder neck contracture and voided volumes ogy 2002; 60: 598. greater than 50 cc were associated. The Effects of Long-Term Administration of Oral Desmopressin on the Baseline Secretion of Antidiuretic Hormone and Serum Sodium Concentration for the Treatment of Nocturia: A Circadian Study

J. H. Bae, M. M. Oh, K. S. Shim, J. Cheon, J. G. Lee, J. J. Kim and D. G. Moon* From the Department of Urology, Korea University College of Medicine, Seoul, Republic of Korea

Purpose: We assessed the effects of long-term oral desmopressin on serum sodium and baseline antidiuretic hormone secretion in elderly patients with nocturia. Materials and Methods: A total of 15 elderly male patients with severe nocturia (greater than 3 voids nightly) who did not show hyponatremia within 7 days of administration of 0.2 mg desmopressin were enrolled in this study. Desmopressin (0.2 mg) was administered orally nightly for 1 year. Before and 1 month after the 1-year medication 24-hour circadian studies were performed to monitor changes in antidiuretic hormone. Every 3 months during the 1-year medication serum changes and timed urine chemistry were monitored. Results: Desmopressin significantly decreased nocturnal urine output and the number of nocturia episodes (p Ͻ0.01). Compared to before treatment desmopressin gradually decreased serum sodium and induced statistically but not clinically significant hyponatremia after 6 months of treatment. After discontinuing desmopressin serum sodium returned to the normal range in all patients. There were no significant differences when baseline and posttreatment endogenous antidiuretic hormone were compared. No serious systemic complications were found during medication. Conclusions: Long-term desmopressin administration gradually decreased the serum concentration and induced significant hyponatremia from 6 months in patients who did not show initial hyponatremia. Long-term administration of desmopressin for 1 year in elderly patients did not affect baseline antidiuretic hormone secretion. For long-term desmopressin administration serum sodium should be assessed regularly, at least every 6 months. Key Words: bladder, nocturia, deamino arginine vasopressin, hyponatremia, circadian rhythm

octuria is one of the most bothersome lower urinary Also, other potential hazards should be considered, such tract symptoms in a significant portion of the adult as the complication of ADH in negative feedback or with- N population. Lately to resolve this problem oral drawal syndrome after long DDAVP use, which is common DDAVP has been recommended as an effective alternative in the long-term use of steroid or opioids. Administration of for managing nocturia in adults. Earlier short-term studies these drugs induces a physiological negative feedback on the (3 weeks) of DDAVP for nocturia showed it to be safe and endogenous system, alterations in hormonal baseline values effective in patients with nocturia. Lose et al noted that and withdrawal syndrome after stopping the medication. DDAVP was well tolerated with 14% of patients withdraw- Accordingly we assessed whether long-term DDAVP ad- ing due to adverse events and most adverse events were ministration might change the blood and urine chemistry, mild at 1-year followup.1,2 resulting in hyponatremia in patients with nocturia but The most significant complication of DDAVP is hypona- without initial hyponatremia. We also determined whether tremia, which can occur within a week of starting therapy or baseline ADH and nocturnal urine output would return to increasing the dose.3 Also, the efficacy of oral DDAVP has the previous level after discontinuing DDAVP. been reported in patients with nocturia refractory to conventional treatments, even without nocturnal polyuria.4–6 PATIENTS AND METHODS Hence, it is inevitable to use DDAVP in the long term in patients with nocturia without initial hyponatremic compli- Patient Selection cations. Even if adverse symptoms are mild, it is important The current study was based on male patients older than 60 to know the electrolyte parameters of hyponatremia and years who visited our outpatient clinic with complaints of fluid overload in advance. nocturia or BPH symptoms. The selected patients had severe problematic nocturia that did not respond to conventional treatment, eg evening fluid restriction, BPH medica- Submitted for publication November 26, 2006. tion, anticholinergics or calcium antagonists. Patients were Study received approval from the Institutional Review Board of fully informed and consented to the study. The basic screen- Korea University Medical Center. ing test included a patient history, physical examination, * Correspondence: Department of Urology, Korea University Guro blood pressure measurement, digital rectal examination and Hospital, 80, Guro-dong, Guro-ku, Seoul 152-703, Republic of Korea (telephone: ϩ82-2-2626-3201; FAX: ϩ82-2-2626-1321; e-mail: a survey of BPH symptoms. Detailed examinations included [email protected]). transrectal ultrasonography, uroflowmetry, prostate specific

0022-5347/07/1781-0200/0 200 Vol. 178, 200-203, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.042 LONG-TERM ORAL DESMOPRESSIN 201 antigen, liver function test, blood glucose, urinalysis and urodynamic study. A total of 15 patients were selected who had nocturia more than 3 times nightly based on a 7-day voiding diary. For the standardization of terminology the International Continence Society deﬁnition from the Inter- national Continence Society Standardisation of Terminology Report 2002 was used in this study.7 Patients with cardiovascular disease, renal failure, liver failure, uncontrolled diabetes or urinary tract infections were excluded. Patients with initial hyponatremia, which developed within week 1 after oral administration of 0.2 mg DDAVP, were also excluded.

Methods of Study FIG. 1. Changes in serum Na during DDAVP administration for 1 year and 1 month after discontinuing DDAVP. Serum Na serially Patients were admitted to the hospital for 3 days for a decreased but not in clinical hyponatremia range except in 1 patient 24-hour circadian study before starting DDAVP. All medi- (Pt. 11). Levels returned to normal 1 month after stopping DDAVP. cations were restricted for 1 week before admittance. During AVR, mean serum Na in all 15 patients. hospitalization the urinary tract was catheterized and an intravenous sampling line was maintained in 1 arm for the 24-hour circadian study. Blood samples were taken at tional zone volume in 15 patients was 29.29 (range 11.17 to 11 p.m. of hospital admission day 2, and then at 2 a.m., 73.88) and 19.43 gm (range 6.13 to 49.61), respectively. 5 a.m., 8 a.m., 2 p.m. and 5 p.m. of day 3. In each serum Mean prostate specific antigen and free prostate specific sample blood urea nitrogen/creatinine, urea, nitrogen, glu- antigen were 2.25 Ϯ 1.94 and 0.09 Ϯ 0.62 ng/dl, respectively. cose, Na, K, Cl, Ca, P, Mg and uric acid were measured. On urodynamic study detrusor overactivity in 2 patients, Additionally, ADH was measured with a vasopressin 125I bladder outlet obstruction in 5 and detrusor hypocontractil- radioimmunoassay kit (DiaSorin, Stillwater, Minnesota). ity in 3 were documented. Detrusor overactivity was noted For the urine study urinary creatinine, urea, nitrogen, glu- in 13% of the patients (2 of 15). DDAVP administration did cose, Na, K, Cl, Ca, P, Mg, uric acid, osmolality and urine not affect the daily total urine volume but it significantly volume were measured. decreased nocturnal urine output from 621 Ϯ 265 to 441 Ϯ After the first hospital admission 0.2 mg DDAVP were 308 ml at month 12 (p Ͻ0.01). After stopping the medication administrated at bedtime every day for 1 year. We deter- nocturnal urine output returned to 750.8 Ϯ 414.7 ml mined this dose uniformly to make certain of the maximal (p Ͻ0.01). effect but 0.4 mg were not considered because it was inappropriate to prescribe as the initial dose. When patients Changes in Serum and Timed Urine were followed on an outpatient basis every 3 months, the Chemistry, and Circadian Variation in ADH 7-day voiding diary, blood sampling and 24-hour urine col- During medication the initial serum Na of 142.2 Ϯ 1.9 lection were requested to evaluate efficacy, and changes in mmol/l was significantly decreased to 136.0 Ϯ 4.27 mmol/l. serum and urine chemistry. After the 1 year of medication Serum Na serially decreased during 1 year but not in the DDAVP was discontinued for 1 month. Patients were hospi- range of clinical hyponatremia except in 1 patient, who did talized a second time and circadian studies were done again to not show any symptoms (fig. 1). Serum Na was reversibly assess changes in baseline ADH, serum and urine chemistry increased to 139.9 Ϯ 1.05 mmol/l at month 13 (p Ͻ0.05). The using the same protocol as at the initial hospitalization. other electrolyte parameters were not changed significantly. After discontinuing DDAVP at month 13 natriuresis with Statistics consequent increased urinary osmolality during medication The table, and figures 1 and 2 show data as the mean Ϯ SD returned to normal (see table). No significant systemic com- or range. Statistical comparisons were done using Student’s plications were found during medication. t test with results considered significant at p Ͻ0.05. At the first hospital admittance of 15 patients with nocturia mean ADH at 11 p.m. on day 2, and at 2 a.m., 5 a.m., RESULTS 8 a.m., 2 p.m. and 5 p.m. on day 3 was 0.7, 1.0, 0.80, 0.94, 0.9, 0.8, 0.85 and 0.7 pg/ml, respectively (fig. 2). At the second Mean age of the 15 patients was 68.6 years (range 60 to 84). hospitalization 1 month after stopping the 1-year medica- On transrectal ultrasonography total prostate and transition mean ADH was 0.66, 0.92, 0.85, 0.75, 0.88 and 0.78

Signiﬁcant parameters before, during and after DDAVP administration Mean Ϯ SD Before Mean Ϯ SD 3 Mos Mean Ϯ SD 6 Mos Mean Ϯ SD 9 Mos Mean Ϯ SD 12 Mos Mean Ϯ SD 13 Mos*

Serum Na (mmol/l) 142 Ϯ 1.94 140 Ϯ 1.70 139 Ϯ 2.04 139 Ϯ 2.54 136 Ϯ 4.27† 140 Ϯ 1.05‡ Serum K (mmol/l) 4.12 Ϯ 0.37 4.23 Ϯ 0.34 4.27 Ϯ 0.36 4.28 Ϯ 0.46 4.18 Ϯ 0.43 4.07 Ϯ 0.43 Serum Cl (mmol/l) 108 Ϯ 2.42 107 Ϯ 2.01 107 Ϯ 3.12 106 Ϯ 2.62 104 Ϯ 5.40 108 Ϯ 2.46 Urine Na (mmol/l) 186 Ϯ 81.1 203 Ϯ 49.4 170 Ϯ 64.5 190 Ϯ 82.6 209 Ϯ 63.7 157 Ϯ 65‡ Urine osmolality 496 Ϯ 119 505 Ϯ 165 434 Ϯ 138 516 Ϯ 158 513 Ϯ 157 390 Ϯ 79.3‡ (mOsm/kg) * One month after stopping DDAVP administration. † Before vs month 12 statistically signiﬁcant (p Ͻ0.05). ‡ Month 12 vs 13 statistically signiﬁcant (p Ͻ0.05). 202 LONG-TERM ORAL DESMOPRESSIN

and after 1-month DDAVP washout serum Na returned to the normal range. Continuous long-term administration of DDAVP might have caused a potential hazard, such as severe hyponatremia, which perhaps could be prevented by periodic drug holidays for 1 month. In this study voiding symptoms returned to the previous state after stopping the medication. We thought that this might have been due to the long duration of the pathological conditions, such as small bladder capacity, low compliance and emotional dose dependence. Thus, those patients must be anticipated to increase functional bladder capacity with anticholinergics or long-term use of DDAVP, unlike children. Therefore, it is important to identify and prevent complications in advance in patients with refractory nocturia and long-term DDAVP use. Another important consideration is hormonal imbalance during long-term hormonal therapy. Long-term use of steroids or opioids might induce a physiological negative feed- FIG. 2. ADH circadian variation in 15 patients before and 1 month after 1-year 0.2 mg DDAVP administration. ADH did not signifi- back on the endogenous system, alterations in hormonal cantly differ between 2 groups. Conc., concentration. baseline and withdrawal syndrome after stopping the medication. Although the long-term safety of oral DDAVP has been proved in children with nocturnal enuresis, there is pg/ml, respectively (fig. 2). ADH levels before medication still a lack of long-term safety data on DDAVP in elderly 1 were not significantly different from those 1 month after patients and adults with nocturia. The elderly and geriatric stopping the 1-year medication (fig. 2). populations are quite different from children in body composition and homeostasis. Those populations are more sus- DISCUSSION ceptible to hormonal and fluid imbalance because of underlying cardiovascular risk factors and the aging process. To The efficacy of DDAVP for nocturia is accepted but to our our knowledge there is no published report on the long-term knowledge long-term safety still is not established. Noctur- safety of oral DDAVP in elderly patients with nocturia in nal polyuria is not a main cause in all patients with nocturia terms of hormonal study. For more beneficial and symptom- and there is concern about the complications of hyponatre- atic treatment of nocturia with oral DDAVP we should have mia and fluid overload in the elderly population. However, proved the long-term safety of hormonal aspects in water most patients with nocturia can be treated safely with oral homeostasis, negative feedback and withdrawal symptoms DDAVP and in the few who are predisposed to hyponatremia of oral DDAVP. In the current study ADH levels before the condition almost invariably develops within a week of medication were not significantly different from those 1 starting therapy or increasing the dose.3 Also, DDAVP is an month after discontinuing the 1-year medication. Also, there antidiuretic agent but, unlike vasopressin, it does not di- was no specific withdrawal problem after stopping the med- rectly affect the cardiovascular system. The International ication. The level of antidiuresis varies directly with the Consultation on Incontinence committee highly recom- plasma concentration of arginine vasopressin and the kid- mended DDAVP for polyuria because there is clear evidence ney is sensitive to the antidiuretic effect of vasopressin. of its efficacy in children with nocturnal enuresis and in Slight changes in circulating levels of the hormone have adults with nocturia resulting from polyuria.8 In a study profound effects on urinary osmolality and urine flow.10 We with more than 25,000 patients Delfanian and Zawada re- also previously reported that selected patients with nocturia ported that the potential risk factors for hyponatremia fol- had nocturnal polyuria and natriuresis because they had no lowing DDAVP administration are hepatic disease, surgery, nocturnal increase in ADH in the circadian study. DDAVP stress, pain, renal disorder, excessive fluid intake and in- may be effective for decreasing nocturnal urine production creased DDAVP dose.9 They also emphasized that the po- in patients with severe nocturia who do not respond to tentially serious side effects, such as hyponatremia and sei- conventional treatment.4 zure, may be prevented by close monitoring of serum Our results demonstrate that DDAVP administration in electrolytes and urine output as well as by fluid restriction elderly patients for 1 year was safe and did not affect the and the avoidance of solutions with low Na content. Simi- baseline secretion of ADH, unlike negative feedback of other larly when we assessed patients during the 1-year medica- steroids or withdrawal syndrome of opioids. However, inclu- tion the initial serum Na of 142.2 Ϯ 1.9 mmol/l was serially sion criteria should be maintained to avoid serious compli- decreased to 136.0 Ϯ 4.27 mmol/l but not in the range of cations. clinical hyponatremia except in 1 patient. These results To our knowledge this is the first report of the long-term indicate that long-term DDAVP might induce gradual hypo- safety of oral DDAVP in elderly patients based on circadian natremia and serum Na should be assessed carefully even in study. Although this study is comprehensive in terms of patients without initial hyponatremia. Based on our results hormonal aspects and hyponatremia during long-term oral serum Na must be evaluated regularly, at least at 6 months, DDAVP use, the major limitations are the small number of and in patients with hyponatremic Na it is important to stop enrolled patients and the still short period of 1 year for the medication via washout. In 1 patient with hyponatremia long-term study. We will continuously follow these patients in this study there were no serious hyponatremic symptoms and try to increase the number of patients. LONG-TERM ORAL DESMOPRESSIN 203

CONCLUSIONS 2. Lose G, Mattiasson A, Walter S, Lalos O, van Kerrebroeck P, Abrams P et al: Clinical experiences with desmopressin for Long-term DDAVP administration for 1 year in elderly pa- long-term treatment of nocturia. J Urol 2004; 172: 1021. tients did not affect baseline ADH secretion. Long-term 3. Abrams P, Mattiasson A, Lose GR and Robertson GL: The role DDAVP therapy gradually decreased serum Na and it might of desmopressin in the treatment of adult nocturia. BJU induce hyponatremia even in patients without initial hypo- Int, suppl., 2002; 90: 32. natremia. For long-term DDAVP administration serum Na 4. Moon DG, Jin MH, Lee JG, Kim JJ, Kim MG and Cha DR: should be assessed carefully, at least at 6 months. In pa- Antidiuretic hormone in elderly male patients with severe tients with hyponatremia that develops during DDAVP ad- nocturia: a circadian study. BJU Int 2004; 94: 571. 5. Asplund R, Sundberg B and Bengtsson P: Oral desmopressin ministrationa1to4-week washout period could be consid- for nocturnal polyuria in elderly subjects: a double-blind, ered for recovery of serum Na and native ADH secretion. placebo controlled randomized exploratory study. BJU Int 1999; 83: 591. 6. Kuo HC: Efﬁcacy of desmopressin in treatment of refractory Abbreviations and Acronyms nocturia in patients older than 65 years. Urology 2002; 59: 485. ϭ ADH antidiuretic hormone 7. van Kerrebroeck P, Abrams P, Chaikin D, Donovan J, Fonda D, ϭ BPH benign prostatic hyperplasia Jackson S et al: The standardisation of terminology in ϭ DDAVP desmopressin nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 179. REFERENCES 8. Andersson KE: The pharmacological treatment of nocturia. BJU Int, suppl., 2002; 90: 25. 1. Lose G, Lalos O, Freeman RM, van Kerrebroeck P and Noctu- 9. Delfanian K and Zawada ET Jr: DDAVP-associated hypona- ria Study Group: Efﬁcacy of desmopressin (Minirin) in the tremia. SDJ Med 2001; 54: 255. treatment of nocturia: a double-blind placebo-controlled 10. Norgaard JP: Pathophysiology of nocturnal enuresis. Scand study in women. Am J Obstet Gynecol 2003; 189: 1106. J Urol Nephrol, suppl., 1991; 140: 1. The Surgical Management of Obstructive Stents Used for Urethral Strictures

Abdelwahab A. Elkassaby, Ahmed M. Al-Kandari and Ahmed A. Shokeir* From the Department of Urology, Ain Shams University (AAE), Cairo and Urology and Nephrology Center (AAS), Mansoura, Egypt, and Department of Surgery (Urology), Adan Hospital, Kuwait University (AMAK), Safat, Kuwait

Purpose: We present our referral experience with patients who had extensive urethral obstruction following UroLume® insertion and were treated with urethroplasty. Materials and Methods: We retrospectively analyzed the records of 13 men with urethral stricture who experienced recurrent obstruction following placement of a UroLume endoprosthesis. In all patients several attempts at urethral dilation and optical urethrotomy failed to overcome the obstruction. Complete excision of the obstructed urethra containing the stent with the surrounding periurethral fibrosis was done in all patients. In 12 patients a 1-stage bipedicled penile island tubularized flap was used to bridge the urethral defect. In 1 patient 1-stage urethroplasty was performed and he is awaiting stage 2. Followup assessment included urine flow, post-void residual urine measurement, retrograde urethrogram and urethroscopy at different intervals. Results: Of the 12 patients who underwent complete treatment 1 had a short segment stricture at the site of the distal anastomosis 3 months after catheter removal, which was successfully managed by internal urethrotomy. He was doing well at the 12-month followup. In 11 patients a successful outcome was noted immediately after catheter removal and it was maintained at a mean followup of 1.8 years (range 1 to 4). Conclusions: Complete excision of the obstructed urethra containing the UroLume stent with the surrounding periurethral fibrosis is an important first step in reconstruction. Subsequent use of a 1-stage bipedicled penile island tubularized flap resulted in excellent long-term results. In a small subset of cases delayed stage 2 repair after skin inlay is a valuable option. Key Words: urethra, stents, urethral obstruction, prostheses and implants, urethral stricture

reatment for complex and recurring urethral stric- scopic treatment by the referring urologists. Upon arrival to tures is a hotly debated topic among urologists. Some us the degree and extent of narrowing were so severe that T patients, especially when young and sexually active, we elected complete surgical urethral reconstruction as de- find it difficult to accept self-catheterization or periodical finitive treatment. To our knowledge the current report is dilation. Introduction of the UroLume prosthesis for recur- the largest ever reported in the urological literature on re- ring and nonresponsive urethral strictures has opened a constructive urethral surgery for obstructive UroLume new frontier in the minimally invasive treatment of poste- stents applied for urethral strictures. rior urethral stricture.1 The stent was developed for the endovascular prevention of recurrent arterial narrowing af- MATERIALS AND METHODS ter balloon angioplasty. Following experimental use of this device in dogs Milroy et al reported early results in the first We retrospectively analyzed the records of 13 men with ure- 2 8 patients. The application of UroLume prostheses was thral stricture who experienced recurrent obstruction following initially reserved for patients older than 50 years who placement of a UroLume endoprosthesis from March 2001 to were unfit or who refused bulbar urethroplasty. Initial August 2005. All patients were referred to 1 urologist (AAE) for 1–4 results were encouraging. Therefore, indications for the persistent or recurrent symptoms of voiding dysfunction fol- UroLume were extended to include younger, fit patients lowing insertion of the primary UroLume by a different urolo- with urethral strictures to replace repeat internal urethrot- gist. omies and more complicated urethroplasty operations.4 Nev- ertheless, long-term results were not satisfactory and more recent studies showed a high complication rate.5–8 Patients We present our referral experience with 13 patients who Mean patient age at stent insertion was 36 years (range 25 experienced significant urethral obstruction following to 57). Patients underwent a mean of 2.1 previous treat- UroLume insertion with failed multiple attempts at endo- ments (range 2 to 4) for urethral stricture. All men previously underwent urethrotomy and/or urethral dilation, and 1 underwent previous anastomotic urethroplasty to repair posttraumatic disruption of the posterior urethra. The anas- Submitted for publication November 6, 2006. tomotic site was a seat of obstruction that was unresponsive * Correspondence: Urology and Nephrology Center, Mansoura University, Mansoura, Egypt (telephone: (20) (50-2262222); FAX: to repeat attempts at internal urethrotomy. The most com- (20) (50-2263717); e-mail: [email protected]). mon cause of urethral stricture was iatrogenic, arising after

0022-5347/07/1781-0204/0 204 Vol. 178, 204-207, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.023 SURGICAL MANAGEMENT OF OBSTRUCTIVE STENTS FOR URETHRAL STRICTURE 205

thesia in 10 cases and general anesthesia in 3. The patient Urethral stricture etiology and anatomical site was placed in the lithotomy position and a midline perineal No. Pts. (%) incision with ␭ lower extensions was made. A significant Etiology: amount of fibrosis was noted. After circumferential dissec- Iatrogenic 7 (53) tion of the bulbar urethra excision of the obstructed urethra, Idiopathic 1 (8) Traumatic 3 (23) including the stent, was performed and sent for histopatho- Infectious 1 (8) logical examination. The 2 ends of the urethra were widely Congenital 1 (8) spatulated for a minimum of 1 cm at either end. Based on Anatomical site: Bulbar 12 (92) the length of the urethral defect and the available nonhairy Bulbomembranous 1 (8) suite ventral penile skin 1-stage repair was feasible in 12 cases. This was done using a bipedicled ventral nonhairy suite penile skin flap measuring an average of 3 ϫ 6to8cm, endoscopic surgery or after an indwelling catheter, and most which was mobilized down with long penile and dartos strictures were bulbar in position (see table). The interval pedicles and then tubularized over a 24Fr urethral catheter between symptoms and initial UroLume insertion was 2 to (fig. 2). We used 5-zero polyglactin sutures to close the tube 18 months. The length of the preexisting stricture before the and then anastomosed to the 2 spatulated urethral ends. UroLume was initially placed was not known. An 18Fr silicon urethral catheter was inserted at the end All patients had stent obstruction due to recurrent stric- of the procedure and a small perineal vacuum drain was left ture. In all patients several attempts at urethral dilation in the area. In all patients a 16F suprapubic and a urethral and optical urethrotomy failed to overcome the obstruction. catheter were placed, and the dressing was applied. In a case They underwent a mean of 2.6 previous treatments (range 2 of long bulbar urethral stricture post-posterior urethral re- to 5) for stent obstruction before referral to us. Upon pre- pair we elected a staged approach due to the increased sentation to us 10 patients had severe obstructive voiding length of the urethral defect to be bridged (8 cm) and the symptoms, as confirmed by a marked decrease in the maxi- nonavailability of enough nonhairy suite penile skin. In this mum flow rate (mean Ϯ SD 4.8 Ϯ 3.2 ml per second) and case stage 1 was the same as described. increased post-void residual urine (mean 120 Ϯ 30 ml). A ventral nonhairy penile island flap was then laid down Three patients were in urinary retention and required su- as an inlay between the roof of the 2 urethral ends over the prapubic catheter insertion. ventral aspect of the corporeal bodies and sutured to the The interval at which symptoms developed after adjacent scrotal and perineal skin edges. This patient awaits UroLume insertion was 8 to 18 months. At this time we stage 2 repair 6 months after stage 1. The urethral and began dealing with the obstructed UroLume. In all pa- suprapubic catheters were maintained for 3 weeks. Peri- tients retrograde urethrogram confirmed significant ure- catheter urethrogram was done and confirmed no extrava- thral obstruction (fig. 1). Stricture location was bulbar in sation in the 12 cases that were completed. 12 patients and bulbomembranous in 1. The strictures were 3 to 5 cm long. Followup Followup assessment included urine flow and post-void re- Surgical Technique sidual urine measurement by ultrasound every 3 months for Each patient received broad-spectrum antibiotic coverage the first year and once yearly thereafter. Retrograde ure- preoperatively. The procedure was done using spinal anes- throgram was performed in all cases at 3 months postoper-

FIG. 1. Preoperative urethrogram shows stent and degree of nar- FIG. 2. Tubularized ventral penile island flap used to bridge ure- rowing. thral gap. 206 SURGICAL MANAGEMENT OF OBSTRUCTIVE STENTS FOR URETHRAL STRICTURE atively and selectively thereafter. Urethroscopy was done at itive results of the UroLume for urethral strictures.1–4 How- 6 months and when needed thereafter. ever, long-term studies describe significant complications, including poor epithelialization, stent separation, hyperplastic RESULTS tissue growth and encrustation or obstruction that necessitate stent removal.5–8 In a report by Hussain et al 55% of cases had Of the 13 patients 12 underwent complete urethral recon- complications and 45% required reoperation.6 struction and 1 underwent stage 1 urethroplasty and is Wilson et al reported recurrent stricture formation and awaiting final reconstruction in the next 2 months. Of the 12 the need for reoperation in most of their cases of UroLume patients who received complete treatment 1 had a short stents used for stricture, and they pointed out that surgery segment stricture at the site of the distal anastomosis 3 is difficult in this subgroup of patients at risk for bleeding.5 months after catheter removal, which was successfully man- Others reported long-term UroLume results for urethral aged by internal urethrotomy. He was doing well at the strictures. They described higher repeat stricture and ob- 12-month followup. In 11 patients a successful outcome was struction rates in patients with extensive periurethral fibro- noted immediately after catheter removal, which was main- sis and considered it unsuitable for these patients.10 tained at a mean followup of 1.8 years (range 1 to 4). Eight When faced with UroLume stent stricture or obstruction, of the 11 patients were followed for 12 to 24 months and the different endoscopic manipulations, including dilation, ure- remaining 3 maintained followup for 25 to 48 months. throtomy and hyperplastic tissue resection, can be done, Followup investigations in all 11 patients mentioned re- especially when the lumen is still open.6 On the other hand, vealed improved urine flow (mean Ϯ SD 19.5 Ϯ 7mlper complete urethral obstruction due to the UroLume is more second) and decreased post-void residual urine (mean Ϯ SD challenging. Some investigators reported endoscopic use of a 35 Ϯ 15 ml). Urethrograms and urethroscopies revealed no holmium laser to cut through the obstructing tissue until the obstruction at 3 and 6 months postoperatively, respectively stent was seen, and subsequently cut and removed.11,12 (fig. 3). These were scattered case reports reflecting the difficulty of Two patients had a febrile urinary tract infection a few this situation. Recently some groups described the surgical days after catheter removal, which was managed success- approach to this difficult situation. Parson and Wright fully by antibiotics. None of the patients had wound compli- reported 3 cases of transperineal excision of occluded cations. Histopathological examination of the excised ure- UroLume stents and 1-stage reconstruction with a success- thra revealed extensive urethral and periurethral fibrosis ful outcome.13 Most recently Zinman et al reported on 7 with a severe chronic inflammatory reaction surrounding patients who had obstructive symptoms and were treated the metal wires of the stent. with simple open urethrotomy, extraction of the stent wires and a dorsal onlay buccal mucosal graft with an excellent DISCUSSION outcome.14 In our study to our knowledge we report the largest series The UroLume metal stent was introduced in 1987 to treat 2,9 to date of reconstructive urethral surgery for obstructive urethral strictures. This stent was inserted via urethros- UroLume stents applied for urethral stricture. We found in copy. It aimed to keep the stricture open and subsequently all of these patients that complete circumferential excision correct obstructive voiding symptoms. Early studies show pos- of the obstructed urethra, including the stent, is an important step in this subgroup with severe obstruction and fibrosis. Use of a ventral bipedicled penile nonhairy skin flap, which was tubularized to compensate for the urethral defect, provided excellent long-term results in our patients. It is still acceptable to consider a staged approach in some further difficult situations, in which an inlay skin flap was used as stage 1, followed by complete tubularization and closure later. An intact prepuce in some patients obviates the need for staged procedures. We believe that the application of the UroLume prosthesis should be reserved for older patients who are unfit or who refuse urethroplasty.

CONCLUSIONS Complete excision of the obstructed urethra containing the UroLume stent with the surrounding periurethral fibrosis is an important first step in reconstructing this difficult condition. Subsequent placement of a 1-stage bipedicled penile island tubularized flap resulted in excellent long-term results. In a small subset of cases delayed stage 2 repair after skin inlay is a valuable option.

REFERENCES

1. Scarpa RM, De Lisa A, Porru D, Paulis M and Usai E: Urolume FIG. 3. Urethrogram 3 months postoperatively reveals excellent double prosthesis in the treatment of complex urethral stric- patent urethra. tures: a 5-year follow-up case report. Urology 1997; 50: 459. SURGICAL MANAGEMENT OF OBSTRUCTIVE STENTS FOR URETHRAL STRICTURE 207

2. Milroy EJG, Cooper RJE, Wallsten H, Chapple CR, El-din A 9. Parikh AM and Milroy EJ: Precautions and complications in and Seddon AM: A new treatment for urethral strictures. the use of the Urolume wall stent. Eur Urol 1995; 27: 1. Lancet 1988; 1: 1424. 10. Milroy E and Allen A: Long term results of UroLume ure- 3. Badlani GH, Press SM, Defalco A, Oesterling JE and Smith thral stent for recurrent urethral stricture. J Urol 1996; AD: Urolume endourothelial prosthesis for the treatment of 155: 904. urethral stricture disease: long term results of the North 11. Gupta NP and Ansari MS: Holmium laser core through inter- American Multicenter UroLume trial. J Urol 1995; 45: 846. nal urethrotomy with explantation of Urolume stent. An 4. Ashken MH, Coulange C, Milroy EJG and Sarramon JP: Eu- ideal approach for complicated posterior urethral stricture. ropean experience with the urethral wall stent for urethral Int J Urol 2004; 1: 343. strictures. Eur Urol 1991; 19: 181. 12. Kural AR, Tufek I, Akpinar H and Gurtug A: Removal of 5. Wilson TS, Lemack GE and Dmochowski RR: UroLume stents: Urolume endoprosthesis using holmium:YAG laser. J lessons learned. J Urol 2002; 167: 2477. Endourol 2001; 15: 947. 6. Hussain M, Greenwell TJ, Shah J and Mundy A: Long term 13. Parson JK and Wright EJ: Extraction of Urolume endopros- results of self-expanding wallstent in urethral stricture. thesis with one-stage urethral reconstruction. Urology BJU Int 2004; 94: 1037. 2004; 64: 582. 7. Corujo M and Badlani GH: Epithelialization of permanent 14. Zinman LN, Stoffel JT and Malone M: Simpliﬁed UroLume stents. J Endourol 1997; 11: 477. stent removal with urethral preservation and dorsal buccal 8. Corujo M and Badlani GH: Uncommon complications of per- graft only (or without segmental urethrectomy). J Urol, manent stents. J Endourol 1998; 12: 385. suppl., 2006; 175: 40, abstract 124. Relationship Between the Integrity of the Pelvic Floor Muscles and Early Recovery of Continence After Radical Prostatectomy

Cheryn Song, Chin Kyung Doo, Jun-Hyuk Hong, Myung-Soo Choo, Choung-Soo Kim and Hanjong Ahn* From the Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

Purpose: We investigated how the preoperatively estimated integrity of pelvic floor muscles related to the recovery of continence after radical prostatectomy. Materials and Methods: A total of 94 patients underwent magnetic resonance image of the prostate and urodynamic studies before undergoing radical prostatectomy and evaluation of voiding symptoms before, and 3 and 6 months after surgery. Incontinence was defined as any unwanted urine leakage. On the magnetic resonance image the thickness of the levator ani and pelvic diaphragm, and prostate volume were measured to correlate with continence status. Results: Incontinence was noted in 41.5% and 15.9% of the patients at 3 and 6 months, respectively. Recovery of continence 3 months after RP was related to the thickness of the pelvic diaphragm on sagittal imaging (p ϭ 0.017), the ratio of the levator ani on the axial image to prostate volume (p ϭ 0.047), functional urethral length (p ϭ 0.007) and incontinence before surgery (p ϭ 0.009). Recovery at 6 months was related to neurovascular bundle sparing (p ϭ 0.013) and marginally to the pelvic diaphragm on sagittal imaging (p ϭ 0.059). On multivariate analysis the pelvic diaphragm on sagittal imaging (HR 2.455, 95% CI 0.894–6.739, p ϭ 0.008) and the ratio of the levator ani on the axial image to prostate volume (HR 1.886, 95% CI 0.952–3.736, p ϭ 0.011) significantly predicted continence at 3 months, while at 6 months only the pelvic diaphragm on sagittal imaging showed a significant relationship (p ϭ 0.024). Conclusions: Pelvic diaphragm thickness and the ratio of levator ani thickness to prostate volume are independent factors predictive of post-prostatectomy incontinence. Patients with better developed pelvic floor muscles, especially in relation to the size of the prostate, can be expected to achieve earlier recovery of continence after radical prostatectomy. Key Words: prostate, prostatectomy, urinary incontinence, pelvic floor, muscles

adical prostatectomy is the definitive treatment of should be achieved according to the factors intrinsic to each choice for patients with localized prostate cancer and patient, which are predetermined before prostatectomy. R it is an integral part of comprehensive treatment for Delancey originated the hammock theory explaining fe- patients with locally advanced prostate cancer.1 Through male stress urinary incontinence.5 In his theory loosening of the expansion of anatomical knowledge and advancement of the various pelvic floor muscles and adjacent fascia support- surgical technique morbidity and issues affecting quality of ing the pelvic organs accounts for urinary incontinence. In life after the surgical procedure have consistently decreased. light of this theory we conjectured that the continence mech- Nonetheless, post-prostatectomy incontinence is reported in anism in men shortly after prostatectomy could similarly be 6% to 20% of the patients and it remains the most troubling explained since we have noted considerable differences side effect of the operation.2–4 The actual incidence may among patients in the bulk and compactness of the pelvic vary depending on the definition of urinary incontinence and muscles during surgical dissection. We investigated how the timing as well as on the method of evaluation, and yet it is preoperatively estimated integrity and intrinsic develop- agreed that a substantial proportion of patients always ex- ment status of the pelvic floor muscles are related to the perience incontinence. Intriguingly it is also accepted that recovery of continence after RP. there always is a group of patients without any urine leakage from the early postoperative period. If progressive recovery of continence 9 to 12 months after surgery is due to MATERIALS AND METHODS functional adaptation of the remaining structures in the Between September 2003 and December 2004, 94 patients continence mechanism, immediate continence control with a mean age of 65 years (range 50 to 77) who underwent RP agreed to participate in the current prospective study Submitted for publication November 28, 2006. and provided written informed consent. One to 2 weeks Study received approval from the Asan Medical Center internal before operation systematic multichannel urodynamic study review board. with pressure flow study according to the standards of the * Correspondence: Department of Urology, University of Ulsan 6 College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, International Continence Society and MRI of the prostate Songpa-gu, Seoul, Republic of Korea 138-736 (telephone: 822-3010- were performed in all patients. To evaluate voiding symp- 3733; FAX: 822-477-8928; e-mail: [email protected]). toms and urinary incontinence each patient was interviewed For another article on a related topic see page 332. by a single specialist nurse before the operation, which was

0022-5347/07/1781-0208/0 208 Vol. 178, 208-211, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.044 PELVIC FLOOR MUSCLE INTEGRITY AND CONTINENCE AFTER PROSTATECTOMY 209 repeated at 3 and 6 months using the International Conti- TABLE 1. Thickness parameters and volume adjusted nence Society Questionnaire for Male. For the current anal- counterparts measured on MRI ysis incontinence was defined as any unwanted urine leak- Ϯ age (score 1 or greater on the questionnaire). Parameters Mean SD MRI images were reviewed separately by 2 of us (CS and Pelvic floor thicknesses (ϫ 10Ϫ2 mm): Ϯ CKD) blinded to clinical and pathological findings as well as LAc 177.1 37.0 Coronal PSc 113.6 Ϯ 29.6 to postoperative continence status. LA thickness was mea- PDc 83.1 Ϯ 22.9 sured from the maximal length converging on the urethra on PDs 93.2 Ϯ 30.2 LAa 131.5 Ϯ 26.2 the coronal image or on the axial image immediately caudal Prostate vol (ml) 28.1 Ϯ 11.3 to the prostate apex. PD thickness was measured on the Vol adjusted parameters (ϫ 10Ϫ2 mm/ml): coronal and sagittal images. PSc was measured as the dis- LAc/prostate vol 7.12 Ϯ 2.83 PSc/prostate vol 4.58 Ϯ 1.99 tance between the urethral midline and the lateral margin PDc/prostate vol 3.32 Ϯ 1.24 of the converging LA muscle on the coronal image (fig. 1). PDs/prostate vol 3.70 Ϯ 1.45 Ϯ Prostate volume was calculated on the axial image by volu- LAa/prostate vol 5.30 2.17 metric conversion after measuring the area on each section. Mean values of each of the 2 independently read parameters were used for statistical analysis. thickness parameters only volume adjusted LAa showed a Student’s t test was used to compare urodynamic and significant difference between the continent and inconti- ϭ MRI parameters between continent and incontinent pa- nent groups (p 0.047, fig. 2). Incontinence before surgery tients at each corresponding time point. The chi-square test also contributed to persistent incontinence at 3 months ϭ was used to analyze clinical and surgical factors, and mul- (p 0.009). On urodynamic study functional urethral length tiple regression analysis was used for multivariate analysis. was longer and continent zone area was larger in patients ϭ Using the ROC curve we determined cutoff values for pre- who were continent at 3 months (p 0.007 and 0.012, dicting continence status. To confirm interrater reliability respectively, table 2). Patient age, clinical/pathological stage between the 2 MRI measurements we performed ␣ scale and neurovascular bundle sparing status were similar and reliability analysis using a 2-way random effects model for did not show a significant relationship with continence re- absolute agreement definition. Intraclass correlation coeffi- covery at 3 months. cients for LAc, LAa, PDc, PDs and PSC were 0.9171, 0.8753, 0.9642, 0.8986 and 0.8862, respectively. All statistical anal- Recovery of Continence 6 Months After RP ysis was done using SPSS®, version 11.5 with p Յ0.05 Of the thickness parameters and volume adjusted parame- considered significant. ters only PDs showed a marginal difference between continent and incontinent patients (103.6 ϫ 10Ϫ2 vs 84.8 ϫ 10Ϫ2 ϭ RESULTS mm, p 0.059). Preoperative incontinence also showed marginal significance (p ϭ 0.050). Notably neurovascular bundle Median serum prostate specific antigen was 9.3 ng/ml (range sparing contributed significantly to continence recovery at 6 1.8 to 42.0) and median Gleason score was 7. Pathological months (no vs unilateral vs bilateral sparing p ϭ 0.013). stage was T2 in 57 patients (60.6%) and T3 in 37 (39.4%). Urodynamic parameters and clinical/pathological stage was Average Ϯ SD prostate volume estimated on MRI was similar among the patients. 28.06 Ϯ 11.25 ml. Table 1 lists thickness parameters measured on MRI and their volume adjusted counterparts. In- Multivariate Analysis continence was noted in 15.9%, 41.5% and 15.9% of the PDs (HR 2.455, 95% CI 0.894–6.739, p ϭ 0.008) and LAa/ patients before, and 3 and 6 months after surgery with prostate volume (HR 1.886, 95% CI 0.952–3.736, p ϭ 0.011) concomitant urge incontinence in 12.8%, 8.5% and 3.2%, significantly predicted continence at 3 months, while at 6 respectively. months only PDs showed a significant relationship (HR 3.120, 95% CI 0.946–10.295, p ϭ 0.024). Return of conti- Recovery of Continence 3 Months After RP nence 3 months after surgery could be expected when PDs All thickness parameters tended to be higher in patients was 0.875 cm or higher (75.9% sensitivity and 57.8% speci- without incontinence, although significance was observed ficity) or the LAa-to-prostate volume ratio was 4.693 cm/ml only in PDs (p ϭ 0.017, fig. 2). Similarly of volume adjusted or higher (64.7% sensitivity and 52.6% specificity). When

FIG. 1. MRI shows measurement of pelvic ﬂoor muscle thickness parameters 210 PELVIC FLOOR MUSCLE INTEGRITY AND CONTINENCE AFTER PROSTATECTOMY

FIG. 2. Thickness parameters and prostate volume adjusted thickness parameters in continent vs incontinent patients 3 months after RP. Asterisk indicates p ϭ 0.017. Dagger indicates p ϭ 0.047.

PDs was 0.855 cm or higher, continence at 6 months could be most study participants regaining continence 1 year postop- expected (68.4% sensitivity and 59.5% specificity). eratively regardless of the exercise. Difference in the continence rates between patients on and not on exercise was DISCUSSION maximum at 3 months and significant until 6 months but similar thereafter. These results are in accordance with the In the course of apical and urethral dissection during RP it current study, confirming that the intrinsic integrity of the may be noted that the pelvic floor muscles converging on pelvic floor muscles determine and voluntary contraction these structures are densely packed and tightly adherent in exercises promote early recovery of continence. some patients, while in others they are more loose arrays Alternatively surgical modification to preserve the abutting the urethra and are easily wiped off. Moreover, rhabdosphincter has also been shown to promote early although almost every patient regains full bladder control 9 recovery. Rocco et al reported that restoring the posterior to 12 months after surgery, there are always patients who aspect of the urethral sphincter before urethrovesical are continent even immediately after catheter removal. We anastomosis markedly decreased time to continence.10 verified whether such intrinsic differences in the develop- Six months after RP continence was most closely related ment status of the pelvic floor muscles supporting the ure- to neurovascular bundle sparing status, while other anatom- thra affect the recovery or interval to recovery of continence ical variables were not as contributory. Neurovascular bun- after RP. dle sparing was reported to result in an improved continence Our results show that the degree of pelvic floor muscle rate11,12 and its relationship to intraurethral pressure was development determines the recovery of continence 3 13 months after RP, which agrees with the anatomical under- demonstrated. By preserving the pelvic plexus and standing of the male urethral sphincter complex. The male branches providing autonomic and/or motor innervation to sphincteric complex consists of the proximal sphincter unit the rhabdosphincter during nerve sparing prostatectomy (bladder neck, prostate and prostatic urethra to the veru- earlier recovery of sphincteric function can be anticipated 14 montanum) and the distal sphincter unit (rhabdosphincter, with functional recovery of these nerves. Based on obser- paraurethral skeletal musculature and supporting fascial vations of the recovery of erectile function after nerve spar- investments).7 After radical removal of the prostate gland ing prostatectomy the restoration of this spared nerve func- continence control is determined by the integrity of the tion occurred a median of 12 months after surgery, which is remaining distal sphincteric unit, of which paraurethral the postulated time required for functional recovery from 13 support by the LA and its voluntary contractile pressure neuropraxic injury, in addition to anatomical integrity. In have the most significant role in the immediate postopera- the same manner the return of neural control of the urethral tive period. sphincter may require a certain period, as demonstrated in In this context the impact of Kegel exercises targeted to the current study. Moreover, we believe that the surgical enhance the pelvic floor musculature and increase urethral technique of sparing the neurovascular bundles may help de- resistance on post-RP incontinence was investigated in pre- crease iatrogenic mechanical injury to the rhabdosphincter. vious studies.8,9 Notably the beneficial effect of these exer- Recent evidence supports the notion that post-RP incon- cises was unvaryingly limited only to early recovery with tinence is in large part secondary to intrinsic sphincter

TABLE 2. Urodynamic parameters in continent vs incontinent patients at each postoperative time 3 Mos 6 Mos Urodynamic Parameters Continent Incontinent Sig. Continent Incontinent Sig.

No. pts (%) 55 (58.5) 39 (41.5) 79 (84.1) 15 (15.9) Ϯ Ϯ Ϯ Ϯ Max urethral closing pressure (cm H2O) 65.6 18.9 62.1 15.2 0.334 66.1 17.9 60.2 15.1 0.255 Functional urethral length (mm) 49.4 Ϯ 20.8 40.5 Ϯ 9.1 0.007 46.1 Ϯ 17.7 41.3 Ϯ 8.5 0.324 Ϯ Ϯ Ϯ Ϯ Continent zone area (cm H2O/mm) 1035.5 467.7 830.3 284.3 0.012 984.1 443.6 836.5 254.3 0.099 Max cystometric capacity (ml) 391.3 Ϯ 87.6 394.2 Ϯ 99.9 0.882 387.7 Ϯ 82.5 388.2 Ϯ 121.3 0.988 No. detrusor instability (%) 24 (45.3) 18 (46.2) 0.844 28 (35.4) 8 (53.3) 0.162 No. decreased compliance (%) 10 (18.9) 6 (15.4) 0.811 11 (13.9) 3 (20.0) 0.892 PELVIC FLOOR MUSCLE INTEGRITY AND CONTINENCE AFTER PROSTATECTOMY 211 deficiency.15,16 Coakley et al measured membranous ure- 3. Catalona WJ, Carvalhal GF and Mager DE: Potency, conti- thral length on preoperative MRI and noted that a longer nence and complication rates in 1870 consecutive radical membranous urethra was associated with more rapid return prostatectomies. J Urol 1999; 162: 433. of continence.17 It is conceivable that they could not deter- 4. Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson mine a significant, distinctive cutoff from their results be- RA, Eley JW et al: Urinary and sexual function after radical cause it could not be predicted how much of the preopera- prostatectomy for clinically localized prostate cancer: the tively measured urethral length would remain after Prostate Cancer Outcomes Study. JAMA 2000; 283: 354. 5. DeLancey JO: Structural support of the urethra as it relates to prostatectomy. Continence is maintained by the structures stress urinary incontinence: the hammock hypothesis. Am J that remain after RP. The pelvic floor muscles not only Obstet Gynecol 1994; 170: 1713. remain relatively unaffected by the surgical procedure, but 6. Schafer W, Abrams P, Liao L, Mattiasson A, Pesce F, Spangberg they also become the key structures in the continence mech- A et al: Good urodynamic practices: uroflowmetry, filling anism after surgery. Our urodynamic parameter results cystometry, and pressure-flow studies. International Con- (that functional urethral length and continent zone area are tinence Society. Neurourol Urodyn 2002; 21: 261. significantly related to continence at 3 months but not inde- 7. Burnett AL and Mostwin JL: In situ anatomical study of the pendently predictive) can similarly be explained. The timing male urethral sphincteric complex: relevance to continence of continence evaluation is also worth mentioning because preservation following major pelvic surgery. J Urol 1998; these anatomical factors were determinants only of early 160: 1301. recovery, becoming relatively insignificant with increasing 8. Parekh AR, Feng MI, Kirages D, Bremner H, Kaswick J and time after surgery. Aboseif S: The role of pelvic floor exercises on post-prostate- Another factor in continuous debate is whether a larger ctomy incontinence. J Urol 2003; 170: 130. prostate does18 or does not15,19 adversely affect continence. 9. Filocamo MT, Li Marzi V, Del Popolo G, Cecconi F, Marzocco Our results demonstrate that, rather than absolute prostatic M, Tosto A et al: Effectiveness of early pelvic floor rehabil- size, the relative ratio of prostate volume to its supporting itation treatment for post-prostatectomy incontinence. Eur pelvic floor muscles is the pivotal factor for early continence Urol 2005; 48: 734. 10. Rocco F, Carmignani L, Acquati P, Gadda F, Dell’Orto P, Rocco control and patients with thicker pelvic floor muscles in B et al: Restoration of the posterior aspect of rhabdosphinc- relation to prostate sizes can be expected to recover conti- ter shortens continence time after radical retropubic pros- nence at 3 months. However, in our study the volume ad- tatectomy J Urol 2006; 175: 2201. justed parameter showed lower significance than the MRI 11. Wei JT, Dunn RL, Marcovich R, Montie JE and Sanda MG: parameter statistically. This may be attributable to the Prospective assessment of patient reported urinary conti- small prostates with little variability (mean volume 28 Ϯ 11 nence after radical prostatectomy. J Urol 2000; 164: 744. ml) of our study participants, which is a finding common in 12. Nelson CP, Montie JE, McGuire EJ, Wedemeyer G and Wei JT: Asian men.20 Intraoperative nerve stimulation with measurement of urethral sphincter pressure changes during radical retropubic CONCLUSIONS prostatectomy: a feasibility study. J Urol 2003; 169: 2225. 13. Narayan P, Konety B, Aslam K, Aboseif S, Blumenfeld W and PD thickness and the ratio of LA thickness to prostate Tanagho E: Neuroanatomy of the external urethral sphinc- volume, as measured on prostate MRI, are independent ter: implications for urinary continence preservation dur- preoperative factors predictive of early recovery from ing radical prostate surgery. J Urol 1995; 153: 337. post-prostatectomy incontinence. Patients with better de- 14. Bianco FJ Jr, Scardino PT and Eastham JA: Radical prosta- veloped pelvic floor muscles, especially in relation to the size tectomy: long-term cancer control and recovery of sexual of the prostate, can be expected to achieve earlier recovery of and urinary function (“trifecta”). Urology 2005; 66: 83. continence after RP. 15. Hammerer P and Huland H: Urodynamic evaluation of changes in urinary control after radical retropubic prostatectomy. J Urol 1997; 157: 233. 16. Majoros A, Bach D, Kexzthelyi A, Hamvas A and Romics I: Abbreviations and Acronyms Urinary incontinence and voiding dysfunction after radical LA ϭ levator ani retropubic prostatectomy (prospective urodynamic study). LAa ϭ axial LA Neurourol Urodyn 2006; 25: 2. LAc ϭ coronal LA 17. Coakely FV, Eberhardt S, Kattan MW, Wei DC, Scardino PT MRI ϭ magnetic resonance image and Hricak H: Urinary continence after radical retropubic PD ϭ pelvic diaphragm prostatectomy: relationship with membranous urethral PDc ϭ coronal PD length on preoperative endorectal magnetic resonance im- PDs ϭ sagittal PD aging. J Urol 2002; 168: 1032. PSc ϭ periurethral sphincter complex 18. Oefelein MG: Prospective predictors of urinary continence RP ϭ radical prostatectomy after anatomical radical retropubic prostatectomy: a multivariate analysis. World J Urol 2004; 22: 267. REFERENCES 19. Hsu EI, Hong EK and Lepor H: Influence of body weight and prostate volume on intraoperative, perioperative, and post- 1. Henry RY and O’Mahony D: Treatment of prostate cancer. operative outcomes after radical retropubic prostatectomy. J Clin Pharmacol Ther 1999; 24: 93. Urology 2003; 61: 601. 2. Eastham JA, Kattan MW, Rogers E, Goad JR, Ohori M, Boone 20. Jin B, Turner L, Zhou Z, Zhou EL and Handelsman DJ: TB et al: Risk factors for urinary incontinence after radical Ethnicity and migration as determinants of human pros- prostatectomy. J Urol 1996; 156: 1707. tate size. J Clin Endocrinol Metab 1999; 84: 3613. Impact of Unilateral Sural Nerve Graft on Recovery of Potency and Continence Following Radical Prostatectomy: 3-Year Longitudinal Study

Shunichi Namiki,* Seiichi Saito, Haruo Nakagawa, Takehiko Sanada, Atsushi Yamada and Yoichi Arai From the Departments of Urology (SN, SS, HN, YA) and Plastic Surgery (TS, AY), Tohoku University Graduate School of Medicine, Tohoku, Japan

Purpose: We conducted a 3-year longitudinal study assessing the impact of unilateral sural nerve graft on recovery of potency and continence following radical prostatectomy. Materials and Methods: A total of 113 patients undergoing radical retropubic prostatectomy were classified into 3 groups according to the degree of nerve sparing, that is unilateral nerve preservation with contralateral sural nerve graft interposition, bilateral nerve sparing and unilateral nerve sparing. Urinary continence and potency were estimated by the UCLA Prostate Cancer Index questionnaire. Results: Patients in the nerve sparing plus sural nerve graft group were younger than those in the bilateral nerve sparing or unilateral nerve sparing groups. At baseline the unilateral nerve sparing plus sural nerve graft group and the bilateral nerve sparing group reported better sexual function than the unilateral nerve sparing group (62.1 and 61.5 vs 49.9, p Ͻ0.05). The bilateral nerve sparing group showed more rapid recovery than the unilateral nerve sparing plus sural nerve graft group after radical retropubic prostatectomy (p Ͻ0.01). After 24 months there were no significant differences observed between the bilateral nerve sparing and the unilateral nerve sparing plus sural nerve graft group (28.7 vs 32.9). The bilateral nerve sparing group reported a better sexual function score than the unilateral nerve sparing group throughout the postoperative period (p Ͻ0.05). The bilateral nerve sparing group maintained significantly better urinary function at 1 month after radical retropubic prostatectomy than the unilateral nerve sparing plus sural nerve graft group (p Ͻ0.05). After 3 months these groups were almost continent. The unilateral nerve sparing group reported lower urinary function scores during the first year compared to the other groups. Conclusions: The nerve graft procedure may contribute to the recovery of urinary function as well as sexual function after radical retropubic prostatectomy. This finding needs to be validated in a randomized trial. Key Words: prostatic neoplasms, prostatectomy, sural nerve, urinary incontinence, impotence

rostate cancer has a signiﬁcant impact on HRQOL. dle. Interposition of sural nerve graft to replace resected Although a variety of treatment options are available cavernous nerves during RP confers a greater chance of P including external beam radiation, brachytherapy recovering erectile function than without grafts. Scardino and hormonal ablation, radical prostatectomy is considered and Kim reported that with nerve grafting for the side of a safe and effective treatment for localized prostate cancer.1 NVB resection, erectile function of the patients undergoing Urinary incontinence and erectile dysfunction represent the unilateral nerve sparing returns to a level approximating principal sources of postoperative adverse events for pa- bilateral nerve sparing.3 On the other hand, several studies tients who have undergone RP. Because initiation of penile have shown that preservation of the NVB is also associated erection is a neurovascular event, preservation of the cav- with improved recovery of urinary control after RP.4,5 ernous nerves during RP is the most important factor for the Although several investigators have reported short-term recovery of erectile function following RP. Catalona et al results with nerve grafting, there is still controversy regard- reported excellent results with overall postoperative potency ing the long-term outcomes of nerve grafts following RP. We rates of 68% and postoperative continence rates of 92%.2 report longer term patterns of HRQOL (ie potency and con- With low volume and low stage disease nerve sparing does tinence) recovery during the ﬁrst 3 years after RP using a not compromise surgical margins. However, nerve sparing validated questionnaire. might not be appropriate in men with high grade tumors or palpable disease extending toward the neurovascular bun- PATIENTS AND METHODS Patient Population and Operative Technique Submitted for publication November 27, 2006. From January 2002 to December 2004 a total of 145 patients * Correspondence and requests for reprints: Department of Urol- with newly diagnosed localized prostate cancer were treated ogy, Tohoku University Graduate School of Medicine, 1-1 Seiryoma- chi, Aoba-ku, Sendai, 980-8574, Japan (telephone: 022-717-7278; with RP at Tohoku University Hospital. There were 15 pa- FAX: 022-717-7283; e-mail: [email protected]). tients with nonnerve sparing and 3 with bilateral sural

0022-5347/07/1781-0212/0 212 Vol. 178, 212-216, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.043 SURAL NERVE GRAFT FOR POTENCY AND CONTINENCE AFTER RADICAL PROSTATECTOMY 213 nerve graft excluded from analysis. An additional 14 pa- returning the questionnaire. They voluntarily provided the tients were excluded who received initial hormonal ablation, self-reported questionnaire by mail. leaving 113 candidates for this study. These patients were classified into 3 groups according to the degree of nerve Statistical Analyses sparing, that is unilateral nerve preservation with con- At baseline a comparison among the 3 groups was performed tralateral sural nerve graft interposition group (UNS plus using the chi-square test or 1-way analyses of variance SNG), a bilateral nerve sparing group and a unilateral nerve (ANOVA). UCLA PCI scores for the various domains are sparing group. The indications for nerve sparing procedure shown as the mean plus or minus standard deviation (SD) depended on preoperative factors (clinical stage, transrectal on 0 to 100 scales, with higher scores always representing ultrasound findings, number and Gleason score of positive better outcomes. Statistical analyses were performed using biopsies, PSA or patient preference) and intraoperative fac- repeated ANOVA or the Mann-Whitney U test for groups to tors, prioritizing cancer control. All patients who had mini- compare the effects of each treatment, with p Ͻ0.05 consid- mal erectile dysfunction and in whom nerve resection was ered statistically significant. anticipated were offered SNG and counseling regarding the risks, benefit and likely impact on postoperative potency RESULTS recovery. Patients ultimately decided whether SNG interposition would be performed. In our study preservation of the Complete demographic and clinical data were available for NVB was assigned based on the results of intraoperative participants at enrollment. Table 1 compares these data 6 electrostimulation as reported by Kurokawa et al. among 3 groups. The age of the UNS plus SNG group was statistically lower than that of the BNS or UNS groups Quality of Life Assessment (p Ͻ0.05 for each). The 3 groups were comparable in terms of Urinary continence and potency were estimated using the uri- preoperative PSA, Gleason scores and pathological tumor nary and sexual function and bother domains of the UCLA stage. Each group showed similar levels of comorbidities and PCI, which assesses prostate specific HRQOL.7 The question- sociodemographic characteristics. Some patients (50.4%) ex- naire had already been translated into Japanese, and the va- perienced comorbidities, the most common of which were lidity and reliability had been previously tested.8 All pa- hypertension (26%), diabetes (7%), gastrointestinal (18%), tients were informed of their cancer diagnosis before being cardiovascular (9%) disease and other kinds of carcinoma asked to fill out the questionnaires. Followup interviews (5%), but these comorbidities have been well controlled. were conducted in person at scheduled study visits of 1, 3, 6, There were 6 patients (5%) who received salvage therapy 12, 18, 24 and 36 months after RP. All patients who agreed because of biochemical recurrence. All patients received bi- to participate in this study received a questionnaire, an calutamide or radiotherapy. No patients used vacuum erec- informed consent form and a prepaid postage envelope for tion devices.

TABLE 1. Demographic and clinical characteristics of study population UNS ϩ SNG BNS UNS p Value

No. pts 19 34 60 Age at survey: Mean Ϯ SD 58.0 Ϯ 5.4 64.1 Ϯ 5.8 65.1 Ϯ 5.7 Ͻ0.001* Median 58 64 65 Range 48–69 47–73 51–77 PSA at diagnosis (ng/ml): Mean Ϯ SD 8.0 Ϯ 4.7 8.3 Ϯ 8.9 8.8 Ϯ 6.7 0.878† Median 6.5 6.4 7.3 Range 3.4–21.8 3.1–53.0 2.1–52.7 No. clinical tumor stage: 0.046† T1 14 30 39 T2 3 4 19 T3 2 0 2 No. pathological tumor stage: 0.183† T2 16 32 48 T3 3 2 12 No. Gleason score: 0.857† 6 or Less 8 14 28 7 or Greater 11 20 32 No. salvage therapy ablation (%) 1 (5) 2 (5) 3 (5) 0.577† No. comorbidities: 0.607† None 12 18 27 1–2 6 13 29 3ϩ 134 No. working status: 0.461† Full-time 10 11 29 Part-time 4 5 6 Retired/no job 5 14 25 No. marital or relationship status: 0.842† Married or living with spouse or partner 17 31 56 Unmarried or not in signiﬁcant relationship 2 3 4 * Mann-Whitney U test. † Chi-square test. 214 SURAL NERVE GRAFT FOR POTENCY AND CONTINENCE AFTER RADICAL PROSTATECTOMY

period at 3 years. At 36 months 25% of the UNS plus SNG TABLE 2. UCLA PCI scores group and 28% of the BNS group considered the ability to Mean Ϯ SD function sexually as fair or good compared with 12% of UNS ϩ SNG BNS UNS p Value patients with UNS alone. In addition, 60% of the UNS plus

Urinary function: Ͻ0.001 SNG group and 55% of the BNS group could achieve an Baseline 95.9 Ϯ 11.9 95.5 Ϯ 12.8 97.4 Ϯ 6.8 erection more than half the time vs 18% of patients with 1 Mo 51.5 Ϯ 32.1* 66.8 Ϯ 23.9* 56.4 Ϯ 26.1* UNS alone. All of the surgery groups had substantial im- 3 Mos 73.4 Ϯ 27.6* 71.4 Ϯ 21.1* 61.2 Ϯ 25.4* 6 Mos 82.3 Ϯ 24.8* 84.2 Ϯ 16.9* 75.8 Ϯ 30.1* pairment in the sexual bother domains throughout the post- 12 Mos 84.0 Ϯ 22.1* 84.2 Ϯ 15.3* 76.2 Ϯ 24.3* operative period (Mann-Whitney U test p Ͻ0.01 for each 18 Mos 88.8 Ϯ 14.3* 87.0 Ϯ 14.6* 81.3 Ϯ 19.9* point). The UNS plus SNG group claimed lower sexual 24 Mos 89.0 Ϯ 12.9 88.7 Ϯ 14.2 86.4 Ϯ 18.9* 36 Mos 90.6 Ϯ 6.5 88.5 Ϯ 20.6 86.3 Ϯ 13.6* bother scores than the other 2 groups at 1 and 3 months Urinary bother: Ͻ0.001 postoperatively (both p Ͻ0.05). Baseline 93.3 Ϯ 11.6 91.1 Ϯ 13.6 94.5 Ϯ 8.9 1 Mo 58.3 Ϯ 38.6* 74.0 Ϯ 25.0* 65.5 Ϯ 28.6* When considering urinary continence no significant dif- 3 Mos 81.9 Ϯ 24.7* 79.6 Ϯ 25.4* 70.3 Ϯ 34.4* ferences were observed in urinary function and bother scores 6 Mos 83.8 Ϯ 20.9* 83.3 Ϯ 28.4* 77.4 Ϯ 29.8* at baseline for each group. The BNS group maintained sig- 12 Mos 86.8 Ϯ 22.0 86.4 Ϯ 14.6 82.1 Ϯ 24.0* 18 Mos 91.7 Ϯ 10.5 89.6 Ϯ 12.3 85.3 Ϯ 20.5 nificantly better urinary function at 1 month after RP than 24 Mos 93.3 Ϯ 9.0 89.4 Ϯ 9.3 83.0 Ϯ 16.6 the SNG group (66.8 vs 51.5, p Ͻ0.05). After 12 months the 36 Mos 91.7 Ϯ 7.9 88.5 Ϯ 12.2 87.5 Ϯ 16.5 BNS and SNG groups were almost continent. The UNS Sexual function: Ͻ0.001 Baseline 62.1 Ϯ 11.6 61.5 Ϯ 16.9 49.9 Ϯ 19.4 group reported lower urinary function scores during the first 1 Mo 7.2 Ϯ 7.6* 12.7 Ϯ 20.8* 6.5 Ϯ 8.2* year than the other groups. Urinary bother at 1 and 3 3 Mos 7.9 Ϯ 4.4* 16.0 Ϯ 18.6* 6.7 Ϯ 8.6* 6 Mos 11.9 Ϯ 6.8* 22.6 Ϯ 17.2* 8.4 Ϯ 10.1* months was significantly worse than baseline in all 3 12 Mos 16.7 Ϯ 12.6* 24.4 Ϯ 17.4* 13.2 Ϯ 14.0* groups. However, at 6 months it returned to the baseline in 18 Mos 24.2 Ϯ 12.0* 25.5 Ϯ 21.5* 13.9 Ϯ 12.0* the UNS plus SNG and BNS groups. The UNS group re- 24 Mos 27.7 Ϯ 10.4* 26.5 Ϯ 20.9* 12.7 Ϯ 12.9* 36 Mos 32.9 Ϯ 17.0* 28.7 Ϯ 28.7* 13.4 Ϯ 13.4* ported lower urinary function scores during the first year Sexual bother: Ͻ0.001 than the other groups. Baseline 80.3 Ϯ 21.7 81.9 Ϯ 20.3 78.8 Ϯ 22.7 Because age affects sexual and urinary function, we also 1 Mo 31.3 Ϯ 27.2* 45.6 Ϯ 31.1* 48.4 Ϯ 32.4* 3 Mos 33.3 Ϯ 35.4* 48.9 Ϯ 33.5* 47.8 Ϯ 36.4* performed age matched analyses. Among patients younger 6 Mos 44.5 Ϯ 30.0* 52.1 Ϯ 28.1* 50.2 Ϯ 34.9* than 66 years 18 were in the UNS plus SNG group, 21 in the 12 Mos 39.0 Ϯ 23.4* 59.4 Ϯ 30.5* 48.1 Ϯ 32.2* 18 Mos 51.7 Ϯ 19.2* 54.4 Ϯ 28.6* 55.0 Ϯ 25.7* BNS group and 26 in the UNS group. With age matched 24 Mos 50.0 Ϯ 19.6* 50.0 Ϯ 20.4* 45.0 Ϯ 29.2* analysis there was no difference in sexual function at base- 36 Mos 58.3 Ϯ 23.6* 45.8 Ϯ 30.0* 54.6 Ϯ 30.6* line among the 3 treatment groups. The same tendency that * Statistically significant changes from baseline (p Ͻ0.05). the BNS group had more rapid recovery of urinary and sexual function than the SNG group was observed just after RP. The UNS plus SNG group continued to show improve- Table 2 presents the recovery of urinary and sexual do- ment, and the differences lost significance in sexual and mains of each group. At baseline the UNS plus SNG and the urinary function by 12 and 3 months, respectively (see BNS groups reported better sexual function than the UNS figure). group (62.1 and 61.5 vs 49.9, respectively, p Ͻ0.05). The BNS group showed more rapid recovery than the UNS plus DISCUSSION SNG group within 12 months (p Ͻ0.01, repeated ANOVA). However, after 24 months there were no significant differ- Nerve grafting is a surgical technique that has been used for ences between the UNS plus SNG and BNS groups. The decades. The grafted nerve serves primarily as a channel or UNS plus SNG group continued to show improvement even scaffold for regenerating axons to reestablish the connection in the third year. The BNS group had a better sexual func- between the severed segments. To our knowledge this is the tion score than the UNS group throughout the postoperative largest published series of sural nerve grafts performed at a

Sequential changes in average sexual function (A) and urinary function (B) scores in unilateral nerve sparing with contralateral sural nerve graft group bilateral nerve sparing group and unilateral nerve sparing group for age matched comparison. SURAL NERVE GRAFT FOR POTENCY AND CONTINENCE AFTER RADICAL PROSTATECTOMY 215 single institution with the longest clinical followup. Our Precise visualization and localization of the NVBs are study has several important findings. With selective graft often problematic during RP because of the variation in replacement of a unilateral nerve resection, sexual function anatomical location of the cavernous nerves as well as poor appears to recover to a level approximating that of bilateral exposure due to the ubiquitous presence of overlying tissues nerve sparing and superior to that of unilateral resection and blood during the procedure. Several studies reported without grafts. Furthermore, the present longitudinal study that macroanatomical and electrophysiological assessments revealed different profiles in terms of recovery of sexual of nerve preservation showed different outcomes. The intra- function after RP. The exact recovery time for return of full operative electrophysiological assessment revealed that ap- sexual function after nerve sparing RP is still under- proximately 20% of the macroanatomical assessments were estimated, and the majority of patients do not recover erec- incorrect.4 Thus, if only macroanatomical assessment was tile function as early as urinary continence. Walsh reported used we could not know the real impact of unilateral sural that maximal erectile recovery was not witnessed until a nerve interposition. With regard to the intraoperative elec- mean period of 18 months after bilateral nerve sparing RP trophysiological test, Holzbeierlein et al claimed that re- because a number of factors such as thermal damage, isch- sponses to NVB using the CaverMap® nerve stimulator did emic injury and the local inflammatory effects of surgical not correlate with the precise anatomical location of the trauma may impair the cavernous nerves.9 Whereas sexual cavernous nerves as a consequence of anesthesia, medica- function was significantly better in the BNS than the UNS tions or surgical manipulation.13 There was a high false- plus SNG group immediately after RP, the latter group negative rate reported in the CaverMap system, possibly continued to show improvement after postoperative year 2 because it measured penile tumescence. However, the most and sexual function reached a level approximating that of important characteristic of our system was that it measured bilateral nerve sparing. However, the UNS plus SNG group intracavernous pressure. Kurokawa et al showed that there reported a significantly lower sexual bother score than the was no false-negative rate in this system, and that intracav- other 2 groups, suggesting that those who underwent RP ernous pressure was not influenced by preoperative potency, with nerve grafting were potentially more interested or mo- type of anesthesia or neoadjuvant hormone therapy, sug- tivated to maintain or resume sexual function postopera- gesting high system accuracy.6 Moreover, we revealed that tively. Therefore, postoperative erectile dysfunction espe- nerve preservation confirmed by the system effectively pre- cially within 12 months was a burden and they reported dicted the recovery of potency.14 Another important aspect lower sexual bother scores. Although our study may not be of the electrophysiological assessment of NVB preservation large enough to generalize whether nerve grafting actually is that the method could provide immediate feedback to helps men who would otherwise not achieve erections suffi- surgeons during the operation. Despite attempts at direct cient for intercourse, these findings will be helpful in coun- visualization and the electrophysiological assessment of seling patients when they are weighing a decision about RP. NVB, whether the preserved nerves will be functionally Unilateral nerve grafting RP is beneficial for the early normal or whether vascular damage will affect continence or recovery of postoperative urinary continence. Urinary incon- potency currently cannot be predicted at the time of sur- tinence is a concern particularly relevant to men undergoing gery.15 Thus, success or failure of the nerve sparing proce- RP because surgery more frequently negatively impacts con- dure is recognized 1 or 2 years after the surgery. Using the tinence than other treatment modalities, and because pa- method described here a surgeon could immediately know tients rate urinary status as one of their greatest concerns the results of the nerve sparing procedure. This early feed- regarding HRQOL. In a multivariate analysis Eastham et al back may further contribute to the improvement of the sur- showed that unilateral nerve preservation was associated gical outcome by the surgeon. with less postoperative incontinence than bilateral NVB This prospective observational study had several limita- resection.10 Our study revealed that although the BNS tions. This group is not a random sample and might not be group showed better urinary function than the UNS plus representative of all men with prostate cancer who choose SNG group at 1 month after RP, there were no differences at RP. For instance, patients electing to undergo SNG interpo- 3 months and both groups improved at comparable rates sition may have been more motivated or surgeon technique after 6 months. The precise mechanism behind the func- may have changed imperceptibly with time. In addition, our tional relationship between nerve sparing and continence study had a relatively small sample size. This poses a sig- remains elusive, and it is most likely multifactorial. NVB nificant problem in the interpretation of the data because preservation may influence continence not only by maintain- recovery of erectile function after RP depends on age as well ing efferent but also afferent innervation. The effect of au- as penile rehabilitation such that younger patients who are tonomic innervation on the sphincter mechanism was con- more motivated as seen in the nerve graft arm of this study vincingly shown by intraoperative stimulation of NVBs are more likely to recover erectile function. Unfortunately during RP.11 Singh et al demonstrated that patients who our study may have insufficient power to address this issue underwent RP with UNS plus SNG had a greater rate of due to the small number of patients younger than 66 years. urinary function recovery relative to patients in whom an Thus, the absence of a significant difference between the SNG interposition was not performed, which was similar to UNSϩSNG group and the BNS group may be due solely to a our finding.12 Other factors that may influence urinary func- lack of power rather than the true equivalence of these tion include the surgical methods of bladder neck recon- groups. We also cannot exclude RP complications such as struction and anastomosis.10 The current study minimized anastomotic stricture which may impact the issue of urinary the confounding influence of surgical technique on urinary continence, although in our series the incidence was low at function. All patients in this study had the bladder neck less than 5%. Finally, we did not distinguish those patients reconstructed and anastomosis performed using the same who use erectile aids such as phosphodiesterase type 5 in- technique. hibitors after RP. Although there is currently no consensus 216 SURAL NERVE GRAFT FOR POTENCY AND CONTINENCE AFTER RADICAL PROSTATECTOMY regarding the implementation of penile rehabilitation pro- 10. Eastham JA, Kattan MW, Rogers E, Goad JR, Ohori M, Boone grams, the initiation time, the frequency of application, the TB et al: Risk factors for urinary incontinence after radical type of vasoactive agent and the dose regimen, a number of prostatectomy J Urol 1996; 156: 1707. recent studies have reported on various approaches.16,17 11. Nelson CP, Montie JE, McGuire EJ, Wedemeyer G and Wei JT: These factors may be a significant predictor of sexual func- Intraoperative nerve stimulation with measurement of urethral sphincter pressure changes during radical retropubic tion recovery. Despite these limitations our findings have prostatectomy: a feasibility study. J Urol 2003; 169: 2225. important implications for men choosing RP for localized 12. Singh H, Karakiewicz P, Shariat SF, Canto EI, Nath RK, prostate cancer, and need to be validated in a multicenter Kattan MW et al: Impact of unilateral interposition sural and randomized trial. nerve grafting on recovery of urinary function after radical prostatectomy. Urology 2004; 63: 1122. CONCLUSIONS 13. Holzbeierlein J, Peterson M and Smith JA Jr: Variability of results of cavernous nerve stimulation during radical pros- These data demonstrate that in patients who underwent RP tatectomy. J Urol 2001; 165: 108. with a nerve sparing procedure, SNG interposition is asso- 14. Namiki S, Terai A, Nakagawa H, Ikeda Y, Saito S, Satoh M et ciated with greater rates of postoperative sexual and urinary al: Intraoperative electrophysiological confirmation of neu- function. Therefore, if NVB resection is considered, SNG rovascular bundle preservation during radical prostatec- interposition represents an important option that may pro- tomy: long-term assessment of urinary and sexual function. foundly impact patient HRQOL. Jpn J Clin Oncol 2005; 35: 660. 15. Lue TF, Gleason CA, Brock GB, Carroll PR and Tanagho EA: Intraoperative electrostimulation of the cavernous nerve: technique, results and limitations. J Urol 1995; 154: 1426. Abbreviations and Acronyms 16. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, BNS ϭ bilateral nerve sparing Barbieri L et al: Recovery of spontaneous erectile function HRQOL ϭ health related quality of life after nerve-sparing radical retropubic prostatectomy with NVB ϭ neurovascular bundle and without early intracavernous injections of alprostadil: PSA ϭ prostate specific antigen results of a prospective, randomized trial. J Urol 1997; 158: RP ϭ radical retropubic prostatectomy 1408. SNG ϭ sural nerve graft 17. Mulhall J, Land S, Parker M, Waters WB, Flanigan RC, UCLA PCI ϭ UCLA Prostate Cancer Index Mulhall J et al: The use of an erectogenic pharmacotherapy UNS ϭ unilateral nerve sparing regimen following radical prostatectomy improves recovery of spontaneous erectile function. J Sex Med 2005; 2: 532.

REFERENCES EDITORIAL COMMENT 1. Arai Y, Egawa S, Tobisu K, Sagiyama K, Sumiyoshi Y, Enormous enthusiasm exists at present to apply cavernous Hashine K et al: Radical retropubic prostatectomy: time nerve graft reconstruction to facilitate erectile function re- trends, morbidity and mortality in Japan. BJU Int 2000; covery in patients undergoing radical prostatectomy and 85: 287. other pelvic surgeries.1,2 Clinical reports do indicate the 2. Catalona WJ, Carvalhal GF, Mager DE and Smith DS: Po- feasibility of this intervention and its seemingly low morbid- tency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999; 162: ity. A concern is whether cavernous nerve grafting is demon- 433. strably effective. This report does represent a fairly rigorous 3. Scardino PT and Kim ED: Rationale for and results of nerve evaluation. The longitudinal natural history as well as the grafting during radical prostatectomy. Urology 2001; 57: use of validated instruments are strengths. However, like 1016. other reports on this subject this study has limitations 4. Kaiho Y, Nakagawa H, Ikeda Y, Namiki S, Numahata K, Satoh which may bias conclusions. These include lack of random- M et al: Intraoperative electrophysiological confirmation of ization, patient selection bias, small sample size and poten- urinary continence after radical prostatectomy. J Urol tial nonuniform use of erectile aids. Further study applying 2005; 173: 1139. prospective data accrual, randomization of equally charac- 5. Burkhard FC, Kessler TM, Fleischmann A, Thalmann GN, terized, preoperatively potent patients to nerve grafting and Schumacher M and Studer UE: Nerve sparing open radical retropubic prostatectomy—does it have an impact on uri- nonnerve grafting arms of treatment, application of vali- nary continence? J Urol 2006; 176: 189. dated assessment tools, and sufficient clinical followup are 6. Kurokawa K, Suzuki T, Suzuki K, Terada N, Ito K, Yoshikawa needed for results to be conclusive. D et al: Preliminary results of a monitoring system to Arthur L. Burnett confirm the preservation of cavernous nerves. Int J Urol 2003; 10: 136. Department of Urology 7. Litwin MS, Hays RD, Fink A, Ganz PG, Leake B and Brook The Johns Hopkins Hospital RH: The UCLA Prostate Cancer Index: development, reli- Baltimore, Maryland ability, and validity of a health-related quality of life measure. Med Care 1998; 36: 1002. 1. Nelson BA, Chang SS, Cookson MS and Smith JA Jr: Morbidity 8. Kakehi Y, Kamoto T, Ogawa O, Arai Y, Litwin MS, Suzukamo and efficacy of genitofemoral nerve grafts with radical ret- Y et al: Development of Japanese version of the UCLA ropubic prostatectomy. Urology 2006; 67: 789. Prostate Cancer Index: a pilot validation study. Int J Clin 2. Secin FP, Koppie TM, Scardino PT, Eastham JA, Patel M, Oncol 2002; 7: 306. Bianco FJ et al: Bilateral cavernous nerve interposition 9. Walsh PC: Nerve grafts are rarely necessary and are unlikely grafting during radical retropubic prostatectomy: Memo- to improve sexual function in men undergoing anatomic rial Sloan-Kettering Cancer Center experience. J Urol radical prostatectomy. Urology 2001; 57: 1020. 2007; 177: 664. Urological Survey

VOIDING FUNCTION AND DYSFUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY

Recommendations for Urodynamic Assessment in the Evaluation of Women With Stress Urinary Incontinence E. B. Takacs and P. E. Zimmern, Department of Urology, University of Iowa, Iowa City, Iowa Nat Clin Pract Urol 2006; 3: 544–550. Urinary incontinence is a common problem that is experienced by women of all ages. The overall evaluation and treatment of incontinence has increased in sophistication, both as a result of the introduction of urodynamic testing in the assessment of patients, and because there are increasing numbers of medical and surgical treatments available for incontinence. What was previously considered a personal problem for women, and which was rarely discussed, has become a more open and acceptable complaint for female patients to bring to their physicians. This Review aims to clarify when urodynamic testing is clearly indicated for patients with symptoms of stress urinary incontinence, and describes the current recommendations from three national and international governing bodies. This Review will also highlight some of the ongoing debates over the performance, interpretation, and utility of urodynamic testing, and provide references for further reading on these topics. Editorial Comment: This is a nice summary of the issues surrounding the question of what, if any, urodynamic assessment is necessary prior to recommending surgery for stress urinary incontinence in a woman. My interpretation of this article is that the inference to be drawn is that there is little objective evidence to support any one viewpoint but there seems to be some consensus of expert opinion regarding the following indications: (1) a history of surgery for incontinence or prolapse; (2) current evidence of significant pelvic organ prolapse; (3) a history of neurological function or extragenitourinary pelvic surgery liable to affect bladder or sphincter function; (4) a history of radiation therapy to the pelvis; and (5) an uncertain diagnosis. The article lists the recommendations of the Agency for Health Care Policy and Research (1996), the American College of Obstetricians and Gynecologists (1995) and the International Consultation on Incontinence (2005). There are 2 reasons to do urodynamic studies in such patients: (1) to validate the diagnosis and affirm the reason for surgery; and (2) to predict surgical outcome (a better way of saying this is to predict surgical failure). With respect to the latter, the main controversies have been (1) the significance of a very low or absent detrusor pressure during normal micturition and (2) the significance of preoperative detrusor overactivity. The authors have not failed, but are simply stating the truth when they conclude, “[I]n summary, the indications for urodynamic testing are still heavily debated.” This is especially so in the previously untreated patient with stress urinary incontinence. Alan J. Wein, M.D., Ph.D. (Hon.)

A Prospective Observational Trial of Pelvic Floor Muscle Training for Female Stress Urinary Incontinence J. R. Balmforth, J. Mantle, J. Bidmead and L. Cardozo, Department of Urogynaecology, Kings College Hospital, London, United Kingdom BJU Int 2006; 98: 811–817. Objective: To assess the impact of pelvic ﬂoor muscle training (PFMT) on bladder neck mobility in a prospective observational study, and to correlate any observed changes with objective, standardized outcome measures of the severity of stress urinary incontinence (SUI). Patients and Methods: Women with the symptom of SUI were recruited prospectively over a 3-year period from a tertiary referral urogynaecology clinic in a teaching hospital. A group of 97 treatment-naive women complaining of SUI and conﬁrmed as

0022-5347/07/1781-0217/0 217 Vol. 178, 217-224, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.156 218 VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY

having urodynamic SUI on video-urodynamic assessment agreed to participate. Bladder neck mobility on perineal ultrasonography was assessed immediately before and on completing a 14-week programme of ‘PFM rehabilitation’. Treatment outcome was assessed using a standardized pad-test and a condition- specific, validated quality-of-life questionnaire (King’s Health Questionnaire). Changes in functional anatomy were quantified using transperineal ultrasonography to measure the bladder neck position at rest, maximum PFM contraction and maximum Valsalva manoeuvre. Bladder neck rotational mobility from rest to maximum incursion and maximum excursion was calculated. Results: Treatment with an intensive package of PFMT and behavioural modification resulted in significant elevation of the bladder neck position at all three measured positions. Displacement of the bladder neck on Valsalva (rotational excursion) was reduced after treatment, suggesting increased levator ‘stiffness’. These changes in functional anatomy were associated with a statistically and clinically significant reduction in urine loss and improvement in condition-specific quality of life. Conclusion: The present results show that PFMT is an effective treatment for SUI and provide an important new insight into how dynamic pelvic floor anatomy can be modified by this widely used intervention. Editorial Comment: This article describes what I think is about as intensive a behavioral modification/pelvic floor muscle training regimen as is practical. Readers are urged to consult the original article for the details but, briefly, the regimen consists of different components: lifestyle interventions (fluid management, diet and bowel management, exercise), strength training (increasing muscle bulk, providing structural support, training in the use of auxiliary muscles) and skills training (specifically, pre-contraction of the pelvic floor muscles to counter raised intra-abdominal pressure—the so-called “knack”). Of the 9 domains of the King’s Health Ques- tionnaire 6 improved significantly. The only parameter that I could find that actually was indicative of urine loss was pad weight on a 30-minute fixed volume test, the bladder being filled with 250 ml saline and the women then performing a 30 minute standardized exercise program. Pad weight decreased from 12.2 to 5.44 gm (p <0.001). The authors point out that the present study does not address the long-term efficacy of pelvic floor muscle training and whether the observed changes in functional anatomy are sustainable. They admit that the idea that PFMT must be sustained at high intensity for the beneficial effects to continue is, in fact, an argument against the technique. However, they point out that prior exercise science studies have shown that less effort is needed to maintain muscle strength than to build it. Alan J. Wein, M.D., Ph.D. (Hon.)

A Randomized Controlled Trial of the Effectiveness of Pelvic Floor Therapies for Urodynamic Stress and Mixed Incontinence K. S. Williams, R. P. Assassa, C. L. Gillies, K. R. Abrams, D. A. Turner, C. Shaw, J. Haslam, C. Mayne and C. W. McGrother; Leicestershire MRC Incontinence Study Team, Department of Health Sciences, University of Leicester, Leicester, United Kingdom BJU Int 2006; 98: 1043–1050. Objectives: To assess the efficacy and cost-effectiveness of pelvic floor muscle therapies (PFMT) in women aged Ͼ or ϭ 40 years with urodynamic stress incontinence (USI) and mixed UI. Patients and Methods: In a three-arm randomized controlled trial in Leicestershire and Rutland UK, 238 community-dwelling women aged Ͼ or ϭ 40 years with USI in whom previous primary behavioural intervention had failed were randomized to receive either intensive PFMT (79), vaginal cone therapy (80) or to continue with primary behavioural intervention (79) for 3 months. The main outcome measure was the frequency of primary UI episodes, and secondary measures were pad-test urine loss, patient perception of problem, assessment of PF function, voiding frequency, and pad usage. Validated scales for urinary dysfunction, and impact on quality of life and satisfaction were collected at an independent interview. Results: All three groups had a moderate reduction in UI episodes after intervention but there was no statistically significant difference among the groups. There were marginal improvements in voiding frequency for all groups, with no statistically significant difference among them. Conclusions: In women who have already had simple behavioural therapies (including advice on PFM exercises) for urinary dysfunction, the continuation of these behavioural therapies can lead to further improvement. The addition of vaginal cone therapy or intensive PFMT does not seem to contribute to further improvement. The improvement in pelvic floor function was significantly greater in the PFMT arm than in the control arm although this did not translate into changes in urinary symptoms. VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY 219

Editorial Comment: The underwhelming results here should not dissuade anyone from thinking that the initial step in all such therapeutic regimens should be a combination of behavioral modification and pelvic floor exercise instruction. The authors express the following opinion, with which I agree: “The results show that any improvement is likely to be related to the time spent with the therapist, and the motivation and support they provide. There is little increase in symptom benefit and detailed PF assessment in targeted exercises, or the use of [vaginal cone therapy] over ‘standard’ information and support on PF exercise. The importance of the therapeutic relationship providing motivation and support should not be underestimated....” Alan J. Wein, M.D., Ph.D. (Hon.)

The Motion: Injectables are Justiﬁed as a First Option for Stress Urinary Incontinence P. Van Kerrebroeck, Department of Urology, University Hospital Maastricht, Maastricht, The Netherlands Eur Urol 2006; 50: 857–858; 860. No Abstract.

Injectables are Justified as a First Option for Stress Urinary Incontinence: Against the Motion J. Corcos, Department of Urology, McGill University and Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada Eur Urol 2006; 50: 858–860. No Abstract. Editorial Comment: This is an interesting debate, with 1 rebuttal by each participant on the subject of injectables as a first option for stress urinary incontinence. The arguments offered by each participant amount to looking at the glass as either half empty or half full. The assertions of Van Kerrebroeck can be summarized as follows: “. . . significant amelioration of symptoms in up to 73% of patients with a cure rate of 24-36% . . . durable on long term follow up.... [L]ong term efficacy can also be achieved through repeat injection.... [S]ome cases of particle migration have been reported, but without significant morbidity....[C]ompli- cations are usually mild, easily manageable and self limited....[I]njections are the treatment of choice in obese individuals, previously operated patients and frail, elderly women, as well as in general patients unwilling or unfit to undergo surgery ....[T]he good risk/benefit ratio is the main advantage of injectables.” The stance of Corcos can be summarized as follows: “. . . no reports in the literature comparing injectables with [pelvic floor exercises] plus lifestyle changes or [minimally invasive slings] ....[O]ne injectable was compared with surgery in a multicenter [randomized controlled trial and] at one year, the cure rate was 72% for surgery vs 53% for collagen....[T]here has been an awareness regarding the disadvantages of bulking agents for some time now.... [M]igration risks of [polytetrafluoroethylene] particles have been reported as well as antigenic reactions....onedeath after fat injection and fat embolism....high urethral erosion rate after [ethylene vinyl alcohol copolymer]....[F]inally, pseudoabscess was observed but not reported with the use of hyaluronic acid polymer....50to75%ofpatients undergoing treatment with injectables will ultimately request surgery creating additional costs to achieve continence.” In the rebuttal Van Kerrebroeck states, “In Dr. Corcos’ article I cannot find any convincing argument against the motion....[T]he lower, but very reasonable efficacy rate of injectables compared with surgery has to be balanced with the safety of modern bulking agents and the total costs of any form of treatment for [stress urinary incontinence] as well as quality of life aspects....[T]he major safety concerns relate more to the older (and now discontinued) materials....[C]linical experience gives ample indication of the major benefit to individuals properly selected.” In the rebuttal Corcos states, “Dr. Van Kerrebroeck admits easily that the literature supporting the use of injectables as first option to treat [stress urinary incontinence] is extremely poor....[T]he whole evidence that we have are only four published articles.” He agrees that injectables are a good treatment option for obese, sick and recurrent patients but points out that that was not the topic of this “debate.” He states that the fact that bulking agents are popular 220 VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY

“just means that the marketing has been well done but does not give more science to the topic.” Half empty or half full? You decide. Alan J. Wein, M.D., Ph.D. (Hon.)

Is it Possible to Improve Elderly Male Bladder Function by Having Them Drink More Water? A Randomized Trial of Effects of Increased Fluid Intake/Urine Output on Male Lower Urinary Tract Function M. Spigt, O. van Schayck, P. Knipschild, K. Westerterp, C. van de Beek, P. van Kerrebroeck, J. Pel, R. van Mastrigt and A. Knottnerus, Department of General Practice, Maastricht University, Maastricht, The Netherlands Urology 2006; 68: 1031–1036. Objectives: Several animal studies have shown that bladder performance improves as a result of diuresis. Whether increased urine output also has beneficial effects on elderly male bladder function and lower urinary tract symptoms is unknown. Methods: We performed a randomized placebo-controlled trial of 141 men, 55 to 75 years of age, with moderate lower urinary tract symptoms. The experimental group drank 1.5 L of extra water daily. The control group consumed one tablespoon of placebo syrup daily. After 6 months, we evaluated bladder contractility, voided volumes, and the severity of lower urinary tract symptoms. The actual increase in water consumption was measured using the deuterium urine dilution method. Results: Water consumption in the intervention group increased by 359 mL (95% confidence interval [CI] 171 to 548) per 24 hours compared with the control group. At 6 months, no statistically significant effect was found in the maximal flow rate (0.9 mL/s, 95% CI Ϫ0.4 to 2.2) compared with placebo. A statistically significant effect was found for bladder pressure (20 cm H2O, 95% CI 6 to 34) and bladder wall stress (1.9 N/cm2, 95% CI 0.3 to 3.5). In addition, it showed that the experimental group had greater maximal (44 mL, 95% CI Ϫ1to90) and average (26 mL, 95% CI 1 to 51) voided volumes per urination. The subjective effect parameters improved in both groups, but no statistically significant differences were found between the two groups. Conclusions: It seems possible to improve some aspects of male bladder function by drinking more water. However, the effects are too small to be clinically relevant. Editorial Comment: This is an interesting way of looking at bladder function and an interesting question, to which the answer is, “not significantly.” In their discussion the authors do make an interesting comment regarding “lifestyle interventions” in the treatment of lower urinary tract symptoms. They state that 69% of urologists have been shown to advise such interventions, which might include fluid restriction, caffeine or alcohol avoidance, rescheduling medications such as diuretics, retraining of “bad” voiding habits and many other instructions. Regarding these, they state, “. . . these instructions seem to be based on clinical experience or findings from etiologic studies, because we found no randomized trials in which the effects of self management as an intervention for men with [lower urinary tract symptoms] were investigated . . . [B]ecause [lower urinary tract symptoms are] more of a functional, than an anatomic, disorder, we believe that self management intervention should be investigated more often.” This sounds reasonable in view of the dearth of such data. Finally, the authors do admit that their method of increasing physiological loading produced effects that were too small (only a 10% increase), as opposed to the 200% to 300% increase in urine output seen in the animal studies that they referred to. Alan J. Wein, M.D., Ph.D. (Hon.)

Tolterodine and Tamsulosin for Treatment of Men With Lower Urinary Tract Symptoms and Overactive Bladder: A Randomized Controlled Trial S. A. Kaplan, C. G. Roehrborn, E. S. Rovner, M. Carlsson, T. Bavendam and Z. Guan, Department of Urology, Weill Cornell Medical College, New York, New York JAMA 2006; 296: 2319–2328. Context: Men with overactive bladder and other lower urinary tract symptoms may not respond to monotherapy with antimuscarinic agents or alpha-receptor antagonists. Objective: To evaluate the efficacy and safety of tolterodine extended release (ER), tamsulosin, or both in men who met research criteria for VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY 221 both overactive bladder and benign prostatic hyperplasia. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted at 95 urology clinics in the United States involving men 40 years or older who had a total International Prostate Symptom Score of 12 or higher and, an International Prostate Symptom Score quality-of-life (QOL) item score of 3 or higher, a self-rated bladder condition of at least moderate bother, and a bladder diary documenting micturition frequency (Ͼorϭ8 micturitions per 24 hours) and urgency (Ͼorϭ3 episodes per 24 hours), with or without urgency urinary incontinence. Patients were recruited between November 2004 and February 2006, and the study was completed May 2006. Interventions: Patients were randomly assigned to receive placebo (n ϭ 222), 4 mg of tolterodine ER (n ϭ 217), 0.4 mg of tamsulosin (n ϭ 215), or both tolterodine ER plus tamsulosin (n ϭ 225) for 12 weeks. Main Outcome Measures: Patient perception of treatment benefit, bladder diary variables, International Prostate Symptom Scores, and safety and tolerability were assessed. Results: A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (PϽ.001), 146 (71%) receiving tamsulosin (Pϭ.06 vs placebo), or 135 (65%) receiving tolterodine ER (Pϭ.48 vs placebo). Patients receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (Ϫ0.88 vs Ϫ0.31, Pϭ.005), urgency episodes without incontinence (Ϫ3.33 vs Ϫ2.54, Pϭ.03), micturitions per 24 hours (Ϫ2.54 vs Ϫ1.41, PϽ.001), and micturitions per night (Ϫ0.59 vs Ϫ0.39, P.02). Patients receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (Ϫ8.02 vs placebo, Ϫ6.19, Pϭ.003) and QOL item (Ϫ1.61 vs Ϫ1.17, Pϭ.003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%). Conclusions: These results suggest that treatment with tolterodine ER plus tamsulosin for 12 weeks provides benefit for men with moderate to severe lower urinary tract symptoms including overactive bladder. Editorial Comment: This is an interesting article which addresses a significant point of controversy with respect to the treatment of older men with lower urinary tract symptoms (LUTS). Classically, older men with lower urinary tract symptoms have been presumed (by most prac- titioners) to have these symptoms on the basis of factors related to prostatic enlargement, bladder outlet obstruction or both. Therefore, classic treatment has been with ␣-adrenergic receptor antagonists, 5␣-reductase inhibitors or both—to address the dynamic and the static components of outlet resistance. Proponents of the use of antimuscarinics in these patients properly point out that the most bothersome symptom to men with LUTS is almost invariably the filling/storage component of their symptomatology and not the voiding/emptying component. Therefore, these intellectually correct clinicians have argued that it would make most sense to treat these patients with at least a component of therapy that would address the filling phase of micturition, ie, at this point in time, an antimuscarinic agent. There are series in the literature (cited in this article) that report favorable results with such a strategy but most are uncontrolled nonrandomized studies. These authors have bravely set out to try and provide some answers to the issues surrounding this controversy by doing a 4-armed placebo controlled study, well described in the abstract. The results, depending on reader vantage point and prejudices, can be described with the half-full/half-empty analogy. It is clear that over the time period utilized there were no adverse effects on voiding function, as measured by peak flow rate and residual urine volume, due to the use of the antimuscarinic agent. This is good news. Andersson attributes this, and it makes sense, to the fact that antimuscarinics provide their effects by competitive inhibition, and that during voluntary micturition the amount of acetylcholine released by the postganglionic parasympathetic fibers simply overwhelms the concentration of antimuscarinic at the receptor effector site produced by oral administration of the drug.1 Thus, their therapeutic effects are due to the fact that the usual serum concentration can effectively inhibit lower concentrations of acetylcholine presumably involved in some of the pathophysiological mechanisms responsible for overactive bladder. As far as the usual indices of tolerability are concerned, the incidence of dry mouth recorded with the antimuscarinic alone was only 7%, much lower than in most published series. As the authors suggest, this may be attributed to the fact that nighttime dosing will yield a lower incidence of dry mouth, probably because the peak rise in serum concentration will occur when the individual is least apt to notice dry mouth. However, the incidence of dry mouth in the antimuscarinic plus ␣-blocker group was 21%. As the authors again point out, this difference needs to be further explored and explained. The incidence of dry mouth in the placebo group was 2%. Constipation incidence was 4% in both antimuscarinic and combination groups, and 2% in the placebo group. With respect to efficacy, the primary outcome indicator was a rather simpleminded perception of the treatment benefit question: “Have you had any benefit from your treatment?” If so, another question was asked: “Have you had little benefit or much benefit?” Statistical consid- 222 BENIGN PROSTATIC HYPERPLASIA

erations aside, in the protocol specified, intent to treat analysis the percent of patients reporting benefit in placebo, antimuscarinic alone, ␣-blocker alone and combination groups was 61.7%, 65.1%, 70.5% and 80%, respectively. The authors properly did an intent to treat analysis in which missing data for patient perception of treatment benefit were handled by imputation, assuming no change from baseline values. The results were 59.5%, 62.7%, 67.9% and 76.4%, respectively. Interestingly, the results to the second part of this question—ie for those who perceive benefit was it of little benefit or much benefit—were not specified. Hopefully, these will become available. Outcome measures for urgency urinary incontinence episodes, urgency episodes, 24-hour frequency, nighttime frequency, and International Prostate Symptom Score and quality of life were all listed in graphic form with the numerical changes on the vertical ordinate and the baseline weeks on the horizontal ordinate. Although there were many results that were statistically significant in favor of the combination vs placebo, whether these are clinically significant (see results in the abstract) is a judgment that can be made only by patient and caregiver. With the small numerical differences the problem is compounded by the fact that the baseline numbers for each group are different as well. For instance in the urinary urgency incontinence episode for 24-hour reduction comparison the baseline for the combination group is 1.40 and the baseline for placebo is 0.98. Although the gross percentages work out to a 62.9% reduction for the combination and a 31.2% reduction for placebo, from the looks of the reductions (actual numbers not given) of urgency urinary incontinence episodes for the antimuscarinic alone and the ␣-blocker alone the percentage reduction in urgency incontinence episodes was actually greater in these 2 groups than in the combination group. Each clinician will have to examine the individual graphs in the context of the baseline numbers to see whether he or she considers these differences significant. Finally, and interestingly, the authors comment on the fact that there were no significant differences in maximum urinary flow rate, and the fact that in previous studies tamsulosin monotherapy significantly increased this variable in similar patient populations. They attribute this to the fact that the peak urinary flow rate in this study was 12.9 ml per second, whereas in previous studies it was 9 to 10 ml per second, and offer the opinion that improvement in peak urinary flow rate may be less likely in patients with greater flow rates at baseline. I think that the practice pattern of many clinicians at this point is to institute therapy in such men with an ␣-blocker and perhaps a 5␣-reductase inhibitor, and consider the addition of an antimuscarinic therapy in those whose filling/storage symptoms do not improve and are bothersome, and who would rather continue conservative medical therapy than proceed to minimally invasive or surgical therapy for outlet obstruction, assuming that this exists. Although the data in this study need further analysis, a further study examining the value/nonvalue of “add-on” antimuscarinic therapy would help to answer the question of what would be the ultimate place of antimuscarinic therapy in the treatment of men similar to those included in the current study. Alan J. Wein, M.D., Ph.D. (Hon.)

1. Andersson KE: Treatment-resistant detrusor overactivity—underlying pharmacology and potential mechanisms. Int J Clin Pract, suppl., 2006; 151: 8.

BENIGN PROSTATIC HYPERPLASIA

Transurethral Microwave Thermotherapy Effectiveness in Small Prostates B. T. Larson, L. Mynderse, J. Ulchaker, C. Pulling and T. R. Larson, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio Urology 2006; 68: 790–794.

Objectives: To dispel the misconceptions that patients with small prostates react differently than patients with larger prostates to cooled transurethral microwave thermotherapy. Cooled transurethral microwave thermotherapy has developed into a valid alternative to treat men with lower urinary tract symptoms due to benign prostatic hyperplasia. However, doubts still remain regarding the ability of this ofﬁce-based technique to treat smaller prostates. Methods: A database of 713 men from six previous studies using cooled transurethral microwave thermotherapy devices developed by Urologix were combined for this analysis. The data were analyzed to determine whether the baseline prostate size had a signiﬁcant effect on American BENIGN PROSTATIC HYPERPLASIA 223

Urological Association Symptom Index, peak flow rate, quality-of-life score, or symptom problem index. Follow-up intervals in this analysis include 6, 12, 24, 36, 48, and 60 months after therapy. Visual analog scale ratings during treatment were also assessed. General linear models and repeated measures analyses were performed. Results: Statistical analysis showed no effect of baseline prostate size on treatment outcomes for more than 5 years. Visual analog scale measurements were also not affected by the baseline prostate size. Conclusions: Transurethral microwave thermotherapy appears to be as efficacious in treating patients with small prostates as those with large prostates and should be offered as a treatment modality to patients with prostates of all sizes. Editorial Comment: The use of minimally invasive, office based procedures for benign prostatic hyperplasia, such as microwave thermotherapy and transurethral needle ablation of the prostate, have become a mainstay in American urology. While data exist regarding long-term efficacy and safety, a number of fundamental questions remain, including long-term durability and optimal patient characteristics. Do patients with a particular subset of symptoms (ie storage versus voiding) or prostate size (ie small versus large) have better outcomes? In this study the authors analyzed a database of 713 men from 6 clinical trials treated with cooled transurethral thermotherapy. The data from this study suggest that cooled transurethral thermotherapy is equally effective in small and large prostates. The authors base their opinion on what they believe are durable results at 5 years in prostate weights divided into quartiles of less than 30, 30 to 40, 40 to 60 and greater than 60 gm. However, on close inspection of the data a host of questions remain. Baseline data for American Urological Association symptom score and peak flow rate are not reported. Did prostates of varying size present differently? Would the conclusions have been the same if the absolute improvement among the 4 groups had been similar although baseline presentation was vastly different? Moreover, the improvement at 5 years degrades compared to 2 and 6 months. In addition, the absolute improvement at 5 years for symptoms and flow rate approaches what we see in medical therapy. In fact, how many patients are considered therapeutic failures and have gone back to medical therapy or required a secondary procedure? In a field driven by marketing and economics attempts to clarify the usefulness of these devices are needed. In a utopian world a comparative head-to-head clinical trial of all the devices would address many of the aforementioned questions. We await such a study. Steven A. Kaplan, M.D.

Randomized Trial Comparing Holmium Laser Enucleation of Prostate With Plasmakinetic Enucleation of Prostate for Treatment of Benign Prostatic Hyperplasia M. C. Neill, P. J. Gilling, K. M. Kennett, C. M. Frampton, A. M. Westenberg, M. R. Fraundorfer and L. C. Wilson, Department of Urology, Tauranga Hospital, Tauranga, New Zealand Urology 2006; 68: 1020–1024. Objectives: To compare the alternative energy sources of the holmium:yttrium-aluminum-garnet laser and bipolar plasmakinetic energy for endoscopic enucleation. Methods: A prospective, randomized controlled trial was undertaken, with 20 patients assigned to each group. The preoperative and postoperative measures included transrectal ultrasound-assessed prostate volume, postvoid residual urine volume, and urodynamic evaluation ﬁndings. The intraoperative measures included procedure length, energy use, and specimen weight. All adverse events were recorded at each postoperative visit in a 1, 3, 6, and 12-month protocol. Results: No differences were found in the preoperative characteristics between the two groups. The signiﬁcant differences favoring holmium laser enucleation of the prostate compared with plasmakinetic enucleation of the prostate were seen in the operative time (43.6 versus 60.5 minutes), recovery room time (47.1 versus 65.6 minutes), and bladder irrigation requirement (5% versus 35%). The outcomes after holmium laser enucleation of the prostate and plasmakinetic enucleation of the prostate were in all other respects similar by the postoperative outcome measures assessed. Conclusions: Plasmakinetic enucleation of the prostate is a safe and technically feasible procedure for the enucleation of prostatic adenomata. Plasmakinetic enucleation of the prostate is limited by the longer operative and recovery room times, as well as a more pronounced postoperative irrigation requirement because of reduced visibility and a greater propensity for bleeding. The transfusion rates and catheterization and hospitalization times were similar. The optimal energy source for enucleation should still be considered the holmium laser, but bipolar energy can be considered by users already experienced with holmium laser enucleation of the prostate. Editorial Comment: I am always intrigued about single center, small population studies assessing various therapies. In general, they are done comparing the gold standard of the authors with 224 BENIGN PROSTATIC HYPERPLASIA

another, usually newer form of therapy. The New Zealand group has been at the forefront of the holmium laser experience. Their own treatment strategy has evolved during the last decade from laser resection to laser enucleation. They have been devoted to the technology, have generated the most data sets with this technique and have reported the best results. In this study enucleation with the holmium laser device was compared to that with the pulsed bipolar device. In essence, in this small group of men the results were similar, with surgical time favoring the holmium laser. Can these data be easily extrapolated to common urological practice? We must be judicious and thoughtful in our evaluation of new techniques and technologies. There are significant learning curves as well as significant startup costs for some of these technologies. Nevertheless, I am confident that regardless of the technique individual urologists ultimately select, whether they use one or several types, their results should approach those reported in the literature. Moreover, it appears from this and other studies that regardless of technique, the best improvement in symptoms and flow rate results from surgical reduction of prostate volume. Steven A. Kaplan, M.D. Transplantation/Vascular Surgery

Anesthesia for Laparoscopic Donor Nephrectomy: Is Nitrous Oxide Contraindicated?

Rizk El-Galley,* Lee Hammontree, Donald Urban,† Albert Pierce and Yasser Sakawi From the Division of Urology, Department of Surgery, and Department of Anesthesiology (AP, YS), University of Alabama at Birmingham, Birmingham, Alabama

Purpose: We performed this study to test the hypothesis that nitrous oxide produces clinically signiﬁcant bowel distention during laparoscopic abdominal surgery.

Materials and Methods: Laparoscopic kidney donors were randomized into 2 groups. Group 1 received N2O and oxygen inhalation through anesthesia, and group 2 received a mixture of air and oxygen. All patients received the same preanesthetic and anesthetic medications. The surgeon was blinded to the use of N2O. The surgeon was given the option to discontinue N2O use (if it was used) if he/she thought that the bowel distention was increasing surgical risk. Postoperative data were collected on bowel symptoms, pain and recovery.

Results: A total of 28 patients were enrolled in the study, 12 of whom received N2O (group 1) and 16 who did not receive N2O (group 2). Mild to moderate bowel distention was reported by the surgeons in 6 patients (50%) in group 1 and 1 patient only ϭ in group 2 (6%, p 0.007). Severe bowel distention was encountered in 4 patients, 3 of whom received N2O (25% of group 1). Nausea and vomiting on postoperative day 1 was reported by 50% of patients in group 1 and 25% of group 2. There was no difference in the pain scores between the 2 groups. No intraoperative or postoperative complications were encountered.

Conclusions: The use of N2O anesthetic causes bowel distention in 50% of abdominal laparoscopic donor nephrectomy operations. The distention was severe enough to interfere with the progress of surgery in 25% of cases and the use of N2O had to be discontinued. Key Words: laparoscopy, nephrectomy, anesthesia, intraoperative complications, postoperative complications

itrous oxide has been used in medicine for more than spaces in the body (eg small and large bowel) is often disre- 200 years and in anesthesia for more than 150 garded. Therefore, we performed this study to test the hy- N years.1 It remains a popular anesthetic agent be- pothesis that nitrous oxide produces clinically important cause it is inexpensive, analgesic and short acting. It is most bowel distention resulting in possible renal and or bowel widely used mixed with oxygen to reduce the concentration injury during dissection in addition to slowing the progres- of other potent volatile anesthetics resulting in minimal sion of the operative procedure. cardiorespiratory depression. Laparoscopic surgery has gained much popularity in the last decade and has become the standard of care for many PATIENTS AND METHODS surgical procedures. This rapid progress entailed steep learning curves for surgeons and anesthesiologists. The use The study protocol was approved by the Investigation Re- view Board at our institution. Kidney donors were inter- of N2O to anesthetize patients during laparoscopic surgery has been a matter of debate between anesthesiologists and viewed by 1 of the study investigators the night before sur- surgeons at our institution. It has been suggested by surgery and the study was explained to them. Patients who agreed to participate in the study were enrolled. Patients geons that it causes bowel distention because N2O can diffuse in the bowel lumen.2 When abdominal distention occurs were randomized by the covering anesthesiologists using the in the course of an operation it may increase surgical diffi- card-withdrawal technique into 2 groups. Group 1 had a 3,4 culty to a considerable degree. It is universally recognized N2O and oxygen mixture while group 2 had a mixture of air that gastric inflation is normally avoidable, but the fact that and oxygen. The surgeon was blinded to the use of N2O. The nitrous oxide increases the volume of enclosed gas filled surgeon was allowed to abort the study and stop the use of N2O if he/she experienced difficulties due to bowel distention. The surgeon remained blinded to whether N2O was used. At the end of the study the surgeon was queried if Submitted for publication November 7, 2006. Study received Investigation Review Board approval. he/she thought the N2O was used based on the degree of * Correspondence: Division of Urology, Department of Surgery, bowel distention during the case. University of Alabama at Birmingham, FOT 1138, 1530 3rd Ave. S, Postoperative bowel symptoms, pain and recovery data Birmingham, Alabama 35294-3411 (telephone: 205-532-3481; FAX: 205-934-4933; e-mail: [email protected]). were collected by asking the patients to fill out a form before † Financial interest and/or other relationship with Boehringer, discharge home. Pain was recorded on a scale of 1 to 5. Sanofi and Pfizer. Nausea and vomiting where recorded as mild, moderate and See Editorial on page 14. severe.

0022-5347/07/1781-0225/0 225 Vol. 178, 225-227, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.030 226 NITROUS OXIDE ANESTHETIC AND BOWEL DISTENTION IN LAPAROSCOPIC NEPHRECTOMY

All patients received the same preanesthetic medication bowel distention in 50% of patients who received N2O during (2 mg midazolam). Anesthetic induction was achieved by anesthesia and in 25% of patients overall made the surgeon injection of 1.5 mcg/kg fentanyl and 4 to 6 mg/kg intravenous stop the study and discontinue N2O. We stopped the enroll- thiopental. Depolarizing muscle relaxants were not used. ment in the study after the mid-term analysis because 3 of 4 For maintenance of anesthesia patients were randomly as- patients who had severe bowel distention that interfered signed to 1 of 2 treatment groups. Group 1 received isoflu- with surgery were in the N2O group. Bowel distention in- rane with 70% N2O in oxygen and group 2 received isoflu- creases the risk of bowel injury and might slow postopera- rane in an air/O2 mixture. At the end of surgery inhaled tive bowel recovery. To our knowledge this is the first study anesthetics were discontinued. To reverse residual neuro- to report on the use of N2O inhalation during laparoscopic muscular blockade 40 to 70 mcg/kg neostigmine and 8 to 14 donor nephrectomy or laparoscopic retroperitoneal surgery. mcg/kg intravenous glycopyrolate were administered. Pre- The effects of N2O inhalation during laparoscopic chole- operative bowel preparation was not used for any of our cystectomy and laparoscopic bariatric surgery has been patients. All patients underwent hand assisted laparoscopic studied in prospective randomized studies with the surgeons 10,11 left donor nephrectomy. The detailed technique was previ- blinded to the use of N2O. Both reports failed to identify ously published by our group.5 Statistical analysis was per- significant bowel distention in the patients who received formed using SAS® 9.1 software for windows. The exact N2O. These results are different from our findings. We be- Fisher test was used for comparison. The alpha error was set lieve that the main difference is in the operative field. Renal to 5% for significance. surgery is a retroperitoneal surgery in which the bowel has to be mobilized and kept retracted during the renal dissec- RESULTS tion. A distended bowel is harder to retract and tends to float in front of the kidney, thus slowing the surgical progress and A total of 28 patients were enrolled in the study, of whom 12 increasing the risks of bowel injury due to surgery. In lapa- received N2O (group 1) and 16 patients did not receive N2O roscopic cholecystectomy and bariatric surgery the operative (group 2). Two additional patients (from group 1) were dis- field is usually limited to the anterior abdominal compart- missed from the study upon initial laparoscopic inspection of ment which makes bowel distention less noticeable. Akca the abdominal cavity because of significant adhesions due to et al reported a trial of 344 patients who were undergoing Ϯ previous surgery. The mean operative time SD in group 1 colonic surgery randomized to receive N2OvsnoN2O inha- was 132 Ϯ 35 minutes vs 145 Ϯ 25 minutes in group 2 lation during anesthesia.3 The surgeons were blinded to the ϭ (p 0.3) Mild to moderate bowel distention was reported by use of N2O. They found that moderate to severe bowel dis- the surgeons in 6 patients (50%) in group 1 and 1 patient tention developed in 23% of patients in the N2O group vs 9% ϭ Ͻ only in group 2 (6%, p 0.007). Severe bowel distention that in the no N2O group (p 0.001). interfered with the progress of surgery was encountered in 3 Postoperative bowel recovery has also been a concern in patients in group 1 (25%) and 1 patient in group 2 (6%). patients who receive N2O inhalation during surgery. Our Nausea and vomiting on postoperative day 1 was reported results showed that 50% of the N2O group reported nausea by 50% of patients in group 1 and 25% of those in group 2, and vomiting vs 25% of patients in the no N2O group. How- but the difference was not statistically significant. In ever, this difference was not significant possibly due to the group 1 3 patients and in group 2 no patients had nausea small sample size of the study. Divatia et al reported a and vomiting on postoperative day 2. Moderate to severe meta-analysis of 37 peer-reviewed articles related to the 12 pain on postoperative day 1 was reported by 92% of patients effects of N2O on postoperative bowel recovery. They found in group 1 and 87% of patients in group 2, and this difference that the omission of N2O inhalation reduced the odds of was not statistically significant. No intraoperative or post- postoperative nausea and vomiting by 28%, and the differ- operative complications were encountered. ence was more significant in females. This finding agrees with our results but we did not have enough patients in the DISCUSSION study to examine the differences in bowel recovery between males and females. Bloomfield et al studied the effects of

In 1990 Eger et al reported that the addition of N2Ode- N2O on postoperative nausea and vomiting in 119 patients creased the isoflurane requirement for clinical anesthesia.6 who had undergone extra-abdominal surgeries (excluding During the administration of nitrous oxide and oxygen mix- thoracoabdominal, intracranial, ophthalmologic and middle ture as an anesthetic the pressure and/or volume of gases ear surgery).13 This eliminates nausea and vomiting that is contained in various body cavities or hollow organs may secondary to bowel handling during surgery. These patients 7–9 become markedly increased. When a 4-to-1 liter mixture were divided into 2 groups, with 1 group receiving N2O and of N2O and oxygen, respectively, is used, the partial pres- oxygen and the second group receiving a mixture of room air sure of nitrous oxide will rapidly increase to 500 or 550 and oxygen. Postoperative vomiting during recovery from mm Hg. N2O is 35 times more soluble than nitrogen. The the anesthesia was reported in 15% of patients who received process of equilibration results in nitrogen molecules pass- N2O vs 5% of those who did not receive it. Similarly, nausea ing from the body cavity into the blood, and nitrous oxide was reported in 40% of patients who received N2Ovs20% ϭ molecules diffuse from the blood into the body cavity at a who did not receive N2O(p 0.005). much greater rate. This increases the volume and intralu- Our study has limitations. The sample size was too small minal pressure of the gastrointestinal tract, which produces to investigate if there were any subgroups of patients who bowel distention during surgery and possibly increases post- would be more likely to have bowel distention secondary to 3 operative emetic complications. the N2O use or if there were gender differences. It seemed The evidence that nitrous oxide causes clinically impor- that some patients were more susceptible to bowel disten- tant bowel distention is debatable. Our results showed that tion than others. However, our study was not powered to NITROUS OXIDE ANESTHETIC AND BOWEL DISTENTION IN LAPAROSCOPIC NEPHRECTOMY 227 analyze subgroups in relation to susceptibility for bowel 8. Saidman LJ and Eger EI: Change in cerebrospinal fluid pres- distention. We believe that the randomization controlled for sure during pneumoencephalography under nitrous oxide other factors that might have contributed to bowel disten- anesthesia. Anesthesiology 1965; 26: 67. tion. However, we were obligated to terminate the study 9. Eger EI and Saidman LJ: Hazards of nitrous oxide anesthesia when we realized that 3 of 4 patients who had significant in bowel obstruction and pneumothorax. Anesthesiology 1965; 26: 61. bowel distention that interfered with surgery were in the 10. Abballe C, Camaioni D, Mascaro A, Boccardi M and Evangelista N2O group. The estimation of bowel distention was based on M: [Anesthesia for laparoscopic cholecystectomy: the use of surgeon impression without objective measurement of the nitrous oxide in the anesthetic mixture]. G Chir 1993; 14: bowel diameter. It would be technically difficult and time- 493. consuming to make an accurate bowel diameter measure- 11. Brodsky JB, Lemmens HJ, Collins JS, Morton JM, Curet MJ ment during laparoscopic surgery. and Brock-Utne JG: Nitrous oxide and laparoscopic bariatric surgery. Obes Surg 2005; 15: 494. 12. Divatia JV, Vaidya JS, Badwe RA and Hawaldar RW: Omis- CONCLUSIONS sion of nitrous oxide during anesthesia reduces the incidence of postoperative nausea and vomiting. A meta-analysis. Anesthesiology 1996; 85: 1055. Our data suggested that the use of N2O anesthetic inhalation causes bowel distention in 50% of abdominal laparo- 13. Bloomfield E, Porembka D and Grimes-Rice M: Avoidance of scopic donor nephrectomy operations. The distention was nitrous oxide and increased isoflurane during alfentanil based anesthesia decreases the incidence of postoperative severe enough to interfere with the progress of surgery in nausea. Anesth Prog 1997; 44: 27. 25% of cases and the use of N2O had to be discontinued. There was a trend toward an increased incidence of nausea EDITORIAL COMMENT and vomiting with the use of N2O. Few topics cause as much heated discussion between sur-

geons and anesthesiologists as whether N2O should be used ϭ Abbreviations and Acronyms during abdominal surgery. The formula D 1/(1 – FiN2O) describes the maximum dilatation (D) that can occur with ϭ N2O nitrous oxide any fraction of inspired (FiN2O) N2O. With 70% N2O only a 3-fold increase in intestinal gas volume is theoretically possible. Normal bowel contains less than 100 ml of air so the REFERENCES maximum increase in volume would be 233 ml, hardly enough to interfere significantly with most procedures.1 1. Metcalfe NH: Military influence upon the development of an- Because severe distention occurred in 1 patient in the aesthesia from the American Civil War (1861–1865) to the nonN O group, factors other than N O must also be at work. outbreak of the First World War. Anaesthesia 2005; 60: 2 2 The 2 study groups were small and there is no statistically 1213. 2. Darvas K, Molnar Z, Irto I, Tarjanyi M and Flautner L: An- significant difference between groups when patients with aesthesiological indications and contraindications of mini- severe distention are compared. mally invasive surgery. Acta Chir Hung 1997; 36: 72. Although this study reports a higher incidence of bowel 3. Akca O, Lenhardt R, Fleischmann E, Treschan T, Greif R, distention with N2O it does not answer the question of Fleischhackl R et al: Nitrous oxide increases the incidence whether N2O is contraindicated. The irony is that N2O has of bowel distension in patients undergoing elective colon far more important properties that should limit its use. N2O resection. Acta Anaesthesiol Scand 2004; 48: 894. depresses vitamin B12 function, and for this reason alone the 4. Orhan-Sungur M, Apfel C and Akca O: Effects of nitrous oxide Food and Drug Administration would probably not allow its on intraoperative bowel distension. Curr Opin Anaesthesiol introduction into clinical use if it were a new drug.2 2005; 18: 620. 5. El Galley R, Hood N, Young CJ, Deierhoi M and Urban DA: Jay B. Brodsky and Harry J. M. Lemmens Donor nephrectomy: a comparison of techniques and results Department of Anesthesia of open, hand assisted and full laparoscopic nephrectomy. Stanford University School of Medicine J Urol 2004; 171: 40. Stanford, California 6. Eger EI, Lampe GH, Wauk LZ, Whitendale P, Cahalan MK and Donegan JH: Clinical pharmacology of nitrous oxide: 1. Levitt MD: Volume and composition of human intestinal gas an argument for its continued use. Anesth Analg 1990; 71: determined by means of an intestinal washout technic. 575. N Engl J Med 1971; 284: 1394. 7. Hunter AR: Problems of anaesthesia in artificial pneumotho- 2. Weimann J: Toxicity of nitrous oxide. Best Pract Res Clin An- rax. Proc R Soc Med 1955; 48: 765. aesthesiol. 2003; 17: 47. Urological Survey

RENAL TRANSPLANTATION AND RENOVASCULAR HYPERTENSION

A Highly Efficient Living Donor Kidney Exchange Program for Both Blood Type and Crossmatch Incompatible Donor-Recipient Combinations M. de Klerk, M. D. Witvliet, B. J. Haase-Kromwijk, F. H. Claas and W. Weimar, Department of Internal Medicine–Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands Transplantation 2006; 82: 1616–1620. Background: Lack of deceased donors for kidney transplant patients in the Netherlands encouraged alternative options to expand the living donor pool for recipients who have a willing donor but cannot donate directly because of a positive crossmatch or ABO blood type incompatibility. A national donor kidney exchange was considered as a possible solution. Methods: From January 2004 until June 2006, 146 couples from seven kidney transplantation centers were enrolled and participated in 10 match procedures. The Dutch Transplant Foundation was responsible for the allocation and the National Reference Laboratory for Histocompatibility in Leiden performed all the serological crossmatches. Results: For 72 out of the 146 (49%) donor-recipient combinations, a match was found. The success rate in the positive crossmatch group was significantly (P ϭ 0.0015) higher than in the ABO-incompatible group (44/69 vs. 28/77); median panel reactive antibodies of the matched recipients in the positive crossmatch group was 38% (0–100) and in the ABO-incompatible group 0% (0–27; P Ͻ 0.001). We were least successful for ABO blood type incompatible pairs with blood type O recipients, but for 9/53 (17%) there were possibilities. These nine blood type incompatible pairs were coupled to nine positive crossmatch pairs, which reflects the efficiency of combining the two categories of donor-recipient combinations into one program. Conclusion: The donor kidney exchange program in the Netherlands, in which all seven kidney transplantation centers participated, proved to be a successful program to expand the number of living donor kidney transplantations. Editorial Comment: Paired donation is increasingly being recognized as an alternative to desensitization protocols for patients with healthy and willing living donors but biological incompatibility due to ABO mismatch or a positive cross-match. Paired donation is where incompatible donor recipient pairs “swap” donors to achieve transplantation that does not require extraordinary recipient immune modulation, in essence avoiding the incompatibility. This report focuses on the Dutch experience during a 2-year period. Seven collaborating transplant centers that agreed on a common protocol used a shared HLA laboratory to identify HLA specificities, and matches were generated by a computer model. A total of 146 pairs were enrolled and 1,019 possible matches were generated during a 2.5-year period. Computer matching was done every 3 months. There were 32 cross-match negative paired donations, and 8 three-way and 24 two-way combinations, for a total of 72 matched pairs. This result represents a successful match rate of 49%, which is high for a paired donation program. At the time of publication this program had resulted in 57 completed transplants. Although the overwhelming majority of these transplants went well, there was 1 graft loss due to thrombosis and 1 early loss to rejection. For 10 pairs there was late stage exclusion, preventing transplantation from moving forward. Interestingly, the success rate in identifying a match was better for the positive cross-match group than for the ABO incompatible group. The most difficult group to match was blood type O recipients with a non-O donor. Paired donation is currently being developed in several regions of the United States, and will likely become more widespread in the near future. David A. Goldfarb, M.D.

0022-5347/07/1781-0228/0 228 Vol. 178, 228, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.080 Sexual Function/Infertility

Indwelling Ureteral Stents and Sexual Health: A Prospective, Multivariate Analysis

M. C. Sighinolﬁ,* S. Micali, S. De Stefani, A. Mofferdin, A. Grande, M. Giacometti, N. Ferrari, M. Rivalta and G. Bianchi From the Department of Urology, University of Modena, Italy

Purpose: Ureteral stents are common devices in urological practice. However, a stent may provoke lower urinary tract symptoms that severely affect quality of life. We evaluated the relationship between ureteral stents and male erection/female sexuality. Materials and Methods: A total of 30 men and 20 women undergoing ureteral stent positioning were considered. Patients affected by risk factors for erectile dysfunction or hormonal and metabolic alterations were excluded. Hystero-ovariectomy and menopause were considered exclusion criteria. Three questionnaires were administered before stenting and 45 to 60 days after stent positioning, including the International Prostate Symptom Score, the International Index of Erectile Function-5 for men and the Female Sexual Function Index for women. Results: Mean age was 45 years in men and 39 years in women. The mean Ϯ SD International Index of Erectile Function-5 score was 23.2 Ϯ 1.27 and the mean Female Sexual Function Index score was 32.15 Ϯ 2.71 before stent positioning. No lower urinary tract symptoms were reported before the procedure. After the ureteral stent was indwelling the mean International Index of Erectile Function-5 score was 13.5 Ϯ 4.01 and the mean Female Sexual Function Index score was 23.6 Ϯ 14.66 (p ϭ 0.000 and 0.007, respectively). Of 30 men 25 reported a pathological International Index of Erectile Function-5 score and 6 of 20 women denied any sexual activity due to stent related anxiety, resulting in the minimum Female Sexual Function Index score. In the remaining 14 women sexual life was not signiﬁcantly impaired by the ureteral stent (p ϭ 0.08). Conclusions: Ureteral stents impaired the quality of sexual life in male and female subjects. In men the most important distress was in regard to erectile function, probably related to lower urinary tract symptoms. Conversely female sexuality appeared to be severely impaired due to stent related psychological concerns. Key Words: ureter, stents, female, male, sexuality

ndwelling ureteral stents are common devices in con- with ureteral stents by specific questionnaires dealing with temporary urological practice. The first ureteral inser- sexual function to discover all variables that mainly impair I tion of a silicone tube dates back to 1967.1 Since then, patient satisfaction. technological progress has improved stent design and materials,2 increasing the indications for indwelling ureteral stents. Furthermore, the insertion procedure is almost stan- METHODS dardized with an undemanding learning curve. However, the widespread use of this practice has led to problems that A total of 50 men and women undergoing ureteral stent are characteristic of ureteral stents. Stents may actually positioning for unilateral ureteral obstruction were enrolled provoke significant LUTS, ranging from frequency and ur- in the study. Inclusion criteria were age younger than 55 years and an active sexual life. Patients with diabetes, hy- gency up to hematuria or infections.3 Such complications pertension, obesity, ischemic cardiovascular pathologies, may severely impact quality of life, causing discomfort, pain and hormonal and metabolic alterations (eg hypogonadism) and anxiety. In some clinical trials investigators tried to were excluded. Previous genital surgery, including hys- quantify symptoms with validated international question- tero-ovariectomy, and menopause were considered exclu- naires demonstrating clear outcomes with respect to mor- sion criteria. bidity and impaired quality of life.4,5 Sexual function and The stents were placed with the patient under local an- stent related discomfort were previously investigated and esthesia and intravenous sedation. All stents were composed sexual satisfaction was evaluated merely through general of silicone and polyurethane, and the choice of stent length quality of life questionnaires6 but not in detail. We evalu- was related to patient height. Plain abdominal x-ray was ated the relationship between ureteral stents and sexual routinely performed the day after endoscopy to verify correct function. We prospectively evaluated a cohort of patients stent placement. Three questionnaires were considered and administered before and 45 to 60 days after stent positioning. The first Submitted for publication November 14, 2006. questionnaire was I-PSS validated in Italian, relating to * Correspondence: Department of Urology, University of Modena, Via del Pozzo 71, 41100 Modena, Italy (telephone: 0039 059 general LUTS before and after the procedure. The other 2 4224766; e-mail: sighinolfi[email protected]). questionnaires were the Italian version of IIEF-5 and FSFI

0022-5347/07/1781-0229/0 229 Vol. 178, 229-231, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.039 230 INDWELLING URETERAL STENTS AND SEXUAL HEALTH for men and women, respectively, dealing with sexual activ- cantly related to sexual impairment (p ϭ 0.2). No encrusta- ity and satisfaction. As variables we considered baseline and tion, infection or stent dislodgment were detected in any end point I-PSS scores, stent permanence from 45 to 60 subjects. days, stent diameter and length, and patient gender and age. DISCUSSION Sampled data were inserted in a database and statistically analyzed with SPSS®, version 8.0 for Windows™. A Ureteral stents have become routine tools in urological prac- complete descriptive analysis of all available variables was tice to resolve ureteral obstruction due to different causes. performed. Statistical analysis was done by the Student t Indications involve the management of hydronephrosis due and 2-tailed Fisher exact tests. Patient gender and age, to stones, ureteral stricture, pregnancy, malignancy or ret- LUTS (I-PSS score), and stent permanence and size were roperitoneal fibrosis. Also, extensive use of these devices for included as covariates in a multivariate regression model a long time has aroused concerns of stent related morbidity, with significance considered at 0.05 for all tests. varying from simple and reversible side effects to severe complications.7 Ureteral stent encrustation,8,9 migration, 10 RESULTS fragmentation or even knotting are reported in the literature as quite frequent problems deriving mainly from long- All 30 men and 20 women completed the study with a mean term indwelling. Furthermore, several investigators de- stent permanence of 97 days (range 55 to 197). Mean age scribed cases of a forgotten stent inside the body, indicating was 45 years (range 34 to 55) in men and 39 years (range 28 the management of this severe problem.11 In a number of to 51) in women. The cause of obstruction was ureteral patients even simple stent permanence may provoke a type stones in 48 cases and retroperitoneal fibrosis in 2. No cur- of morbidity that is mainly related to bladder irritative rent malignancies were considered. Stent length was 24 to symptoms. Hematuria, dysuria, urgency and bacteriuria 28 cm according to patient height. Stent diameter was 4.7Fr with or without clinical urinary tract infection can severely in 45 patients and 6Fr in the remainder. affect the patient. Another problem is flank pain due to The mean Ϯ SD IIEF-5 score was 23.2 Ϯ 1.27 (range 21 to vesicoureteral reflux and persistent or de novo hydronephro- 25) and the mean FSFI score was 32.15 Ϯ 2.71 (range 28 to sis, which is an uncommon but reported event.4 As a result, 36) before stent positioning. None of the patients reported several patients experience depression, anxiety, loss of work bladder irritative symptoms or LUTS before the procedure days and sleeplessness.6,12,13 Overall quality of life is im- (I-PSS score less than 8). After the ureteral stent was in- paired in 45% to 80% of patients.6,13 dwelling the mean IIEF-5 score was 13.5 Ϯ 4.01 (range 8 to Several groups have attempted to explain stent related 24) and the mean FSFI score was 23.6 Ϯ 14.66 (range 2 to morbidity, considering the placement technique and stent 36) at the same time. Erection in men and the global FSFI characteristics. Rane et al found that stents crossing the score were significantly impaired by the ureteral stent midline in the bladder with incomplete loops at the lower (p ϭ 0.000 and 0.007, respectively). Only 5 of 30 patients end give rise to higher morbidity.14 Liatsikos et al investi- reported an IIEF-5 score of greater than 21. gated the position of the proximal end with the upper pole When we independently considered female sexuality, 6 of position better tolerated than the pelvic positoin.15 20 women (30%) denied any sexual activity, resulting in the The social impact of the problem has progressively arisen minimum FSFI score of 2. In the remaining 14 women (70%) since 2003, when Joshi et al described a new questionnaire sexual life was not significantly impaired by the ureteral directly related to stent morbidity (Ureteral Stent Symptom stent (mean FSFI score 32.85 Ϯ 2.62, p ϭ 0.08). The table Questionnaire), a valid and reliable instrument to evaluate lists these results. global impairment of quality of life.16 This new assessment Erectile failure in men was significantly related to patho- tool was required to standardize results and avoid the vari- logical I-PSS scores (p ϭ 0.001). Other variables that af- ability among series derived from the different question- fected sexual life with statistical significance were gender naires used. The Ureteral Stent Symptom Questionnaire (p ϭ 0.000) with the IIEF score more impaired than the FSFI deals with general health, sexual health and work perfor- score and the time of stent permanence (p ϭ 0.008). The mance. The quality of sexuality seems to be impaired by the variable of stent size (diameter and length) was not signifi- pain domain and by decreased social life and vitality. In our series we explored the actual condition of sexual function using IIEF-5 and FSFI. Using questionnaires dealing only with the sexual sphere allowed us to relate the IIEF and FSFI outcomes decrease in global scores to patient age and gender, I-PSS Mean Ϯ IIEF: score, stent size and permanence. Moreover, we investigated Ϯ Before stent 23.2 1.27 female sexuality in all domains before and after stenting After stent 13.5 Ϯ 4.01 p Value 0.0000 with desire, subjective arousal, lubrication, orgasm, satis- Mean Ϯ FSFI: faction and pain considered separately.17 The outcome of our Before stent 32.15 Ϯ 2.71 After stent 23.6 Ϯ 14.66 prospective study shows significantly impaired sexuality in p Value 0.007 each gender, especially in men. As previously stated by No. men after stent: 30 Damiano et al,18 stent size did not impair the quality of Normal score 5 Pathological score 25 erection or female sexuality. On the other hand, LUTS af- No. women after stent: 20 fected erectile function, as previously described for other Normal score 14 pathological conditions, such as benign prostatic hyperpla- Pathological score 6* sia.19,20 The duration of stent permanence is another con- * FSFI score of 2 indicated no sexual activity. cern impairing male sexuality. The decrease in the IIEF-5 INDWELLING URETERAL STENTS AND SEXUAL HEALTH 231 score was considered in a regression model in relation to the 4. Richter S, Ringel A, Shalev M and Nissenkorn I: The indwell- days of stenting (45 to 60) and the time of stenting was found ing ureteric stent: a ‘friendly’ procedure with unfriendly to be a statistically significant variable affecting erection. high morbidity. BJU Int 2000; 85: 408. Furthermore, in a small extra cohort of male patients10 5. Chew BH, Knudsen BE and Denstedt JD: The use of stents in considered within 20 days after stent positioning there was contemporary urology. Curr Opin Urol 2004; 14: 111. 6. Leibovici D, Cooper A, Lindner A, Ostrowsky R, Kleinmann J, no evidence of sexual dysfunction (data not shown), whereas Velikanov S et al: Ureteral stents: morbidity and impact on a 57.4% rate of global impairment was clearly noted at the quality of life. Isr Med Assoc J 2005; 7: 491. end of study followup. 7. Joshi HB, Stainthorpe A, Keeley FX Jr, MacDonagh R and When considering female sexuality, we found a statisti- Timoney AG: Indwelling ureteral stents: evaluation of qual- cally significant decrease in the global FSFI score 45 to 60 ity of life to aid outcome analysis. J Endourol 2001; 15: 151. days after stent positioning. However, 14 of the 20 women 8. Bariol S, Farebrother T, Ruthven S and MacNeil F: Compari- achieved an acceptable final score (mean 32.85 Ϯ 2.62) son of urinary stone and stent encrustation: biochemical without a statistically significant decrease from baseline analysis. J Endourol 2003; 17: 741. (p ϭ 0.1). The remaining 6 women achieved a post-stenting 9. Bultitude MF, Tiptaft RC, Glass JM and Dasgupta P: Manage- score of 2 (low or absent sexual desire) because they denied ment of encrusted ureteral stents impacted in upper tract. Urology 2003; 62: 622. any kind of sexual activity due to the concern of a foreign 10. Sighinolfi MC, De Stefani S, Micali S, Mofferdin A, Baisi B, body inside the ureter. Adequate sexual counseling before Celia A et al: A knotted multi-length ureteral stent: a rare the procedure may prevent this psychological distress, pro- complication. Urol Res 2005; 33: 70. viding normal sexual health to women undergoing stent 11. Park K, Jeon SS, Park H and Kim HH: Clinical features positioning. determining the fate of a long-term, indwelling, forgotten double J stents. Urol Res 2004; 32: 416. 12. Damiano R, Oliva A, Esposito C, De Sio M, Autorino R and CONCLUSIONS D’Armiento M: Early and late complications of double pigtail ureteral stent. Urol Int 2002; 69: 136. Ureteral stent positioning represents a routine endourologi- 13. Joshi HB, Stainthorpe A, MacDonagh RP, Keeley FX Jr, cal practice to resolve ureteral obstruction. The device can Timoney AG and Barry MJ: Indwelling ureteral stents: be left inside the urinary tract even for long periods depend- evaluation of symptoms, quality of life and utility. J Urol 2003; 169: 1065. ing on the underlying pathological condition. However, ure- 14. Rane A, Saleemi A, Cahill D, Sriprasad S, Shrotri N and teral stents can severely impair global quality of life and the Tiptaft R: Have stent-related symptoms anything to do quality of sexual health in male and female subjects. In men with placement technique? J Endourol 2001; 15: 741. the most important distress is in regard to erectile function, 15. Liatsikos EN, Gershbaum D, Kapoor R, Fogarty J, Dinlenc CZ, probably related to LUTS and stent permanence. Female Bernardo NO et al: Comparison of symptoms related to sexuality can be extremely affected due to stent related positioning of double-pigtail stent in upper pole versus re- psychological concerns. nal pelvis. J Endourol 2001; 15: 299. 16. Joshi HB, Newns N, Stainthorpe A, MacDonagh RP, Keeley FX Jr and Timoney AG: Ureteral stent symptom questionnaire: development and validation of a multidimensional Abbreviations and Acronyms quality of life measure. J Urol 2003; 169: 1060. FSFI ϭ Female Sexual Function Index 17. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh IIEF ϭ International Index of Erectile Function R et al: The Female Sexual Function Index (FSFI): a multi- I-PSS ϭ International Prostate Symptom Score dimensional self-report instrument for the assessment of LUTS ϭ lower urinary tract symptoms female sexual function. J Sex Marital Ther 2000; 26: 191. 18. Damiano R, Autorino R, De Sio M, Cantiello F, Quarto G, Perdona S et al: Does the size of ureteral stent impact urinary symptoms and quality of life? A prospective ran- REFERENCES domized study. Eur Urol 2005; 48: 673. 19. Shiri R, Hakkinen JT, Hakama M, Huhtala H, Auvinen A, 1. Zimskind PR, Fetter JR and Wilkerson JL: Clinical use of long Tammela TL et al: Effect of lower urinary tract symptoms term indwelling silicone rubber ureteral splints inserted on the incidence of erectile dysfunction. J Urol 2005; 174: cystoscopically. J Urol 1967; 97: 840. 205. 2. Finney RP: Experience with new double ureteral catheter 20. Seftel A: Correlation between LUTS (AUA-SS) and erectile stent. J Urol 1978; 120: 678. dysfunction (SHIM) in an age-matched racially diverse 3. Pollard SG and Macfarlane R: Symptoms arising from Double-J male population: data from the prostate cancer awareness ureteral stents. J Urol 1988; 139: 37. week (PCAW). J Urol 2005; 174: 1940. Ejaculatory Disorders May Affect Screening for Prostate Cancer

Jochen Walz,* Paul Perrotte,* Andrea Gallina,* Francois Bénard,* Luc Valiquette,† Michael McCormack,* Francesco Montorsi‡ and Pierre I. Karakiewicz§,ʈ From the Cancer Prognostics and Health Outcomes Unit (JW, AG, PIK) and Department of Urology (PP, FB, LV, MM, PIK), University of Montreal, Montreal, Quebec, Canada, and Department of Urology, Vita-Salute University, Milan, Italy (AG, FM)

Purpose: Ejaculatory disorders will be experienced in most men who are treated for localized prostate cancer. Baseline rates of ejaculatory disorders are unknown in men at risk for prostate cancer. Therefore, we explored the prevalence of those disorders and associated bother in men without evidence of prostate cancer who participated in an annual prostate cancer screening event. Materials and Methods: A cohort of 1,273 men without clinical evidence of prostate cancer completed the self-administered Danish Prostate Symptom Score for sexual dysfunction. This questionnaire quantifies the rate of reduced ejaculatory volume, ejaculatory pain and the rate of coexistent erectile dysfunction. Results: Mean age was 57.6 years (range 40 to 89). Of all men 46% (563) had reduced ejaculatory volume and 66% (356) of affected men were bothered by this condition. Ejaculatory pain was reported in 11% (134) and 89% (118) of these men reported associated bother. Finally, 45% (554) reported erectile dysfunction and 73% (403) reported associated bother. Reduced ejaculatory volume was associated with erectile dysfunction (p Ͻ0.001) and advanced age (p Ͻ0.001). Ejaculatory pain was not associated with one of these variables. Conclusions: Virtually all men will be affected by ejaculatory disorders after definitive treatment for localized prostate cancer. Therefore, it is important to observe that half of these individuals already have underlying reduced ejaculatory volume before treatment. Moreover, 1 of 10 men will be affected by ejaculatory pain. Both disorders are a significant source of bother and should be considered when treatment related quality of life is assessed. Key Words: ejaculation, pain, prostatic neoplasms, mass screening, impotence

exual dysfunction is common in aging men and con- ample, Wernicke et al reported 8 times higher odds of having siderably affects quality of life.1 Recent advances in ejaculatory difficulties in patients who received a high radi- S the diagnostics and therapeutics of erectile dysfunc- ation dose to the proximal penis compared to those who tion have increased the awareness of ED and other SDs. received a low dose.5 The prevalence of ejaculatory disorders Ejaculatory disorders represent a subtype of SD, and may be before and after PCa treatment is unknown. Similarly stratified into premature ejaculation, retrograde ejacula- bother related to ejaculatory disorders has not been quanti- tion, inhibited ejaculation, and reduced ejaculatory volume fied. Knowledge of baseline REV and of baseline EjP preva- with the extreme forms of anejaculation and ejaculatory lence is important because it can be used to extrapolate the pain.2,3 Patients who undergo treatment for localized PCa proportion of REV or EjP attributable to PCa treatment. will virtually always experience one or several disorders Most data on ejaculatory disorders are population based, or associated with ejaculation. This may vary from anejacula- focus on cohorts with BPH or LUTS. These cohorts demon- tion after RP to REV or EjP after radiotherapy.4,5 For ex- strate REV rates that vary from 13% to 74% and EjP rates that vary from 5% to 18%.1,2,6,7 Half of patients with BPH/ LUTS with REV are bothered by this problem and even 1,2,6 Submitted for publication November 22, 2006. more men are bothered by EjP. These data indicate that Study received approval from the Ethics Committee of the Uni- ejaculatory disorders are a relevant health problem with a versity of Montreal. significant impact on the well-being of the affected individ- * Nothing to disclose. uals. To our knowledge no study has addressed the preva- † Financial interest and/or other relationship with Merck Canada, GSK, Sanofi Aventis, Boehringer-Ingelheim, Pfizer, Eli Lilly, Bayer lence of REV and EjP in a PCa screening population or in a and Paladin. cohort with an age distribution that corresponds to a PCa ‡ Financial interest and/or other relationship with European Urol- screening cohort. It is known that baseline function in ogy, Pfizer, Bayer, Eli Lilly, Pierre Fabre, AMS and GSK. § Correspondence: Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center (CHUM), 1058, rue St-Denis, Montréal, Québec, Canada H2X 3J4 (telephone: 514-890-8000- 35336; FAX: 514-412-7363; e-mail: pierre.karakiewicz@umontreal. Editor’s Note: This article is the fifth of 5 published in ca). this issue for which category 1 CME credits can be ʈ Supported by the Fonds de la Recherche en Santé du Québec, the CHUM Foundation, the Department of Surgery and Les Urologues earned. Instructions for obtaining credits are given Associés du CHUM. with the questions on pages 358 and 359.

0022-5347/07/1781-0232/0 232 Vol. 178, 232-238, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.037 EJACULATORY DISORDERS AND PROSTATE CANCER SCREENING 233

participants through this event allowed convenient access to TABLE 1. Prevalence and degree of REV, EjP and ED, and respective associated bother in affected men the cohort and ensured a high response rate. The awareness event was advertised in local newspapers and invitations No. (%) were distributed at the venue. It was organized by a multi- No. REV 1,220 disciplinary group of urologists, oncologists, radiation on- Do you have ejaculation of semen? cologists, paramedical staff and support group members at Yes, in normal quantity 657 (54) Yes, in slightly reduced quantity 352 (29) our institution. The aim of the event was to educate, inform Yes, in significantly reduced quantity 135 (11) and raise public awareness about PCa. No 76 (6) No. bother due to REV 541 If ejaculation is reduced or absent, is this a problem for you? Questionnaire No problem 185 (34) All men were invited to complete a self-administered ques- Small problem 156 (29) Moderate problem 127 (23) tionnaire which consisted of the Danish Prostate Symptom Major problem 73 (14) Score addressing sexual problems (DAN-PSS-sex, tables 1 No. EjP 1,200 through 4).10 The DAN-PSS-sex is a validated questionnaire Do you have pain/discomfort during ejaculation? No 1,066 (89) consisting of the 3 domains REV, EjP and ED, and their Yes, slight 109 (9) respective bother.10 Bother is quantified only if functional Yes, moderate 18 (1.4) detriments are reported. Erectile dysfunction was defined as Yes, severe 7 (0.6) No. bother due to EjP 134 erections with reduced rigidity or inability to get an erection. If you have pain/discomfort during ejaculation, is this a The validity of the DAN-PSS-sex questionnaire was con- problem for you? No problem 15 (11) firmed in a large international study which also included 7 Small problem 71 (53) Canadian patients. The study was approved by the Ethics Moderate problem 32 (24) Committee of the University of Montreal. Major problem 16 (12) No. ED 1,218 Are you able to get an erection? Yes, with normal rigidity 664 (55) Statistical Analyses Yes, with slightly reduced rigidity 348 (28) Statistical analyses consisted of chi-square tests and chi- Yes, with severely reduced rigidity 149 (12) No, erection not possible 57 (5) square based trend tests, and were performed using com- No. bother due to ED 502 mercially available statistics software. All tests were 2-sided If you have trouble getting an erection, is this a and statistically significant at p Ͻ0.05. problem for you? No problem 135 (27) Small problem 126 (25) Moderate problem 115 (23) RESULTS Major problem 126 (25) The cohort consisted of 1,273 men. Mean age was 57.6 years (median 57, range 40 to 89). Because some participants did screening or referral populations may differ from that in not complete all questions, the numbers of evaluable indi- studies elucidating normative values from population based viduals were 1,220 (95.8%) for REV, 1,200 (94.2%) for EjP studies.8,9 We addressed this issue by assessing REV and and 1,218 (95.6%) for ED. EjP, and associated bother in a cohort of 1,273 men with no Of all men 46% (563) reported REV (table 1). Slight clinical evidence of PCa who participated in a PCa screening reduction was reported by 29% (352), significant reduction event. by 11% (135) and no ejaculation by 6% (76). Of men who reported REV 66% (356) were bothered by this condition. MATERIALS AND METHODS Mild, moderate and severe bother was reported by 29% (156), 23% (127) and 14% (73), respectively. Study Population Ejaculatory pain was reported by 11% (134) (table 1). Our cohort consisted of 1,273 men at risk for but without an Slight, moderate and severe EjP were reported by 9% (109), established diagnosis of PCa, who participated in an annual 1.4% (18) and 0.6% (7), respectively. Of all subjects who 2-day PCa awareness event in March 2006. Recruitment of reported EjP 89% (119) were bothered by this condition.

TABLE 2. Effect of age on REV and associated bother No. Younger Than No. 50–60 No. Older Than Total No. Chi-Square 50 Yrs (%) Yrs (%) 60 Yrs (%) (%) Trend Test

No. pts 251 454 507 1,212 Do you have ejaculation of semen? Yes, in normal quantity 195 (77.7) 290 (63.9) 169 (33.3) 654 (53.9) Ͻ0.001 Yes, in slightly reduced quantity 44 (17.5) 125 (27.5) 181 (35.6) 350 (28.9) Ͻ0.001 Yes, in signiﬁcantly reduced quantity 9 (3.6) 30 (6.6) 96 (18.9) 135 (11.1) Ͻ0.001 No 3 (1.2) 9 (2.0) 61 (12.0) 73 (6.0) Ͻ0.001 No. pts 54 159 326 539 If ejaculation is reduced or absent, is this a problem for you? No problem 6 (11.1) 52 (32.7) 126 (38.7) 184 (34.1) Ͻ0.001 Small problem 22 (40.7) 53 (33.3) 81 (24.8) 125 (28.9) 0.005 Moderate problem 12 (22.2) 36 (22.6) 78 (23.9) 126 (23.4) 0.7 Major problem 14 (25.9) 18 (11.3) 41 (12.6) 73 (13.5) 0.07 234 EJACULATORY DISORDERS AND PROSTATE CANCER SCREENING

TABLE 3. Effect of age on EjP and associated bother No. Younger Than No. 50–60 No. Older Than Total No. Chi-Square 50 Yrs (%) Yrs (%) 60 Yrs (%) (%) Trend Test

No. pts 251 452 492 1,195 Do you have pain/discomfort during ejaculation? No 220 (87.6) 404 (89.4) 437 (88.8) 1,061 (88.8) 0.7 Yes, slight 24 (9.6) 37 (8.2) 48 (9.8) 109 (9.1) 0.8 Yes, moderate 4 (1.6) 9 (2.0) 5 (1.0) 18 (1.5) 0.3 Yes, severe 3 (1.2) 2 (0.4) 2 (0.4) 7 (0.6) 0.2 No. pts 31 47 56 134 If you have pain/discomfort during ejaculation, is this a problem for you? No problem 2 (6.5) 4 (8.5) 9 (16.1) 15 (11.2) 0.1 Small problem 15 (48.8) 28 (59.6) 29 (51.8) 72 (53.7) 0.97 Moderate problem 7 (22.6) 10 (21.3) 15 (26.7) 32 (23.9) 0.6 Major problem 7 (22.6) 5 (10.6) 3 (5.4) 15 (11.2) 0.02

Slight, moderate and severe bother due to EjP was reported analysis due to missing information on age. REV was re- by 54% (72), 24% (32) and 11% (15), respectively. ported more frequently by older men (p trend Ͻ0.001), who Of all men 45% (554) reported some ED (table 1). Slightly were bothered to a lesser extent by this problem than or severely reduced rigidity during erections was reported in younger men (p trend Ͻ0.001). Age had no effect on the 28% (348) and 12% (149), respectively. Complete inability to reported rate of EjP or on the associated bother (p trend ϭ 0.7, get an erection was reported by 5% (57). Of those with any p trend ϭ 0.13, table 3). Table 4 shows the effect of age on ED degree of ED 27% (137), 25% (128) and 28% (138) perceived and associated bother. Older men reported ED more frequently it as a small, moderate or severe bother, respectively. (p trend Ͻ0.001) than younger men. However, they were less Figure 1 shows the distribution of bother severity accord- bothered by this problem (p trend ϭ 0.006). ing to the 3 questionnaire domains, namely REV, EjP and ED. Some degree of bother was reported by 66% of men with REV, 89% of men with EjP and 73% of men with ED. Severe DISCUSSION bother was reported by 14%, 12% and 25% in REV, EjP and Knowledge of baseline REV and EjP prevalence in men at ED groups, respectively. When bother of any source (REV, risk for PCa is important because it can be used to extrap- EjP, ED) was considered it was reported by 48% (606) of the olate the proportion of REV or EjP attributable to PCa whole population. treatment. We showed that 46% of all men in such a popu- Figure 2 shows the distribution of REV severity according lation have underlying REV (table 1). For 66% of these men to any extent of ED. Of men with no REV 74% reported no REV represented a bothersome condition and 14% were ED. Conversely, of men with severe REV 78% reported any severely bothered. Ejaculatory pain was reported by 11% of degree of ED. The severity of REV increased in proportion men, which represented for almost all (89%) of them a both- with any degree of ED (p trend Ͻ0.001). When addressing ersome problem. Erectile dysfunction was reported by 45% any bother due to REV stratiﬁed to the subgroups of no, of participants and represented a source of bother for 73% of mild, moderate and severe ED the respective percentages these men. Only a third of men affected by any kind of were 57% (96), 70% (141), 79% (88) and 55% (23). No asso- ejaculatory or erectile disorder were not bothered by either ciation between ED and EjP could be seen (p trend ϭ 0.4). of these conditions. Ejaculatory pain caused the highest rate Similarly, there was no association between ED and bother of overall bother (89%) and ED caused the highest rate of due to EjP (p trend ϭ 0.7). severe bother (25%, ﬁg. 1). Table 2 shows the effect of age on REV and its associated The overall rate of ED in our cohort was 45%, which is bother. There were 21 (1.6%) men who were excluded from comparable with previous studies from Canada (prevalence

TABLE 4. Effect of age on ED and associated bother No. Younger Than No. 50–60 No. Older Than Total No. Chi-Square 50 Yrs (%) Yrs (%) 60 Yrs (%) (%) Trend Test

No. pts 251 453 507 1,211 Are you able to get an erection? Yes, with normal rigidity 183 (72.9) 298 (65.8) 181 (35.7) 662 (54.7) Ͻ0.001 Yes, with slightly reduced rigidity 51 (20.3) 114 (25.2) 180 (35.5) 345 (28.5) Ͻ0.001 Yes, with severely reduced rigidity 16 (6.4) 36 (7.9) 96 (18.9) 148 (12.2) 0.001 No, erection not possible 1 (0.4) 5 (1.1) 50 (9.9) 56 (4.6) 0.001 No. pts 60 139 298 497 If you have trouble getting an erection, is this a problem for you? No problem 4 (6.7) 25 (18) 67 (22.5) 96 (19.3) 0.006 Small problem 19 (31.7) 30 (21.6) 88 (29.5) 137 (27.6) 0.6 Moderate problem 11 (18.3) 35 (25.2) 80 (26.8) 126 (25.4) 0.2 Major problem 26 (43.3) 49 (35.5) 63 (21.1) 138 (27.8) Ͻ0.001 EJACULATORY DISORDERS AND PROSTATE CANCER SCREENING 235

normal, SD may exert a more important effect on patient health related quality of life. This might particularly be the case in younger patients. Our data showed that younger men are significantly more bothered by REV than older men. However, this relationship is speculative because no longitudinal studies have addressed the effect of PCa treatment on REV. Furthermore, our findings are also important when quality of life detriments after RP are addressed. Postoper- atively all patients are affected by REV. Our data indicate that nearly 1 of 2 men is to some degree affected by REV even before surgery. Thus, it can be stated that REV is directly attributable to PCa treatment in whatever proportion exceeds the baseline prevalence of REV, namely 46%. The same can be stated for erectile dysfunction. Our data as well as the Salonia et al and Michl et al data demonstrated that only 43% to 55% of men undergoing RP are fully potent 11,12 FIG. 1. Distribution of degree of bother associated with any degree before treatment. of REV, EjP and ED. Bars represent percentages in 4 bother sub- Most available data addressing REV are population groups. based, or focus on patients with BPH or LUTS. Population based studies report REV rates of 13% to 46%.2,6 The observed REV rate of 46% in the current series is situated at 49%), as well as with results from other studies that report the upper level of these previously described rates. Our data ED rates (prevalence 43% to 55%).9,11,12 We intentionally corroborate the results regarding the association between did not exclude men with ED from the analysis because increasing age and increasing REV in the population based those men were able to ejaculate despite ED. Thus, exclusion studies of Rosen et al or Blanker et al.2,6 Conversely, we of these subjects might have biased the results. ED had a could not corroborate the results of Rosen et al regarding the significant impact on REV and REV increased with the association between REV bother and age.6 In a cohort of severity of ED (fig. 2). These results are comparable to 12,815 men Rosen et al found that bother due to REV did not previous population based studies in which REV is also change across age strata. We observed a significant trend associated with ED.2,7 Interestingly, we found that bother toward higher bother in younger men affected by REV. Fur- due to REV is decreased in men with severe ED. It could be thermore, we observed a higher overall rate of associated postulated that ED has a stronger effect on men than REV. bother (current study 66% vs Rosen et al 50% to 58%).6 Thus, the presence of severe ED takes precedence over other Blanker et al had no information on associated bother in the associated SDs. However, consistency cannot be confirmed study cohort of 1,605 men.2 However, they reported the in this cross-sectional study. Finally, ED had no association same association between increasing REV severity and in- with EjP. creasing ED severity as in our series. Ejaculatory pain was Age had a significant impact on REV because REV rates reported in 4% to 7% of individuals of population based increased with advanced age (table 2). This trend was ob- studies. Of individuals with EjP 88% reported associated served across all REV severity levels. When bother due to bother.6,13,14 We observed a higher rate of EjP (11%) com- REV was stratified according to age we found that younger men experienced more severe bother due to REV than their older counterparts. It could be postulated that REV is less prevalent but more bothersome in young individuals. Con- versely, age had no effect on the rate of EjP or on the rate of bother due to EjP (table 3). Age predisposed to ED in a similar manner as to REV. Increasing age was associated with increased ED and younger individuals were more bothered by ED than their older counterparts (table 4). Our results emphasize that ED is not the only relevant SD in men undergoing PCa screening. Instead, these men are also significantly affected by REV and EjP. It can be postulated that SD has several facets which should all be considered when evaluating sexual function in men. Thus, the consideration of REV and EjP domains in addition to the ED domain might contribute to a more complete evaluation of the contemporary male. The SD complex is also relevant for patients after PCa treatment. The effect of REV may be negligible for most patients shortly after treatment for localized PCa because cancer control considerations are key at that time. However, FIG. 2. Association between degrees of REV and ED. Bars represent once cancer control and immediate health issues return to percentages in 2 ED categories. 236 EJACULATORY DISORDERS AND PROSTATE CANCER SCREENING pared to these studies. However, the rates of associated absence of PCa diagnosis. Further studies will be necessary bother were comparable. to address this issue. Finally, the erectile and ejaculatory Studies investigating REV and EjP in BPH or LUTS domains are comprised of 3 questions in the DAN-PSS-sex patient cohorts showed higher rates of both disorders than questionnaire, thus, more detailed and specific data were in this cohort. Moreover, these studies demonstrated a not ascertained. clear association between increased REV and increased LUTS.6,7,14 Nickel et al and Litwin et al showed that especially the rate of ejaculatory pain can be increased in up to CONCLUSIONS 17% to 19 % of men with LUTS suggestive to BPH.7,13 Moreover, Hoesl et al also demonstrated that the severity of Virtually all men will be affected by REV after definitive ED is significantly correlated with the severity of LUTS, treatment for localized PCa. Therefore, it is important to even after adjusting for age.15 We do not report on the observe that half of these individuals already have underly- association between LUTS and either REV or EjP, which ing REV before treatment. Moreover, 1 of 10 men will be might represent a potential limitation. It remains to be seen affected by EjP. Both disorders are significant sources of what the relationship is between ejaculatory disorders and bother and should be considered when treatment related LUTS in screening cohorts. quality of life is assessed. Comparison of our results to those of population based cohorts indicates that the rates of REV and EjP might be higher in PCa screening cohorts or in age matched popula- Abbreviations and Acronyms tions. The same is true for REV associated bother. This is BPH ϭ benign prostatic hyperplasia surprising because a larger proportion of men in this cohort DAN-PSS-sex ϭ Danish Prostate Symptom Score should have been symptom-free. These men were recruited for sexual dysfunction for this study during a PCa awareness event and not in a ED ϭ erectile dysfunction urological office or outpatient clinic, where they might have EjP ϭ ejaculatory pain presented with a certain symptom or disorder. This observed LUTS ϭ lower urinary tract symptoms fact emphasizes that there are indeed limitations and diffi- PCa ϭ prostate cancer ϭ culties in extrapolation of data from population based stud- REV reduced ejaculatory volume ϭ ies to screening populations. RP radical prostatectomy SD ϭ sexual dysfunction The exact etiology of REV and of EjP is unknown. Local anatomical aspects like prostatic enlargement or bladder outlet obstruction might represent contributing factors. They could have a direct physical effect or could impair REFERENCES nerve function and/or blood supply.16 A psychological origin has also been suggested based on the coexistence of depres- 1. Rosen RC, Giuliano F and Carson CC: Sexual dysfunction and sive symptoms with SD in older men. The same men are lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Eur Urol 2005; 47: 824. frequently affected by arteriosclerosis, which may also con- 17 2. Blanker MH, Bohnen AM, Groeneveld FP, Bernsen RM, Prins tribute to these symptoms. Other organic causes like acute A, Thomas S et al: Correlates for erectile and ejaculatory 18 or chronic prostatitis are also possible. We did not assess dysfunction in older Dutch men: a community-based study. the prevalence of underlying comorbidities in the current J Am Geriatr Soc 2001; 49: 436. cohort. However, a similar population that participated in 3. McMahon CG, Abdo C, Incrocci L, Perelman M, Rowland D, the same awareness event, which was held at the same Waldinger M et al: Disorders of orgasm and ejaculation in venue 2 years earlier showed a low prevalence of comorbidi- men. J Sex Med 2004; 1: 58. ties which ranged from 0.5% to 10.1%.19 Therefore, based on 4. Kleinberg L, Wallner K, Roy J, Zelefsky M, Arterbery VE, Fuks questionnaire brevity and on participation rates we decided Z et al: Treatment-related symptoms during the first year not to include the previously used comorbidity module. following transperineal 125I prostate implantation. Int J Small sample size may represent one of the limitations Radiat Oncol Biol Phys 1994; 28: 985. 5. Wernicke AG, Valicenti R, Dieva K, Houser C and Pequignot E: of our study compared to studies such as the one reported Radiation dose delivered to the proximal penis as a predic- by Rosen et al, in which more than 12,000 men were tor of the risk of erectile dysfunction after three-dimen- 6 evaluated. On the other hand, the high response rate (94% sional conformal radiotherapy for localized prostate cancer. to 96%) represents an advantage of the current study. High Int J Radiat Oncol Biol Phys 2004; 60: 1357. response rates decrease the effect of potential selection bi- 6. Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E ases that may be introduced by nonresponders. This was et al: Lower urinary tract symptoms and male sexual dys- shown in a study by Blanker et al in which nonresponders of function: the multinational survey of the aging male a questionnaire based study reported, in a second round of (MSAM-7). Eur Urol 2003; 44: 637. evaluation, better general well-being and fewer voiding 7. Nickel JC, Elhilali M and Vallancien G: Benign prostatic hy- symptoms than the first round responders.20 Another limi- perplasia (BPH) and prostatitis: prevalence of painful ejaculation in men with clinical BPH. BJU Int 2005; 95: 571. tation of the study consists of the lack of information about 8. Litwin MS: Health related quality of life in older men without possible subsequent PCa diagnosis. It is likely that some of prostate cancer. J Urol 1999; 161: 1180. the participants were diagnosed with PCa. This knowledge 9. Karakiewicz PI, Aprikian AG, Bazinet M and Elhilali MM: could have affected the potential ability of REV or EjP to Patient attitudes regarding treatment-related erectile dys- predict PCa diagnosis. Our data do not indicate that REV or function at time of early detection of prostate cancer. Urol- EjP prevalence might differ according to the presence or ogy 1997; 50: 704. EJACULATORY DISORDERS AND PROSTATE CANCER SCREENING 237

10. Hald T, Nordling J, Andersen JT, Bilde T, Meyhoff HH and Interestingly enough the correlation between ejaculation Walter S: A patient weighted symptom score system in the and risk of PCa continues to represent a trigger point for evaluation of uncomplicated benign prostatic hyperplasia. debate. Indeed, Walz et al report on the results of an original Scand J Urol Nephrol, suppl., 1991; 138: 59. epidemiological study assessing the prevalence of ejacula- 11. Michl UH, Friedrich MG, Graefen M, Haese A, Heinzer H and tion and erection disorders in a population of men partici- Huland H: Prediction of postoperative sexual function after pating in a 2-day PCa awareness event in 2006. Even more nerve sparing radical retropubic prostatectomy. J Urol importantly prevalence and predictors have been debated in 2006; 176: 227. 12. Salonia A, Zanni G, Gallina A, Sacca A, Sangalli M, Naspro R a cohort of men not primarily complaining of LUTS or blad- et al: Baseline potency in candidates for bilateral nerve- der outlet obstruction, but in men participating in a PCa sparing radical retropubic prostatectomy. Eur Urol 2006; screening program. 50: 360. The authors have used an elegant and rigorous method- 13. Litwin MS, McNaughton-Collins M, Fowler FJ Jr, Nickel JC, ology in assessing the rate of 3 sexual disorders (reduced Calhoun EA, Pontari MA et al: The National Institutes of ejaculatory volume, ejaculatory pain and erectile dysfunc- Health chronic prostatitis symptom index: development tion) by means of an internationally validated psychometric and validation of a new outcome measure. Chronic Pros- instrument (eg DAN-PSS-sex) which has been widely used tatitis Collaborative Research Network. J Urol 1999; 162: to investigate the prevalence of any specific dysfunction and 369. the related degree of subject distress. This report provides 14. Frankel SJ, Donovan JL, Peters TI, Abrams P, Dabhoiwala several points of discussion with an interesting link to the NF, Osawa D et al: Sexual dysfunction in men with lower most frequently reported disorders (namely PCa and ejacu- urinary tract symptoms. J Clin Epidemiol 1998; 51: 677. lation dysfunction) in the uro-oncological and sexual medi- 15. Hoesl CE, Woll EM, Burkart M and Altwein JE: Erectile dysfunction (ED) is prevalent, bothersome and underdiagnosed cine fields. in patients consulting urologists for benign prostatic syn- Ejaculation disorders are clinically frequent in a PCa drome (BPS). Eur Urol 2005; 47: 511. screening population even before any PCa treatment. In- 16. Chang S, Hypolite JA, Zderic SA, Wein AJ, Chacko S and deed, while LUTS and sexual dysfunction are highly preva- DiSanto ME: Enhanced force generation by corpus caver- lent in aging men, and although the link between ED and nosum smooth muscle in rabbits with partial bladder outlet LUTS has recently become a rising star on the urological obstruction. J Urol 2002; 167: 2636. skyline, to the best of my knowledge this is the first study to 17. Goldstein I: The mutually reinforcing triad of depressive symp- address this issue in a large cohort of men with neither toms, cardiovascular disease, and erectile dysfunction. clinical evidence nor a diagnosis of PCa. REV was reported Am J Cardiol 2000; 86: 41F. in 46% men and was distressful in 66%. EjP affected 11% of 18. Colpi G, Weidner W, Jungwirth A, Pomerol J, Papp G, Har- men, 89% of whom were bothered by this condition. These greave T et al: EAU guidelines on ejaculatory dysfunction. results are extremely interesting because—as arguably em- Eur Urol 2004; 46: 555. phasized by Walz et al—the comparison of their data with 19. Lewinshtein DJ, Perrotte P, Lebeau T, Ramirez A, Benayoun S and Karakiewicz PI: Normal urinary and sexual function in those of population based cohorts indicates that the rates of men without evidence of prostate cancer from Montreal, REV and EjP might be higher in PCa screening cohorts or in Canada. BJU Int 2006; 97: 1273. age matched populations. 20. Blanker MH, Groeneveld FP, Prins A, Bernsen RM, Bohnen Is this of major interest to the urological reader? The real AM and Bosch JL: Strong effects of definition and nonre- point of originality and interest in the current study should sponse bias on prevalence rates of clinical benign prostatic have been the prevalence of these ejaculatory disorders in hyperplasia: the Krimpen study of male urogenital tract men presenting for a PCa screening and with an actual final problems and general health status. BJU Int 2000; 85: 665. diagnosis of PCa compared to those without such a diagnosis. Indeed, this would be significant in terms of predictive value at diagnosis (see previous data reporting ED as a prevalent finding in patients with undiagnosed PCa)3 to EDITORIAL COMMENT consider patients older than 50 years and complaining of bothersome ejaculatory disorders as being at potential It was only a few years ago when Leitzmann et al showed greater risk for having PCa or for PCa developing. Unfortu- that ejaculation frequency is not related to increased risk nately this point of major interest has not been raised by the 1 of prostate cancer. High ejaculation frequency was found authors, who ultimately justified it as a limitation of their to be possibly associated with a lower risk of organ con- analysis. fined PCa. Why has ejaculation been postulated as a hy- ED is highly prevalent in men at risk for PCa. In their pothetical risk factor for PCa? In an era when the corre- cohort of PCa screening men the authors reported a dra- lation among hormonal milieu, sexual health and PCa matic prevalence of 45% of some degree of erectile function pathophysiology was intensively but, compared with the impairment. ED was a bothersome condition in 73% of present scenario, potentially not exhaustively investi- those men. This result is strongly linked with previous gated, Krain supposed that ejaculation frequency could experiences (references 11 and 12 in article) demonstrat- mirror the frequency of sexual activity and, therefore, it ing that in men who preoperatively verbally self-reported would be an indicator of higher androgenic activity and, full sexual potency and strong motivation to maintain thus, a marker for a high risk population.2 Fortunately postoperative erectile function there is large prevalence of this does not sound like the case, or, better, the correla- severe ED. Unfortunately once more the authors did not tion between serum testosterone levels and risk of PCa is have the opportunity to use ED presence as a potential still controversial. predictive factor of subsequent PCa finding, although they 238 EJACULATORY DISORDERS AND PROSTATE CANCER SCREENING clearly explained that such a PCa awareness event did not 1. Leitzmann MF, Platz EA, Stampfer MJ, Willett WC and Gio- allow them to detail how many men did actually have PCa vannucci E: Ejaculation frequency and subsequent risk of at the final diagnosis. The previously mentioned lack of prostate cancer. JAMA 2004; 291: 1578. data significantly weakens the whole study. 2. Krain LS: Some epidemiologic variables in prostatic carcinoma in California. Prev Med 1974; 3: 154. Andrea Salonia 3. Carbone DJ Jr, Harrison LH and McCullough DL: Incidence of Department of Urology previously undiagnosed urologic malignancies in a popula- Scientific Institute H. San Raffaele tion presenting solely with the compliant of erectile dysfunc- Milan, Italy tion. J Urol, suppl., 1999; 161: 180, abstract 695. Urological Survey

MALE AND FEMALE SEXUAL FUNCTION AND DYSFUNCTION; ANDROLOGY

Age Related Variation of Salivary Testosterone Values in Healthy Japanese Males A. Uchida, R. G. Bribiescas, P. T. Ellison, M. Kanamori, J. Ando, N. Hirose and Y. Ono, School of International Liberal Studies, Waseda University, Tokyo, Japan Aging Male 2006; 9: 207–213. Objective: We examined age associated variation in salivary testosterone values among Japanese males as well as anthropometric measurements. Methods: Salivary samples were collected in pretreated sodium azide treated tubes. The first series: 15–79-year-old males (n ϭ 99); two morning and two evening samples were collected at home for two days. The second series: 90-year-old males (n ϭ 29); one morning sample was collected. Testosterone values were determined using an iodine125-based radioimmunoassay kit modified for saliva. Results: Results show 1) a significant decrease in salivary testosterone values from 20s to 40s and older, 2) no significant decline after 40 through 90 years old, 3) no significant age-related differences in the degree of intraindividual diurnal fluctuation across age groups of 40–70s, and 4) higher BMI is associated with the lower salivary testosterone among 40–70s. Conclusions: These results suggest that neither a constant decrease of salivary testosterone values or markedly reduced intraindividual fluctations are universal aspects of aging. Older males may maintain relatively high testosterone levels compared to younger men and a relatively ‘robust’ neuroendocrinological system. Editorial Comment: If these data are confirmed by other investigators, salivary testosterone levels may supplant serum testosterone levels. This test may represent an advance in the ability to diagnose hypogonadism. Allen Seftel, M.D.

Prevalence of Prostate Cancer Among Hypogonadal Men With Prostate-Specific Antigen Levels of 4.0 ng/ml or Less A. Morgentaler and E. L. Rhoden, Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Urology 2006; 68: 1263–1267. Objectives: To determine the prevalence of prostate cancer in hypogonadal men with a prostate-specific antigen (PSA) level of 4.0 ng/mL or less. Methods: A total of 345 consecutive hypogonadal men with a PSA level of 4.0 ng/mL or less underwent evaluation with digital rectal examination and prostate biopsy before initiating a program of testosterone replacement therapy. All men had low serum levels of total or free testosterone, defined as less than 300 and 1.5 ng/dL, respectively. Results: Cancer was identified in 15.1%. The cancer detection rate was 5.6%, 17.5%, 26.4%, and 36.4% for a PSA level of 1.0 or less, 1.1 to 2.0, 2.1 to 3.0, and 3.1 to 4.0 ng/mL, respectively (P Ͻ 0.05). Cancer was detected in 26 (30.2%) of 86 men with a PSA level of 2.0 to 4.0 ng/mL. Cancer was detected in 21% of men with a testosterone level of 250 ng/dL or less compared with 12% of men with a testosterone level greater than 250 ng/dL (P ϭ 0.04). Men with free testosterone levels of 1.0 ng/dL or less had a cancer rate of 20% compared with 12% for men with greater values (P ϭ 0.04). The odds ratio of cancer detection for men in the lowest tertile compared with the highest tertile was 2.15 (95% confidence interval 1.01 to 4.55) for total testosterone and 2.26 (95% confidence interval 1.07 to 4.78) for free testosterone. Conclusions: Prostate cancer was present in more than 1 of 7 hypogonadal men with PSA of 4.0 ng/mL or less. An increased risk of prostate cancer was associated with more severe reductions in testosterone. Editorial Comment: This study revives a quiescent argument. Should all men with hypogonadism undergo prostate biopsy before beginning testosterone replacement therapy? These data would suggest yes. Allen Seftel, M.D.

0022-5347/07/1781-0239/0 239 Vol. 178, 239-244, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.088 240 MALE AND FEMALE SEXUAL FUNCTION AND DYSFUNCTION; ANDROLOGY Endogenous Testosterone Levels and Smoking in Men. The Fifth Tromso Study J. Svartberg and R. Jorde, Department of Medicine, University Hospital of North Norway, Tromso, Norway Int J Androl Nov 29, 2006; Epub. Smoking is a risk factor of coronary heart disease (CHD), while the role of testosterone in the development of CHD is controversial. The reported effects of cigarette smoking on testosterone levels in men are conflicting, and smoking may be an important confounding factor when evaluating the relationship between testosterone levels and CHD. Thus, the objective of the present study was to examine the associations of smoking status and number of cigarettes smoked per day with total and free testosterone levels in a cross-sectional population-based study of 3427 men participating in the fifth Tromso study. Total testosterone, luteinizing hormone, follicle-stimulating hormone and sex hormone-binding globulin levels were measured with immunoassay while free testosterone levels were calculated. Waist circumference was also measured and two standardized questionnaires were completed, including smoking status and number of cigarettes smoked. The data were analysed with analysis of variance and covariance and multiple regression analysis. Smoking men had significantly higher levels of total and free testosterone compared with men who never smoked (p Ͻ 0.001 and Ͻ0.01 respectively). Both total and free testosterone levels increased significantly with increasing number of cigarettes smoked daily (p Ͻ 0.001). Smoking men had 15% higher total and 13% higher free testosterone levels compared with men who never smoked. Thus, smoking seems to be an important confounding factor when evaluating testosterone levels, and could possibly mask borderline hypogonadism. Editorial Comment: These data are quite interesting. Smoking is positively correlated to serum testosterone levels. It will be of interest to understand the mechanism behind this association. Allen Seftel, M.D.

The Relative Contributions of Aging, Health, and Lifestyle Factors to Serum Testosterone Decline in Men T. G. Travison, A. B. Araujo, V. Kupelian, A. B. O’Donnell and J. B. McKinlay, New England Research Institutes, Watertown, Massachusetts J Clin Endocrinol Metab 2007; 92: 549–555. Context: Though it is known that serum testosterone (T) concentrations decline with age, the relative contributions of changes in health and lifestyle to that decline have not been adequately assessed. Objective: To establish the relative importance of aging, health and lifestyle in contributing to male testosterone decline. Design: A prospective cohort study of health and endocrine functioning in randomly selected men, with a baseline (T1: 1987–89) and two follow-up (T2: 1995–97, T3: 2002–04) visits. Setting: An observational study of men residing in greater Boston, MA, USA. Participants: 1667 men aged 40–70 at baseline; follow-up on 947 (57%) and 584 (35%) at T2 and T3, respectively. Main Outcome Measures: Total serum testosterone (TT), calculated free testosterone (FT), sex hormone-binding globulin (SHBG). Results: There were substantial declines in TT and FT levels associated with aging alone. However, many health and lifestyle changes were associated with accelerated decline. A 4–5 kg/m(2) increase in BMI, or loss of spouse, was associated with declines in TT comparable to that associated with approximately 10 years of aging. Results were similar for FT, but fewer factors were associated with SHBG after age was taken into account. Conclusions: Both chronologic aging and changes in health and lifestyle factors are associated with declines in serum T. Comorbidities and lifestyle inﬂuences may be as strongly associated with declining T levels as is aging itself over the short- to mid-term. These results suggest the possibility that age-related hormone decline may be decelerated through the management of health and lifestyle factors.

Characterization of Verbal and Spatial Memory Changes From Moderate to Supraphysiological Increases in Serum Testosterone in Healthy Older Men M. M. Cherrier, A. M. Matsumoto, J. K. Amory, M. Johnson, S. Craft, E. R. Peskind and M. A. Raskind, Department of Psychiatry and Behavioral Sciences, University of Washington Medical School, Seattle, Washington Psychoneuroendocrinology 2007; 32: 72–79. MALE AND FEMALE SEXUAL FUNCTION AND DYSFUNCTION; ANDROLOGY 241

Background: It has been suggested that cognitive changes in response to T supplementation may occur within an ideal range. The objective of this study was to compare the cognitive responses of older, eugonadal men in whom moderate or large increases in serum testosterone levels was induced by exogenous testosterone supplementation. Design: Randomized, double-blind, placebo-controlled study with subsequent grouping of participants according to average increase in circulating T from baseline. Setting: Community dwelling participants. Participants: Fifty-seven healthy, eugonadal, community dwelling male volunteers, mean age 67 years (ϩ/Ϫ11 years). Interventions: Participants were randomized to receive weekly intra- muscular (I.M.) injections of either 50, 100 or 300mg T enanthate or placebo (saline) injection for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, weeks 3 and 6 of treatment and after 6 weeks of wash-out. Main Outcome Measures: Performance on cognitive tests of verbal and spatial memory. Results: Men with moderate increases in serum T and/or its metabolites demonstrated significant improvements in verbal and spatial memory. In contrast, men with large or low increases in circulating T levels, failed to demonstrate significant changes in memory. Conclusion: These results suggest that in healthy older men, beneficial changes in cognitive function induced by T supplementation are most evident with moderate changes in cognition from moderate to high T supplementation increases in T levels. Large or no to low increases in T levels do not appear to appreciably effect cognition. Editorial Comment: These 2 interesting studies add to the knowledge base about testosterone in men. The study by Travison et al suggests the possibility that an age related hormone decline may be decelerated through the management of health and lifestyle factors. This finding would suggest that a healthy lifestyle has benefits that may be yet unrecognized. The study by Cherrier et al suggests that testosterone replacement therapy, to a high level, is associated with positive changes in cognition. This finding is interesting and represents an important benefit of testosterone replacement. Allen Seftel, M.D.

Penile Length Alterations Following Penile Prosthesis Surgery S. Deveci, D. Martin, M. Parker and J. P. Mulhall, Departments of Urology, Weill Medical College of Cornell University, Presbyterian Hospital and Memorial Sloan Kettering Cancer Center, New York, New York Eur Urol 2007; 51: 1128–1131. Objective: Determine the impact of penile prosthetic surgery on penile length. Methods: Stretched flaccid penile length was measured in men undergoing first-time penile implant surgery. Measurements were done before implantation and at 1 and 6 mo postoperatively. Patients were evaluated by the International Index of Erectile Function (IIEF) preoperatively and the IIEF and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) at 6 mo postoperatively. Patients also provided subjective assessment of penile changes at 6 mo postoperatively. Preoperative and postoperative IIEF and EDITS scores were compared as were the patients who complained of penile length loss with those who did not. Results: Of the 56 patients, 50% were diabetic and 28.5% had previous radical prostatectomy; 78% of the implants were three- piece(Alpha-1,Mentor) and 22% were two-piece (Ambicor, American Medical Service). There were no statistically significant differences in penile length after the surgery compared to preoperative measurements. Forty of 56 patients (72%) reported a decrease in penile length, 10 of 50 (19%) reported no change, and 6 of 56 (9%) had a slight increase. Subjective penile length loss was more common in patients who had undergone radical prostatectomy before prosthesis implantation (32%). No statistical difference in EF domain scores occurred between patients who complained of penile length loss and those who did not; however, men complaining of length loss had lower IIEF satisfaction domain and EDITS scores. Conclusion: Penile prostheses do not have a negative impact on measured stretched flaccid penile length. Treatment satisfaction scores do not depend on subjective penile length loss. Editorial Comment: These data are reassuring. The lack of change in the flaccid length following implantation is noteworthy. It would have been helpful to have data that evaluated penile length in the erect state before and after implantation. Allen Seftel, M.D. 242 MALE INFERTILITY

Reactive Oxygen Species as an Independent Marker of Male Factor Infertility A. Agarwal, R. K. Sharma, K. P. Nallella, A. J. Thomas, Jr., J. G. Alvarez and S. C. Sikka, Center for Advanced Research in Human Reproduction, Infertility and Sexual Function, Glickman Urological Institute and Department of Obstetrics-Gynecology, Cleveland Clinic Foundation, Cleveland, Ohio Fertil Steril 2006; 86: 878–885. Objective: To determine the abnormal patterns of reactive oxygen species (ROS) production in male factor infertility (MFI) patients and to define the ROS reference values in such patients. Design: A retrospective study. Setting: Male infertility clinic at a tertiary healthcare center. Patient(s): We examined 132 MFI patients (all normal sperm parameters, n ϭ 24, and all abnormal sperm parameters, n ϭ 38) and 34 healthy donors. Intervention(s): Routine semen analysis, measurement of ROS. Main Outcome Measure(s): Sperm parameters, ROS levels (10(4) cpm/20 ϫ 10(6) sperm). Result(s): Normal, healthy donors had significantly higher (PϽ.0001) sperm concentration, motility, and morphology compared with all MFI patients. Univari- ate analysis indicated a significant association between MFI and log (ROS ϩ 1) (odds ratio [OR] ϭ 3.84), besides sperm parameters and age. A multivariate model using logistic regression analysis also indicated an independent association of log ROS with MFI (OR ϭ 4.25). The ROS cutoff values of 1.2–1.4 had a sensitivity of 0.70–0.78 with a corresponding specificity of 0.82. However, at a cutoff point of 1.2, the OR was 68.6, which increased with an increase in the cutoff. Conclusion(s): High ROS is an independent marker of MFI, irrespective of whether these patients have normal or abnormal semen parameters. We suggest the inclusion of ROS measurement as part of idiopathic infertility evaluation. Treatment with antioxidants may be beneficial in such patients. Editorial Comment: Bulk semen analysis is not a particularly good measure of male reproductive potential. These investigators assessed levels of ROS in 132 patients with male factor infertility, including those with normal sperm parameters, and compared the results to those of 34 sperm donors. Univariate and multivariate analysis demonstrated a significant association of ROS and male factor infertility independent of bulk semen parameters. Highlighting the inad- equacy of bulk semen parameters in consistently predicting male reproductive dysfunction, measures of sperm concentration, motility and strict morphology were similar between normal donors and those with male factor infertility and all normal sperm parameters. Reactive oxygen species levels represent an interesting and perhaps revealing potential tool in screening for male reproductive dysfunction. Craig Niederberger, M.D.

Sperm DNA Fragmentation: Paternal Effect on Early Post-Implantation Embryo Development in ART A. Borini, N. Tarozzi, D. Bizzaro, M. A. Bonu, L. Fava, C. Flamigni and G. Coticchio, Tecnobios Procreazione, Centre for Reproductive Health, Bologna, Italy Hum Reprod 2006; 21: 2876–2881. Background: The relationship between early embryo post-implantation development in couples undergoing assisted reproductive techniques (ARTs) and sperm chromatin alterations has not been satisfactorily explained. The aim of this study was to assess the relationship between sperm DNA fragmentation in IVF/ICSI patients, sperm parameters (concentration, motility and morphology) and ART outcome, especially with regard to clinical pregnancy and pregnancy loss (spontaneous miscarriage or biochemical pregnancy). Methods: DNA fragmentation was evaluated by TUNEL assay, performed on sperm suspen- sions after density gradient separation, in 132 men undergoing an ART cycle (82 IVF and 50 ICSI) and correlated with sperm parameters and ART outcome. Results: A highly signiﬁcant negative correlation was found between DNA fragmentation and sperm parameters. There was a close relationship between DNA fragmentation and post-implantation development in ICSI patients: the clinical pregnancy and pregnancy loss rates signiﬁcantly differed between patients with high and low sperm DNA fragmentation (P ϭ 0.007 and P ϭ 0.009, respectively). Conclusions: Sperm DNA fragmentation seems to affect embryo post-implantation development in ICSI procedures: high sperm DNA fragmentation can compromise ‘embryo viability’, resulting in pregnancy loss. MALE INFERTILITY 243

Editorial Comment: Using in vitro fertilization and intracytoplasmic sperm injection, embryol- ogists have nearly solved the problem of fertilization in infertile couples. However, even using ICSI, implantation and birth rates remain substantially lower than fertilization rates. These authors investigated the possibility of DNA damage accounting for the discrepancy between fertilization and implantation rates by measuring DNA fragmentation with the TUNEL assay in sperm from 132 couples undergoing IVF and IVF/ICSI. Sperm density, motility and morphology were all negatively correlated with sperm DNA fragmentation. When patients were separated into groups according to the degree of sperm DNA fragmentation with a threshold value of 10% the clinical pregnancy and pregnancy loss rates were signiﬁcantly different between those with high and low sperm DNA fragmentation. Thus, DNA fragmentation as measured by the TUNEL assay appears to have an adverse impact on implantation. The next step is to determine which sperm has the highest ﬁdelity DNA before injecting it into an ovum, without the assay itself damaging the sperm. Craig Niederberger, M.D.

Chromosome Abnormalities in One Thousand Infertile Males With Nonobstructive Sperm Disorders H. Elghezal, S. Hidar, R. Braham, W. Denguezli, M. Ajina and A. Saad, Department of Cytogenetics and Reproductive Biology, Farhat Hached University Teaching Hospital, Sousse, Tunisia Fertil Steril 2006; 86: 1792–1795. One hundred thirty-ﬁve in 1,000 (13.5%) Tunisian male infertile patients with nonobstructive spermatogenesis disorders were found to have chromosomal abnormalities. Editorial Comment: Screening guidelines of the American Urological Association and American Society for Reproductive Medicine recommend karyotypic analysis in men with sperm density less than 5 million per ml. However, karyotyping is expensive, and the incidence of karyotypic anomalies varies by ethnicity and geographic locale. These investigators screened 1,000 men in Tunisia with nonobstructive infertility and found an incidence of karyotypic anomalies of 13.5%. The most frequent anomaly was Klinefelter syndrome, with an incidence of 7%. Thus, although expensive, it is sensible to use karyotypic screening in men of Tunisian descent. Craig Niederberger, M.D.

Aging May Adversely Affect Testicular Sperm Recovery in Patients With Klinefelter Syndrome M. Emre Bakircioglu, H. F. Erden, T. Kaplancan, N. Ciray, F. Bener and M. Bahceci, Department of Urology, German Hospital, Istanbul, Turkey Urology 2006; 68: 1082–1086. Objectives: To investigate the clinical parameters or laboratory analyses that may have a predictive value for successful sperm retrieval in Klinefelter syndrome (KS). Methods: A total of 74 patients with nonmosaic KS were included in this study. All patients were azoospermic and underwent microdissection testicular sperm extraction for sperm recovery. The predictive values of patient age, testicular volume, serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels were assessed for successful sperm recovery. Results: Testicular sperm recovery was successful in 42 (56.7%) of 74 men. The serum follicle-stimulating hormone, luteinizing hormone, and total testosterone levels did not show any difference between the patients with successful and those with unsuccessful sperm recovery. However, the patients with successful sperm recovery were significantly younger (31.6 ϩ/Ϫ 4.3 years) than those with failed attempts (35 ϩ/Ϫ 5.1 years, P ϭ 0.002). In the receiver operating characteristics curve analysis, a cutoff of 30.5 years of age had a sensitivity of 78% and a specificity of 48% for successful sperm retrieval. Logistic regression analysis showed that sperm recovery was inversely related to patient age (odds ratio 0.854, 95% confidence interval 0.76 to 0.95). Conclusions: Microdissection testicular sperm extraction is an effective sperm recovery technique in patients with KS. Our data have demonstrated that aging might adversely affect the sperm recovery rate in men with KS. These results suggest that earlier infertility assessment and testicular sperm extraction in men with KS might play a critical role in their treatment. Editorial Comment: Spermatogenic dysfunction in men with Klinefelter syndrome is more severe in the nonmosaic form than in the mosaic form. These authors report their experience 244 MALE INFERTILITY

extracting sperm using microdissection in 74 men with nonmosaic Klinefelter syndrome. Over- all, 57% of patients yielded sperm by microdissection, and endocrine levels did not distinguish between men in whom sperm could or could not be found. However, younger men tended to yield sperm, with age 30.5 years identiﬁed as a reasonable threshold by receiver operating characteristic curve analysis. Thus, in counseling men with nonmosaic Klinefelter syndrome the urologist may recommend microdissection testicular sperm extraction at a younger age, especially if cryopreservation of testicular derived sperm is offered. Craig Niederberger, M.D.

Fertility in Men With Down Syndrome: A Case Report M. Pradhan, A. Dalal, F. Khan and S. Agrawal, Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Fertil Steril 2006; 86: 1765.e1–e3. Objective: To inform clinicians about fertility in males with Down syndrome. Design: Case report. Setting: Medical Genetics Department of a tertiary-care hospital. Patient(s): A 26-year-old man with conﬁrmed nonmosaic trisomy 21. Intervention(s): Karyotype, amniocentesis, paternity testing using microsatellite markers. Main Outcome Measure(s): Conﬁrmed paternity in the son of a male with nonmosaic trisomy 21. Result(s): A male with nonmosaic Down syndrome fathered a normal son, and the paternity was proven by microsatellite marker analysis. Conclusion(s): Although Down syndrome males have been reported to be infertile, it may not always be true. Infertility in males has been attributed to defective spermatogenesis, but ignorance of the sexual act may be one of the contributing factors. It is important to advise postpubertal Down syndrome males on contraceptive measures. Editorial Comment: It is widely assumed that men with nonmosaic trisomy 21 (Down syndrome) are sterile. Using accepted molecular biological techniques, the authors present the third reported case of paternity in a male with nonmosaic trisomy 21. Thus, clinicians may consider men with nonmosaic trisomy 21 as potentially fertile, and counsel these men and their families accordingly. Craig Niederberger, M.D. Management of High Grade Renal Trauma: 20-Year Experience at a Pediatric Level I Trauma Center

C. G. Henderson, S. Sedberry-Ross, R. Pickard, D. I. Bulas, B. J. Duffy, D. Tsung, M. R. Eichelberger, A. B. Belman and H. G. Rushton From the Divisions of Pediatric Urology (CGH, ABB, HGR), Pediatric Surgery (BJD, DT, MRE), and Diagnostic Imaging and Radiology (RP, DIB), Children’s National Medical Center and Department of Urology (SSR), George Washington University School of Medicine and Health Sciences, Washington, D. C.

Purpose: In the last 20 years the management of high grade, blunt renal trauma at our institution has evolved from primarily an operative approach to an expectant nonoperative approach. To evaluate our experience with the expectant nonoperative management of high grade, blunt renal trauma in children, we reviewed our 20-year experience regarding evaluation, management and outcomes in patients treated at our institution. Materials and Methods: We retrospectively studied all patients sustaining renal trauma between 1983 and 2003. Medical records were reviewed for mechanism of injury, assigned grade of renal injury, patient treatment, indications for and timing of surgery, and outcome. Injuries were categorized as either low grade (I to III) or high grade (IV to V). Results: We reviewed the medical records of 164 consecutive children who sustained blunt renal trauma between 1983 and 2003. A total of 38 patients were excluded for inadequate information. Of the remaining 126 children 60% had low grade and 40% had high grade renal injuries. A total of 11 patients (8.7%) required surgical or endoscopic intervention for renal causes, including 2 for congenital renal abnormalities and 1 for clot retention. Eight patients (6.3%) required surgical intervention for isolated renal trauma, of whom 2 (1.6%) required immediate surgical intervention for hemodynamic instability and 6 (4.8%) were treated with a delayed retroperitoneal approach. Only 4 patients (3.2%) required nephrectomy. All patients receiving operative intervention had high grade renal injury. Conclusions: Initial nonsurgical management of high grade blunt renal trauma in children is effective and is recommended for the hemodynamically stable child. When a child has persistent symptomatic urinary extravasation delayed retroperitoneal drainage may become necessary to reduce morbidity. Minimally invasive techniques should be considered before open operative intervention. Early operative management is rarely indicated for an isolated renal injury, except in the child who is hemodynamically unstable. Key Words: trauma severity indices; wounds and injuries; wounds, nonpenetrating; abdominal injuries

uring the last 20 years the management of HGBRT CNMC between 1983 and 2003. Imaging information from at our institution has evolved from primarily an op- 52 of these children was included in a previous report.6 A D erative to a nonoperative approach. Our early expe- total of 38 children were excluded due to incomplete medical rience with the nonoperative expectant approach in 4 pedi- records or lack of available radiographs (lost or returned atric patients was reported previously by Waxman et al.1 elsewhere). The remaining 126 children who comprise this Nonoperative treatment of HGBRT in children has subse- report ranged from 2 months to 17 years old (mean 9 years). quently gained increasing acceptance at other centers. Non- There were 56 females and 70 males. All cases were man- operative management has been reported to be effective in aged by the trauma team according to Advanced Trauma 2–7 40% to 87% of the cases. During the same period the Life Support standards, and all were subjected to early diagnosis and grading of renal trauma at our institution has abdominal CT when hemodynamically stable. 1,8,9 evolved from excretory urography to CT. To evaluate our The medical records were reviewed for mechanism of experience with the expectant nonoperative management of injury, grade of renal injury, management, indications for HGBRT in children, we reviewed our experience of evalua- and timing of surgery, and outcome. All available hospital tion, management and outcome in cases treated at our in- wide medical records were reviewed for pertinent followup stitution during a 20-year period. radiographic evaluations and blood pressure measurements following discharge. One pediatric radiologist (DIB) re- MATERIALS AND METHODS viewed all radiological studies to verify the grade of renal We retrospectively reviewed the medical records of 164 con- injury. Injury grade was based on the American Association secutive children with blunt renal trauma presenting at for the Surgery of Trauma Organ Injury Severity Scale. Injuries were categorized as either low grade (I to III) or high grade (IV to V). For patients requiring surgery for renal Submitted for publication September 27, 2006. injury the indications and timing of intervention were noted. Study received institutional review board approval. Immediate operative intervention was considered to be less

0022-5347/07/1781-0246/0 246 Vol. 178, 246-250, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.048 HIGH GRADE RENAL TRAUMA IN CHILDREN 247

TABLE 1. Mechanisms of injury TABLE 3. Number of patients and renal units by grade No. Pts Renal Injury Grade No. Renal Units No. Pts

Motor vehicle accident 38 I3936 Pedestrian struck by motor vehicle 35 II 17 16 Fall 23 III 24 24 Abuse 6 IV 36 35 Bicycle accident 5 V1515 Sports injury 5 Totals 131 126 Blunt torso trauma 3 Sledding 3 Assault 2 Equestrian 2 Skiing 2 II renal injury had persistent hematuria resulting in uri- All-terrain vehicle 1 In-line skating 1 nary clot retention that required cystoscopy for clot evacuation. Consequently, only 8 patients (6.3%) required surgical than 24 hours from initial evaluation at CNMC or known intervention exclusively for renal trauma, including 4 pa- immediate operative intervention elsewhere. Delayed surgi- tients with grade IV injury (1 bilateral) and 4 with grade V cal treatment was defined as greater than 24 hours after injury. Two of these patients required immediate surgical evaluation at CNMC. intervention, and 6 were treated with delayed (4 days to 89 weeks) surgical intervention. Indications for a delayed surgical approach in 5 of 6 patients included persistent fever RESULTS greater than 38.5C and/or worsening abdominal pain cou- During the 20-year interval 5 of the 126 children sustained pled with radiographic imaging that indicated significant bilateral renal trauma, resulting in injury to a total of 131 urinary extravasation (table 6). renal units. Motor vehicle accidents (38 patients), pedestri- ans struck by motor vehicle (35) and falls (23) were the most Radiographic Followup common mechanisms of injury (table 1). There were 70 in- Of 34 patients with grade IV renal injury 20 (59%) under- juries to the left kidney and 61 injuries to the right kidney. went followup imaging at 1 month to 10 years after injury Urinalysis results are outlined in table 2. Four patients had (mean 13.3 months, median 6). Imaging modalities included gross hematuria but no radiographic evidence of renal radioisotope scans in 14 patients (DMSA in 7, diethylene- trauma, and were excluded from the study. The injuries triamine pentaacetic acid in 3, GHA in 3, mercaptoacetyl- were grade I in 28% of the cases, grade II in 13%, grade III triglycine in 1), CT in 5 and renal/bladder sonography in 1. in 19%, grade IV in 28% and grade V in 12% (table 3). Three kidneys fully recovered without any evidence of renal Associated nonrenal injuries are outlined in table 4. There injury. A total of 17 patients had evidence of permanent was no increased incidence of associated nonrenal injuries renal injury. Two patients had focal scarring without loss of with higher grades of renal trauma. function, while 9 had scarring with partial loss of function Management by renal injury grade is outlined in table 5. (relative differential renal function 24% to 43%, see figure). A total of 37 patients underwent surgery for various indica- Three patients had abnormal findings but the percentage of tions. Of these patients 26 required orthopedic, neurosurgi- lost function was unknown. Three patients never regained cal or general surgical intervention only. All renal injuries in function of the injured renal unit. these patients were treated nonoperatively. Of 15 patients who sustained grade V renal injury 2 died Only 11 patients (8.7%) required surgery for renal causes, of closed head injury and 2 underwent nephrectomy. As a including 2 with congenital renal anomalies found inciden- result, only 11 patients were eligible for renal followup. Of tally during the trauma evaluation (table 6). One of these these patients 6 (55%) underwent followup imaging at 1 to patients had a grade I renal injury and was diagnosed with 14 months after injury (mean 3.8, median 4). Five patients a left obstructed megaureter, and 1 sustained a grade IV underwent isotope imaging (GHA in 3, DMSA in 2) and 1 renal injury and was diagnosed with UPJ obstruction. Both underwent CT. Five patients demonstrated renal scarring patients were treated nonoperatively for the renal injuries. with evidence of functional loss. A renal abnormality was Subsequently, a ureteral reimplant was performed to correct the UVJ obstruction, and pyeloplasty was performed to repair the UPJ obstruction. In addition, 1 patient with a grade TABLE 4. Associated nonrenal injuries by grade No. Grade I–III No. Grade IV/V Total No. Site Injury (%) Injury (%) (%) TABLE 2. Hematuria by grade Lung 34 (44.7) 23 (46) 57 (45.2) No. Microscopic No. Gross Liver 26 (34.2) 10 (20) 36 (28.6) Renal Injury Grade Hematuria Hematuria Head 25 (32.9) 9 (18) 34 (27) I208Spleen 24 (31.6) 17 (34) 41 (32.5) II 11 5 Adrenal 13 (17.1) 6 (12) 19 (15.1) III 10 9 Ribs 10 (13.2) 4 (8) 14 (11.1) IV 26 7 Long bone 9 (11.8) 7 (14) 16 (12.7) V141Spine 8 (10.5) 3 (6) 11 (8.7) Pelvis 6 (7.9) 3 (6) 9 (7.1) Hematuria was not observed in 3 patients with grade I renal injury, and Skull 5 (6.6) 1 (2) 6 (4.8) was unavailable in 5 patients with grade I, 5 with grade III and 2 with Pancreas 4 (5.2) 1 (2) 5 (4) grade IV renal injury. Bowel 2 (2.6) 4 (8) 6 (4.8) 248 HIGH GRADE RENAL TRAUMA IN CHILDREN

TABLE 5. Treatment by grade

No. No. No. Renal Operation Total Injury Nonoperative Nonrenal No. Grade Treatment Operation Immediate Delayed Pts

I 30 5 0 0 36* II 11 4 0 0 16† III 20 4 0 0 24 IV 19 11 0 5‡ 35 V 9 2 2 2§ 15 Patient with grade V renal injury on CT who was treated nonoperatively. Glucoheptanate scan 4 months after injury shows smaller * Includes 1 reimplant for congenital UVJ obstruction. left kidney with 32.8% function. † Includes 1 cystoscopy for clot evacuation. ‡ Includes 1 pyeloplasty for UPJ obstruction. § Includes 1 missed UPJ avulsion. Of 15 patients with grade V renal injury 10 underwent followup blood pressure determination. Followup ranged observed in 1 patient but relative differential renal function from 1 month to 4.3 years (mean 22 months, median 14). Age was not reported. at followup ranged from 5 to 17 years. Systolic pressure Five renal units lost function, with 2 providing 30% of ranged from 90 to 132 mm Hg, and diastolic pressure ranged total renal function and 3 providing 17% to 21% of total from 50 to 99 mm Hg. renal function. All defects were consistent with previous Two patients (13%) with grade V renal injuries had renal injury. It is noteworthy that 1 additional patient un- mildly increased blood pressure, which raised concern for derwent DMSA scan on day 2 of hospitalization. There was development of hypertension. At 14 months after injury a no evidence of renal function in the injured kidney. Due to 13-year-old male had mildly increased diastolic pressure, the short interval between renal injury and post-injury im- with a measurement of 120/88 mm Hg. The GHA scan aging, this patient was not included in the followup group, showed that the left kidney contributed 29% of total renal although it can be assumed that there was no return of renal function, with evidence of upper and lower pole scarring. function. The other patient was an 11-year-old with a mildly increased systolic pressure of 132 mm Hg. At 51 months of Blood Pressure Followup followup there were no radiographic studies for this child. Of 34 patients 3 to 18 years old with grade IV renal injury 22 No additional blood pressure measurements are available (65%) underwent followup blood pressure measurement at 1 for these children to date. month to 9.5 years (mean 29.2 months, median 10) after injury. Systolic pressures ranged from 64 to 144 mm Hg, and DISCUSSION diastolic pressures ranged from 40 to 78 mm Hg. One patient (3%) had increased blood pressure. This pa- For the last 20 years we have pursued a primary nonopera- tient was a 16-year-old male who had a mildly increased tive approach to the management of HGBRT in children. To systolic pressure of 144 mm Hg at 10 months of followup. A evaluate the results of this approach, we focused on high DMSA scan revealed lower pole scarring in the right kidney. grade renal injuries in this review, since they are associated Close blood pressure monitoring was recommended. The with the highest morbidity and mortality. A growing body of patient has persistent mild blood pressure increase but has literature supports the primary nonoperative management not required medical treatment. Refractory hypertension of renal trauma in children. A recent review by Buckley and developed in 1 patient with bilateral grade IV injuries, ne- McAninch demonstrated that 98.2% of blunt renal injuries cessitating right renal artery bypass. The bypass later (327 of 333) in children were successfully managed nonop- failed, although the hypertension resolved. eratively.2 In their series only 1.8% of the cases required

TABLE 6. Operative treatment due to renal causes Renal Injury Pt No. Grade Operative Timing Imaging Findings Operative Indications Procedures

1 I 2nd Hospitalization Congenital UVJ obstruction Congenital UVJ Reimplant obstruction 2 II 2nd Hospitalization Large retained clot Urinary clot retention Cystoscopy ϩ clot evacuation 3 IV Delayed Severe urinary Persistent fever, Infected hematoma evacuation, necrotic renal extravasation extravasation tissue debridement ϩ drainage 4 IV Delayed Expanding urinoma Expanding urinoma Urinoma drainage, subsequent ureteral stent 5 IV Delayed Nonperfusion of rt kidney ϩ Septic shock, dead Rt nephrectomy ϩ rt hemicolectomy, both rt colon bowel ϩ kidney necrotic 6 IV (bilat) 2nd Hospitalization Right renal artery stenosis Hypertension ϩ renal Rt renal artery bypass artery stenosis 7 IV 2nd Hospitalization UPJ obstruction UPJ obstruction Open pyeloplasty 8 V Immediate Active extravasation Hemodynamically Nephrectomy unstable 9 V Immediate Active extravasation Arterial avulsion with Nephrectomy active bleeding 10 V Delayed Severe urinary Persistent fever ϩ Evacuation of hematoma ϩ drain placement extravasation extravasation 11 V Delayed Severe urinary Persistent fever ϩ Nephrectomy (missed UPJ avulsion) extravasation extravasation HIGH GRADE RENAL TRAUMA IN CHILDREN 249 renal exploration and all renal units were salvaged. Of pa- is minimal with this delayed operative approach, resulting tients who underwent renal exploration (31 penetrating, 6 in reduced intraoperative and postoperative morbidity.1,6,7 blunt) 39% underwent followup imaging, which revealed no For some patients with persistent extravasation of urine further loss of function from the time of initial injury. It is from a grade IV or V injury endoscopic or minimally invasive noteworthy that among their cohort of 333 patients only 12 techniques may be effective in controlling the urinary (3.6%) sustained HGBRT. leak.12 Russell et al described their experience with endo- To our knowledge our study of 49 patients with HGBRT scopic treatment in 20 patients with grade IV injury, of (39%) represents the largest reported series of HGBRT in whom 5 had urinary extravasation that was treated success- children. Only 8 patients (16.3%) required surgical interven- fully with minimally invasive techniques.3 We used com- tion specifically for renal injuries. Our low operative rate is bined percutaneous and endoscopic drainage in 1 patient far below the operative rates of 33% to 60% for HGBRT cited with a grade IV injury who had persistent urinary drainage. in other recent reports.2–7 Similar to recently reported Urinary extravasation resolved and the kidney was pre- series, 98.7% of low grade renal injuries in our patients served. Three patients with grade IV injury and 2 with were successfully treated nonoperatively. One patient in grade V injury who had persistent extravasation were our series with a grade II injury required cystoscopy for treated with open drainage because they either predated clot retention. Similar to the experience of Buckley and the era of percutaneous treatment or had significant he- McAninch,2 when all grades of trauma are considered in our matoma that was not amenable to percutaneous drainage. cohort only 8 patients (6.3%) required surgery exclusively The remaining 31 patients in our series with grade IV for renal trauma. renal injuries and 11 patients with grade V injuries did Initial nonsurgical management for blunt renal trauma not require intervention. has been shown to be effective in salvaging renal units, Patients treated nonoperatively rarely have significant resulting in a reduced nephrectomy rate. Delayed operative long-term sequelae. Even with HGBRT healing results in intervention is rarely necessary. The nonoperative approach preservation of function in residual viable parenchyma and can be followed in almost all hemodynamically stable pa- the vast majority of patients remain normotensive. Delayed tients regardless of renal trauma grade. In recent reports of surgery following hospital discharge is rarely neces- pediatric renal trauma advocating this approach the overall sary.7,8,13 Hypertension is a known long-term sequela of operative and nephrectomy rates ranged from 1.8% to 13.9% HGBRT. The true known incidence is underreported due to and 0 to 10.9%, respectively.2–7 In our experience a total of the traditionally poor long-term followup in trauma series. 11 of 126 patients (8.7%) required surgical intervention, The reported incidence is 0% to 6.6% in the pediatric liter- including 2 with congenital anomalies. Only 8 patients ature.3,4,6,10 In our experience 1 patient (0.8%) required (16.3%) with high grade injury required surgical interven- delayed surgery for refractory hypertension due to renal tion specifically for renal trauma, including 4 of 34 (12%) artery stenosis, and 3 (2.4%) had mildly increased blood with grade IV injury and 4 of 15 (27%) with grade V injury. pressure, suggesting the need for long-term followup. Four of 126 patients (3.2%) required nephrectomy, including 2 of 15 immediate nephrectomies (13%) for grade V injuries CONCLUSIONS with vascular avulsions. Two patients underwent delayed nephrectomy, including 1 of 34 (3%) with a grade IV injury Initial nonsurgical management for HGBRT in children is and 1 of 15 (7%) with a grade V injury and a missed UPJ effective and is recommended for the hemodynamically sta- avulsion, both of which were associated with infection. ble child. When a child has persistent symptomatic urinary In the rare hemodynamically unstable patient early op- extravasation delayed retroperitoneal drainage may become erative intervention is necessary and often results in total necessary to reduce morbidity. Minimally invasive percuta- nephrectomy. As stated previously, 2 nephrectomies in our neous and/or stenting techniques should be considered be- series were performed in hemodynamically unstable pa- fore open operative intervention. Early operative manage- tients with grade V injury who had vascular avulsions not ment is rarely indicated for an isolated renal injury except in amenable to renal salvage. In circumstances involving vas- the child who is hemodynamically unstable. cular avulsion renal salvage may be possible with immediate surgical or endovascular intervention.2 However, this approach requires early recognition with almost immediate Abbreviations and Acronyms intraoperative renal vascular reconstruction.10,11 In our ex- ϭ perience renal units with major vascular avulsion were not CNMC Children’s National Medical Center CT ϭ computerized tomography salvageable. The patient with a grade V injury associated DMSA ϭ dimercapto-succinic acid with a missed UPJ avulsion should also have undergone GHA ϭ glucoheptonic acid immediate intervention and possible nephrectomy. HGBRT ϭ high grade blunt renal trauma The majority of hemodynamically stable patients who UPJ ϭ ureteropelvic junction require operative intervention are best treated with a de- UVJ ϭ ureterovesical junction layed (more than 72 hours) operative approach. Active bleeding has usually stopped, obviating the need to gain initial vascular control before exploration of the retroperito- REFERENCES neum. Consequently, those cases requiring intervention can 1. Waxman J, Belman AB and Kass EJ: Traumatic amputation of be managed by a more limited retroperitoneal flank or per- the left lower renal pole in children. J Urol 1985; 134: 114. cutaneous approach. This method allows for drainage of 2. Buckley JC and McAninch JW: Pediatric renal injuries: man- urinoma and, when necessary, hematoma evacuation and agement guidelines from a 25-year experience. J Urol 2004; limited debridement of necrotic renal parenchyma. Bleeding 172: 687. 250 HIGH GRADE RENAL TRAUMA IN CHILDREN

3. Russell RS, Gomelsky A, McMahon DR, Andrews D and renal injuries, and nearly all injuries that do not cause life Nasrallah PF: Management of grade IV renal injury in threatening bleeding (reference 12 in article). However, the children. J Urol 2001; 166: 1049. message is still not being universally embraced. In a recent 4. Margenthaler JA, Weber TR and Keller MS: Blunt renal series of 1,360 adults with renal lacerations 23% underwent trauma in children: experience with conservative manage- operation, and an appalling 64% of these procedures were ment at a pediatric trauma center. J Trauma 2002; 52: 928. nephrectomy.2 In pediatrics this study is (by my count) the 5. Rogers CG, Knight V, MacUra KJ, Ziegfeld S, Paidas CN and Mathews RI: High-grade renal injuries in children—is con- 11th good report supporting expectant management of most 3 servative management possible? Urology 2004; 64: 574. childhood renal injuries. I think it is fair to say that the 6. Nance ML, Lutz N, Carr MC, Canning DA and Stafford PW: evidence is in. If you are a nonbeliever, it is time to embrace Blunt renal injuries in children can be managed nonopera- this fact. tively: outcome in a consecutive series of patients. In this large series most patients were treated nonopera- J Trauma 2004; 57: 474. tively. Only 2 of 15 patients (13%) with grade V injuries 7. Broghammer JA, Langenburg SE, Smith SJ and Santucci (both were actively bleeding to death) required immediate RA: Pediatric blunt renal trauma: its conservative man- nephrectomy. Two additional patients (13%) needed delayed agement and patterns of associated injuries. Urology surgery. Amazingly, 11 patients (73%) with grade V injuries 2006; 67: 823. did not need an operation at all, and most importantly, these 8. Abdalati H, Bulas DI, Sivit CJ, Majd M, Rushton HG and Eichelberger MR: Blunt renal trauma in children: healing of patients were not subjected to a needless nephrectomy dur- renal injuries and recommendations for imaging follow-up. ing exploration. Pediatr Radiol 1994; 24: 573. Impressively, none of the 35 patients with grade IV inju- 9. Bretan PN Jr, McAninch JW, Federle MP and Jeffrey RB Jr: ries required immediate renal surgery. Only 5 of these pa- Computerized tomographic staging of renal trauma: 85 con- tients (14%) required delayed renal surgery. No patient with secutive cases. J Urol 1986; 136: 561. lesser injuries required renal surgery. And that is how it 10. Radmayr C, Oswald J, Muller E, Holtl L and Bartsch G: Blunt should be. renal trauma in children: 26 years clinical experience in an I have always said that it takes more bravery to observe alpine region. Eur Urol 2002; 42: 297. a patient with signiﬁcant renal injury than it does to remove 11. Wessells H, Deirmenjian J and McAninch JW: Preservation of the kidney unnecessarily and go back to bed. Studies such as renal function after reconstruction for trauma: quantitative assessment with radionuclide scintigraphy. J Urol 1997; this tell us that the uncomfortable feeling of watching a 157: 1583. severe renal injury is something we need to get used to. 12. Santucci RA and Fisher MB: The literature increasingly supports Richard A. Santucci expectant (conservative) management of renal trauma—a Department of Urology systematic review. J Trauma 2005; 59: 493. Wayne State University School of Medicine 13. Keller MS, Coln CE, Garza JJ, Sartorelli KH, Green MC and Weber TR: Functional outcome of nonoperatively managed Detroit Receiving Hospital renal injuries in children. J Trauma 2004; 57: 108. Detroit, Michigan 1. Hammer CC and Santucci RA: Effect of an institutional policy of EDITORIAL COMMENT nonoperative treatment of grades I to IV renal injuries. J Urol 2003; 169: 1751. When we published our experience that most patients with 2. Wessells H, Suh D, Porter JR, Rivara F, MacKenzie EJ, Jurkovich renal injury were best treated nonoperatively in 2003 we GJ et al: Renal injury and operative management in the were met with reactions ranging from admiring agreement United States: results of a population-based study. J Trauma 1 to derision and dismay. In the last 20 years ample informa- 2003; 54: 423. tion has accrued to support an expectant approach to most 3. Santucci RA: Editorial comment. J Trauma 2004; 57: 478. Ectopic Ureterocele: Long-Term Results of Open Surgical Therapy in 54 Patients

Aida Beganovic´, Aart J. Klijn, Pieter Dik and Tom P. V. M. De Jong* From the Department of Pediatric Urology, University Medical Center Utrecht, Utrecht, The Netherlands

Purpose: We assessed the long-term results of total reconstructive bladder surgery as initial treatment of ectopic ureteroceles. Materials and Methods: Long-term followup was evaluated in 54 children treated for ectopic ureteroceles with total upper and lower urinary tract reconstructive surgery between 1988 and 2003, with special focus on the primary outcome factors continence and urinary tract infections. Results: Patient age at surgery was 0 to 8.8 years old (median 1.0), including 34 patients younger than 1 year. Followup was 2.3 to 15.6 years (median 9.6). Of the patients 94% became continent. During the last 2 years 17% of the patients experienced 1 or 2 uncomplicated episodes of urinary tract infection. One of the patients with incontinence received chemoprophylaxis due to frequent urinary tract infections. Secondary endoscopic procedures were necessary in 10 patients due to persistent reflux, and in 7 patients due to obstructive voiding. Reflux was present preoperatively in 33 patients, and low grade reflux was present postoperatively in 7, all of whom were treated conservatively. A total of 11 children presenting with dysfunctional voiding will be or have been trained in biofeedback. Conclusions: The vast majority of patients treated with total reconstructive bladder surgery become continent and do not suffer from lower urinary tract symptoms during the long term. The reoperation rate is low compared to series beginning with endoscopic surgery. Based on the results of this study, we suggest that total reconstructive upper and lower urinary tract surgery be the treatment of choice for ectopic ureteroceles. Key Words: ureterocele, reconstructive surgical procedures, urologic surgical procedures, urinary incontinence

he treatment of ectopic ureteroceles remains a topic of MATERIALS AND METHODS discussion. In the literature it is becoming apparent T that total reconstructive bladder surgery could be the Followup was done in 40 girls and 14 boys with ectopic treatment of choice for this specific type of congenital anom- ureterocele treated with total reconstructive surgery at our aly of the urinary tract.1–5 Still, there remains concern that institution between 1988 and 2003. We evaluated long-term total reconstructive bladder surgery might have a negative morbidity with continence and urinary tract infections as influence on the urodynamic behavior of the bladder, espe- outcome factors. When no recent followup was available for cially when performed during infancy. No evidence exists to patients at our institution data were obtained from control- support the concern that manipulation at the trigone will ling pediatricians and from telephone contact with the fam- result in increased urodynamic morbidity at any age, and ily. Two patients moved abroad and were lost to followup. there is abundant evidence to the contrary.2,6–10 Patients too young for clinical assessment of continence by In their review of the literature on puncturing ectopic September 2005 were excluded from the study. ureteroceles Coplen and Barthold concluded that nearly all Ureterocele was detected in 28% of the cases by prenatal patients with ectopic ureteroceles will end up undergoing ultrasound. Postnatally, 64% of the patients presented with bladder surgery.11 It is interesting that in the literature urosepsis, recurrent urinary tract infections or obstructed most studies briefly mention incontinence but it is rarely voiding, and 8% presented with incontinence. Ectopic ure- handled as an outcome factor for treatment of the ectopic terocele was diagnosed by ultrasound, voiding cystourethrog- ureterocele. We performed long-term followup in a group of raphy and renogram in all cases. Videourodynamic testing 54 children with ectopic ureterocele who had been operated was done preoperatively in 20% of the patients. Cystoscopy on at our hospital, and evaluated them with respect to con- was performed preoperatively, and in a few cases was the tinence and urinary tract infections. The main purpose was definitive tool to discriminate between ectopic and intraves- to investigate whether this approach can be justified without ical ureterocele. prior endoscopic treatment. In 50 of 54 patients the procedure consisted of complete surgical removal of the ureterocele with reconstruction of the lower urinary tract and upper pole resection of poorly Submitted for publication November 15, 2006. functioning upper pole moieties at referral, as described * Correspondence: Department of Pediatric Urology, University previously.7,12 Surgery was planned immediately after ec- Children’s Hospital, University Medical Center Utrecht, Lundlaan topic ureterocele was diagnosed, except in patients present- 6, P. O. Box 85090, 3508AB Utrecht, The Netherlands (telephone: 31-30-250-4004; FAX: 31-30-250-5348; e-mail: T.P.V.M.dejong@ ing with life threatening urosepsis. These patients were umcutrecht.nl). primarily treated with drainage of the infected upper pole.

0022-5347/07/1781-0251/0 251 Vol. 178, 251-254, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.063 252 TOTAL RECONSTRUCTIVE BLADDER SURGERY OF ECTOPIC URETEROCELES

Secondary endoscopic procedures were performed in 17 TABLE 1. Results cases, with 10 due to persistent reflux and 7 due to obstruc- No. pts 54 tive voiding. This transurethral procedure included endo- % Female 74 Median yrs age (range) 1.0 (0–8.8) scopic treatment of persistent reflux in 5 patients, cystos- Median yrs followup (range) 9.6 (2.3–15.6) copy only in 3 and incision of scar tissue at or near the No. incontinent (%) 3 (6) ureteral orifice that pulled the orifice widely open in 2. No. infrequent leakage (%) 4 (7) No. urinary tract infection (%) 9 (17) The obstruction treatment consisted of endoscopic resec- No. secondary endoscopy (%) 17 (31) tion of distal urethral cecoureterocele remnants in 5 patients and superficial bladder neck incision for obstructive voiding in 2. Primary lower tract reconstruction, with upper pole cu- Young age was not a contraindication for surgery, and all taneous ureterostomy was performed in 8 neonates to re- children were treated with prophylactic antibiotics preoper- duce the extent of surgery at a young age. Three of these atively. In 3 girls and 1 boy the initial treatment was upper pole patients had good function of the upper pole moiety, and a resection due to the small size of the ectopic ureterocele. In secondary upper pole ureter reimplantation was performed the boy and 1 of the girls the ureterocele had to be removed instead of upper pole resection. Secondary nephrectomy of later because of either obstructed voiding with prolapse of the poorly functioning lower pole kidneys was done in 1 case due ureterocele into the urethra, or misinterpretation of the ure- to hypertension and in 1 case due to nephroblastomatosis in terocele, which was primarily diagnosed as a large Gartner’s the upper pole (pathological examination revealed that this cyst. The ureterocele remained in place in the 2 other girls, condition was not present in the lower pole). Secondary open who were included in the long-term followup, leaving 52 bladder reconstruction was performed in 1 case due to a patients who underwent open removal of the ureterocele. diverticulum. Of the 4 patients initially treated with only an upper pole dissection 2 did not require any subsequent procedure. RESULTS A total of 55 ectopic ureteroceles were followed, which were on the left side in 27 patients, the right in 26 and bilateral in DISCUSSION 1. Patient age at surgery was 0 to 8.8 years (median 1.0), and 34 patients were 1 year or younger. Followup ranged from When treating ureteroceles there primarily should be a clear 2.3 to 15.6 years (median 9.6). Median age at followup was distinction between the intravesical and ectopic types, using 13 11.8 years (table 1). the classification of the American Academy of Pediatrics. Of the patients 94% became continent and dry. Among Intravesical and ectopic ureteroceles are frequently reported these patients 11% have frequent voiding (more than 8 times in the same study, which complicates the literature, since daily) and 1 (2%) has infrequent voiding (fewer than 4 times the results often lack a good differentiation for these 2 anom- daily). Urine loss at least once a week is experienced by 7% alies. Although most current urological studies demonstrate of the patients (1 boy, 3 girls). that endoscopic treatment of intravesical ureteroceles is One of the 3 incontinent patients is receiving antibiotic likely to be successful and definitive, the intravesical ure- prophylaxis due to frequent urinary tract infections. All 3 terocele has little effect on the urodynamic behavior of the incontinent patients are girls with a short and insufficient bladder.8,11,14,15 urethra based on a large cecoureterocele, who have under- Unfortunately, the reports regarding the treatment of gone or will undergo further reconstructive surgery. Their ectopic ureteroceles lack uniformity. There is general agree- ages at the time of primary surgery were 0.1, 1.4 and 4.2 ment that this form of ureterocele carries an increased risk years. Of the total group 17% experienced 1 or 2 uncompli- of voiding dysfunction, although several authors have shown cated urinary tract infections during the last 2 years, with that voiding dysfunction is part of the disease in many no patient requiring chemoprophylaxis. patients, even when the patient is not operated on. Some Preoperative reflux was present in 33 patients. The most authors maintain that trigonal surgery causes part of the recently available radiographic results showed that at fol- dysfunction, without providing any support from the litera- lowup 7 patients had low grade reflux (according to the ture. Vereecken et al reported that 10% of the children who International Reflux Grading system), including 1 with de underwent trigonal surgery had voiding problems, compared novo reflux. All of these patients were treated conserva- to 15% of those who were treated with other modalities.10 tively. Dysfunctional voiding by clinical assessment and They concluded that extreme trigonal surgery in dupli- proved urodynamically was present in 11 patients, who will cated kidneys poses no risk of bladder dysfunction. Abra- be or have been trained in biofeedback. hamsson et al reported that 59% of the children who were

TABLE 2. Endoscopic decompression of ectopic ureteroceles References No. Pts No. Pretreatment Reﬂux (%) No. Posttreatment Reﬂux (%) No. Secondary Procedures (%) No. Incontinence (%)

Castagnetti19 24 9 (38) 15 (63) 13 (54) 0 Cooper et al16 22 NA NA 14 (64) NA Husmann et al15 72 44 (61) 53 (74) 55 (76) NA Jayanthi and Koff17 21 14 (67) 17 (81) 19 (90) NA Pﬁster20 21 7 (33) 15 (71) 18 (86) 0 TOTAL RECONSTRUCTIVE BLADDER SURGERY OF ECTOPIC URETEROCELES 253

TABLE 3. Bladder surgery of ectopic ureteroceles References No. Pts No. Pretreatment Reﬂux (%) No. Posttreatment Reﬂux (%) No. Secondary Procedures (%) No. Incontinence (%)

Decter et al1 10 10 (100) 0 1 (10) 0 Gomes et al14 18 18 (100) 1 (6) 1 (6) 0* de Jong et al7 40 24 (60) 9 (23) 14 (35) 0 Shekarriz et al4 18 15 (83) 1 (6) 0 0† * One dysfunctional voider and 1 frequent voider. † One patient with symptoms of bladder instability and 1 with occasional episodes of urinary tract infection.

surgically treated for an ectopic ureterocele had infre- final surgical treatment with lower urinary tract reconstruc- quent voiding.6 Three of their 32 patients had inconti- tion. nence. However, none of these 3 cases was managed by bladder surgery. The conclusion of that study was that bladder dysfunction does not seem to be the result of Abbreviations and Acronyms surgery, but rather an integral part of the disorder. We NA ϭ not available agree with this conclusion. Coplen and Barthold summarized the literature on the puncturing of ectopic ureteroceles, concluding that nearly all patients with ectopic ureteroceles will eventually undergo REFERENCES bladder surgery.11 Recent publications on this subject are summarized in table 2. Unfortunately, not all studies in- 1. Decter RM, Sprunger JK and Holland RJ: Can a single indi- clude incontinence in the analysis. In most cases endoscopic vidualized procedure predictably resolve all the problem- treatment is not a final solution for patients with an ectopic atic aspects of the pediatric ureterocele? J Urol 2001; 165: 2308. ureterocele. The studies summarized in table 3 reveal that 2. Husmann DA, Ewalt DH, Glenski WJ and Bernier PA: Ure- surgery at the bladder level can be a definitive solution for terocele associated with ureteral duplication and a nonfunc- this anomaly in most cases. Thus, morbidity and medical tioning upper pole segment: management by partial consumption are probably better served with primary open nephroureterectomy alone. J Urol 1995; 154: 723. reconstruction. 3. Sauvage P, Becmeur F, Moog R and Kauffman I: Is one-stage Available studies in the literature are often missing the ureterocele repair possible in children? Prog Urol 2002; 12: outcome factor “continence,” which makes them difficult to 443. compare. When reports briefly mention continence most of 4. Shekarriz B, Upadhyay J, Fleming P, Gonzalez R and Barthold the patients treated are not yet toilet trained, and, therefore, JS: Long-term outcome based on the initial surgical ap- the followup time should be extended. Furthermore, several proach to ureterocele. J Urol 1999; 162: 1072. 5. Ziylan O, Oktar T, Korgali E, Nane I, Alp T and Ander H: studies have demonstrated that the percentage of patients Lower urinary tract reconstruction in ectopic ureteroceles. requiring additional surgery after endoscopic treatment in- Urol Int 2005; 74: 123. 16,17 creases when the followup is extended. 6. Abrahamsson K, Hansson E, Sillen U, Hermansson G and From earlier series we know that lower urinary tract Hjalmas K: Bladder dysfunction: an integral part of the symptoms can be expected in up to 50% of patients with ectopic ureterocele complex. J Urol 1998; 160: 1468. ectopic ureteroceles, regardless of the type of surgical treat- 7. de Jong TP, Dik P, Klijn AJ, Uiterwaal CS and van Gool JD: ment.6 From the literature we can conclude that urinary Ectopic ureterocele: results of open surgical therapy in 40 incontinence can be expected in 13% to 18% of any control patients. J Urol 2000; 164: 2040. group.18 Interestingly, several studies have shown a lower 8. Holmes NM, Coplen DE, Strand W, Husmann D and Baskin incidence of incontinence than would be expected in con- LS: Is bladder dysfunction and incontinence associated with ureteroceles congenital or acquired? J Urol 2002; 168: trols.8 Our final outcome is that 6% of our patients suffer 718. from incontinence, 7% suffer from involuntary urinary loss 9. Sherman ND, Stock JA and Hanna MK: Bladder dysfunction at least once a week and 20% of those who became dry after bilateral ectopic ureterocele repair. J Urol 2003; 170: required cognitive bladder training for lower urinary tract 1975. symptoms. 10. Vereecken RL and Proesmans W: Extensive surgery on the trigone for complete ureteral duplication does not cause incontinence or voiding problems. Urology 2000; 55: 267. 11. Coplen DE and Barthold JS: Controversies in the management CONCLUSIONS of ectopic ureteroceles. Urology 2000; 56: 665. According to our results, the majority of the patients with an 12. Hendren WH and Mitchell ME: Surgical correction of uretero- ectopic ureterocele treated with primary lower tract recon- celes. J Urol 1979; 121: 590. 13. Glassberg KI, Braren V, Duckett JW, Jacobs EC, King LR, struction become continent and do not suffer from compli- Lebowitz RL et al: Suggested terminology for duplex systems, cated urinary tract infections in the long term. The reopera- ectopic ureters and ureteroceles. J Urol 1984; 132: 1153. tion rate after primary complete open reconstruction is low 14. Gomes J, Mendes M, Castro R and Reis A: Current role of compared to series using primary endoscopic surgery. Com- simplified upper tract approach in the surgical treatment of parison of our results to the literature justifies the policy of ectopic ureteroceles: a single centre’s experience. Eur Urol forgoing endoscopic ureterocele treatment and aiming for 2002; 41: 323. 254 TOTAL RECONSTRUCTIVE BLADDER SURGERY OF ECTOPIC URETEROCELES

15. Husmann D, Strand B, Ewalt D, Clement M, Kramer S and 18. de Kort LM, Verhulst JA, Engelbert RH, Uiterwaal CS and Allen T: Management of ectopic ureterocele associated with de Jong TP: Lower urinary tract dysfunction in children renal duplication: a comparison of partial nephrectomy and with generalized hypermobility of joints. J Urol 2003; 170: endoscopic decompression. J Urol 1999; 162: 1406. 1971. 16. Cooper CS, Passerini-Glazel G, Hutcheson JC, Iafrate M, 19. Castagnetti M, Cimador M, Sergio M and de Grazia E: Trans- Camuffo C, Milani C et al: Long-term followup of endoscopic urethral incision of duplex system ureteroceles in neonates: incision of ureteroceles: intravesical versus extravesical. does it increase the need for secondary surgery in intraves- J Urol 2000; 164: 1097. ical and ectopic cases? BJU Int 2004; 93: 1313. 17. Jayanthi VR and Koff SA: Long-term outcome of transurethral 20. Pﬁster C, Ravasse P, Barret E, Petit T and Mitrofanoff P: The puncture of ectopic ureteroceles: initial success and late value of endoscopic treatment for ureteroceles during the problems. J Urol 1999; 162: 1077. neonatal period. J Urol 1998; 159: 1006. Kidney Folding: The Y-Plasty—A Means of Creating a Dependent Ureteropelvic Junction in the Child With Giant Hydronephrosis

A. Barry Belman and H. Gil Rushton From the Departments of Urology and Pediatrics, Children’s National Medical Center, George Washington University, Washington, D. C.

Purpose: Occasionally, in the presence of severe dilatation and parenchymal thinning, postoperative obstruction or stasis may secondarily occur even after creation of a funneled ureteropelvic junction. Preferential filling of a severely dilated lower pole may kink or distort the ureteropelvic junction, causing this problem. Materials and Methods: A requirement for renal folding is a large hydronephrotic kidney with severe mid renal parenchymal thinning. After pyeloplasty if it is apparent that secondary obstruction is a possibility, and simple lateral or posterior fixation of the lower pole to retroperitoneal fascia will not resolve the problem, the lower pole can be brought superiorly adjacent to the upper pole and fixed in position with 2 or 3, 2-zero or 3-zero polyglactin sutures, creating a “Y” configuration with the ureteropelvic junction dependent from all calices. We reviewed the records of 5 children who underwent this procedure. Results: Five patients with severe upper tract dilatation were treated successfully. Four underwent primary pyeloplasty with concomitant renal folding, and 1 had persistent hydronephrosis with recurrent pyonephrosis before undergoing this procedure secondarily. All patients achieved excellent results with normal drainage postoperatively. Conclusions: Renal folding is a simple surgical maneuver that can be applied easily and successfully when the situation warrants. It allows creation of a dependent, funneled ureteropelvic junction in the presence of giant hydronephrosis. Key Words: hydronephrosis, ureteral obstruction, kidney pelvis, urologic surgical procedures

he goal of pyeloplasty is to create a funnel-shaped lower pole has the potential either to obstruct the uretero- dependent ureteropelvic junction that allows drainage pelvic junction or to result in severe stasis. To achieve a T of urine in an unimpeded fashion. Occasionally, in dependent UPJ and minimize intrarenal stasis, the floppy cases where there is severe intrarenal hydronephrosis with kidney is folded on itself, bringing the lower pole up to the marked parenchymal thinning the lower pole of the kidney upper pole in a U-shaped configuration. We describe the pro- is extraordinarily dependent and floppy, causing secondary cedure and results in 5 patients during a span of 20 years. obstruction or severe stasis and retention of urine even when the anastomosis is widely patent. The markedly di- MATERIALS AND METHODS lated lower pole is preferentially distended by urine physically distorting the anastomosis, thereby preventing or im- A prerequisite for successful folding is a large dilated col- peding drainage. Standard means of dealing with this lecting system with significant parenchymal thinning, par- condition include “pexing” the lower pole of the kidney lat- ticularly in the mid renal region. On completion of pyelo- erally to separate the lower pole from the UPJ physically, plasty, including excision of redundant pelvis, the kidney is and performing ureterocalicostomy to maintain the depen- folded, bringing the dilated lower pole superiorly adjacent to dent relationship necessary for good drainage. the upper pole. The capsule of the lower pole is sutured to When the lower pole is large, lateral or posterior fixation the capsule of the upper pole with 2 or 3, 2-zero or 3-zero alone may not adequately achieve the desired goal of depen- polyglactin sutures. This approach configures the collecting dent drainage, and ureterocalicostomy becomes the alterna- system into a Y shape, with the lower and upper poles tive. However, ureterocalicostomy is not a simple procedure. superiorly positioned and the UPJ dependent (fig. 1). It may be difficult to achieve a satisfactory anastomosis We reviewed the records of 5 children 1 month to 5 years between what may be markedly attenuated infundibulo- old who underwent this procedure. Evaluation included caliceal tissue and a narrow ureter. Additionally, if the me- sonography and preoperative and postoperative furosemide dial portion of the lower system is not thinned out, the paren- stimulated renography. Renal scans were done at 6 weeks chyma may need to be widely excised on either side of the and 1 year postoperatively until 2000, after which it was collecting system to avoid delayed stenosis. Nevertheless, this determined that a second scan was not necessary if the approach remains an option of dealing with this condition.1 study done at 6 weeks showed normal drainage.2 Through the years we have applied a relatively simple maneuver in the face of giant hydronephrosis when a dilated RESULTS This procedure was successfully applied in 5 patients, in- Submitted for publication October 31, 2006. cluding 1 who underwent the operation secondarily several Study received institutional review board approval. years following a “successful” pyeloplasty performed else-

0022-5347/07/1781-0255/0 255 Vol. 178, 255-258, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.062 256 KIDNEY FOLDING: Y-PLASTY

FIG.1. A, massive hydronephrosis secondary to UPJ obstruction. B, following pyeloplasty dilated lower pole is seen abutting UPJ. C, kidney is “folded” (arrow), bringing lower pole (X) to upper pole (X=) and creating dependent unimpeded UPJ. where (defined as a wide open UPJ as noted at time of possible. Occasionally, the lower pole requires fixation kidney folding). This girl had persistent severe hydrone- (“pexing”) to the posterior abdominal wall fascia to facilitate phrosis and recurrent pyonephrosis that resolved after fold- drainage. Even more rarely, as a primary procedure it may ing. All patients had demonstrated severe hydronephrosis become necessary to anastomose the most inferior calix to preoperatively with significant delay in drainage (more than the ureter to achieve this result (ureterocalicostomy). How- 20 minutes), and all exhibited marked improvement and ever, ureterocalicostomy requires a significantly dilated stabilization of function on postoperative nuclear medicine lower pole infundibulum and calix to achieve success, since evaluation. Figure 2 represents the preoperative and post- normally thick parenchyma not only can make the anasto- operative sonograms in a patient who underwent pyelo- mosis technically difficult, but also increases the risk of plasty and folding of a sole functioning kidney at age 1 delayed contraction and anastomotic obstruction. Instead, month. The preoperative 99mtechnetium mercaptoacetyl- under these circumstances renal folding should be consid- triglycine renal scan in the same patient, revealed an in- ered as a simpler option with a high likelihood of success. In creasing drainage curve (fig 3). Figure 4 shows the 6-week the presence of severe intrarenal hydronephrosis, particu- postoperative renal scan in the same patient after successful larly with central renal parenchymal thinning, the lower pyeloplasty with folding. pole can easily be brought superiorly adjacent to the upper pole, thereby making the pelvis (and UPJ) dependent. This DISCUSSION approach not only reduces stasis, but also obviates the risk Management of the dilated upper urinary tract is usually of the lower pole preferentially distending and compressing, straightforward. In the presence of upper tract obstruction and distorting the newly formed anastomosis. the UPJ is made dependent by excising redundant pelvis As is typical of what is often thought to be an original and forming the anastomosis in as dependent a position as idea, on review of the literature studies were discovered

FIG.2. A, preoperative sonogram reveals giant renal pelvis with markedly compressed renal parenchyma. B, postoperative sonogram shows signiﬁcantly reduced hydronephrosis and kidney “fold” (arrow). Calix seen at top of image is lower pole calix. KIDNEY FOLDING: Y-PLASTY 257

FIG. 3. Preoperative isotope renal scan demonstrates massively dilated nondraining left kidney with minimal function of cystic dysplastic right kidney (top). Lower ﬁgure reveals increasing drainage curve. Fr, frame.

showing similar solutions to this problem. In 1947 Stewart create a dependent UPJ. Of the 20 kidneys 18 demonstrated introduced a renal folding technique rather than transection improvement in drainage and dilatation. of crossing lower pole vessels that were causing obstruction More recently, Zupancic et al published their results with (a procedure apparently popular at that time).3 Additionally, caliceal plication without folding to reduce intrarenal hydro- in 1966 Sorrentino reported successful “renal folding” in a nephrosis in the presence of giant hydronephrosis in 10 19-year-old female with a solitary kidney obstructed by a children 2 to 14 years old.6 However, they did not address high ureteropelvic insertion.4 In that case no pyeloplasty the question of secondary obstruction from preferential was necessary, and drainage improved with simple folding. lower pole ﬁlling, which is the thrust of our study. In 1998 Hemal et al reported on 16 patients (20 kidneys) in whom nephroplication and nephropexy were performed for CONCLUSIONS concomitant UPJ obstruction and giant hydronephrosis.5 Multiple absorbable sutures were used to plicate the upper Admittedly, ours is a small experience. However, the need to middle pole and, separately, the lower to middle pole. The for this maneuver is rare, and our success and that of others lower pole was then tacked to the posterolateral muscles to suggest that this or a similar technique should be considered 258 KIDNEY FOLDING: Y-PLASTY

FIG. 4. Postoperative renal scan shows marked reduction in renal size, change in orientation of kidney and drainage into bladder (top). Drainage curve normalized with t1/2 (time it takes for half of isotope to drain from kidney) of 8 minutes (bottom). Fr, frame. T0, furosomide administration. Tempty, emptying time. Tft, mean lifetime. when there is concern about secondary obstruction or poor 4th ed. Edited by AB Belman, LR King and SA Kramer. drainage from a severely dilated kidney. The procedure is a London: Martin Dunitz Ltd 2002; p 616. simple surgical maneuver that ensures the formation of a 2. Pohl HG, Rushton HG, Parks JS, Belman AB and Majd M: dependent UPJ and decreases upper tract stasis. Early diuresis renogram ﬁndings predict success following pyeloplasty. J Urol 2001; 165: 2311. 3. Stewart HH: A new operation for the treatment of hydronephrosis in association with a lower polar (or aberrant) artery. Abbreviations and Acronyms Br J Urol 1947; 35: 51. UPJ ϭ ureteropelvic junction 4. Sorrentino M: Treatment of giant hydronephrosis. Br J Urol 1966; 38: 255. 5. Hemal AK, Aron M and Wadhwa SN: Nephroplication and REFERENCES nephropexy as an adjunct to primary surgery in the management of giant hydronephrosis. Br J Urol 1998; 81: 673. 1. Fung LCT and Lakshmanan Y: Anomalies of the renal collecting 6. Zupancic B, Popovic L, Mikulic D, Vrtar Z, Fattorini I and Augustin system: ureteropelvic junction obstruction (pyelocalyectasis) G: Calyceal plication with pyeloplasty in the treatment of giant and infundibular stenosis. In: Clinical Pediatric Urology, hydronephrosis in children. Eur J Pediatr Surg 2006; 16: 176. Myocyte Apoptosis in Primary Obstructive Megaureters: The Role of Decreased Vascular and Neural Supply

Seyedmehdi Payabvash, Abdol-Mohammad Kajbafzadeh,* Seyed Mohammad Tavangar, Maryam Monajemzadeh and Zhina Sadeghi From the Department of Urology, Pediatric Urology Research Center (A-MK, SP, ZS) and Department of Pathology (MM), Children’s Hospital Medical Center and Department of Pathology, Shariati Hospital (SMT), Tehran University of Medical Sciences, Tehran, Iran

Purpose: We compared myocyte apoptosis index, microvessel density and nerve supply as well as muscular and collagen composition in the obstructed ureteral endings of children with primary obstructive megaureter and normal controls. Materials and Methods: Tissue specimens were obtained during ureteral reimplantation in 16 patients with primary obstructive megaureter. For the control group normal ureteral endings were taken at autopsy from 19 age and sex matched children. In all specimens we determined the myocyte apoptosis index, number of CD31 positive microvessels, ␣-actin positive muscular component and number of nerve terminals. The collagen fibers were also specifically stained. Results: The myocyte apoptosis index was higher in obstructed vesicoureteral junctions (10.14% Ϯ 1.03%) compared to controls (2.11% Ϯ 0.21%, p Ͻ0.001). Mean number of vascular elements per microscopic field was lower in ureteral endings of patients with obstructive megaureter compared to controls (p Ͻ0.001). The number of nerve endings was also significantly lower in obstructed ureteral endings. There was a negative correlation between the number of microvessels and myocyte apoptosis index in both study groups. In obstructed megaureters the number of nerve endings was also negatively correlated with myocyte apoptosis index but positively correlated with the number of microvessels. In obstructed vesicoureteral junctions the proportion of muscular component was lower and the proportion of collagen fibers was higher compared to normal controls. Positive correlation was found between the myocyte apoptosis index and the percentage of collagenous component in both study groups. Conclusions: Congenital defective vascular development may result in myocyte apoptosis, and reduction of neural elements and muscular components in obstructed vesicoureteral junctions. Subsequent substitution of connective tissue may lead to functional obstruction in primary obstructive megaureter. Key Words: growth and development, apoptosis, extracellular matrix, ureteral obstruction

egaureters are generally classified as refluxing, ob- proposed as underlying mechanisms. Ureteral dilatation oc- structed, nonrefluxing/nonobstructed or refluxing/ curs as a result of urine accumulation proximal to the aber- M obstructed.1 Primary obstructive megaureter refers rant distal segment. to large ureters with intrinsic obstruction of the vesi- Although prior series have reported the concomitant de- coureteral junction or intramural ureteral ending. There is crease in smooth muscle cells and increase in extracellular general agreement that there is no true narrowing at the connective tissue of megaureters,6 the role of myocyte apo- distal intravesical ureteral ending, but there is a functional ptosis in the pathogenesis of POMU has rarely been studied. obstruction arising from an aperistaltic juxtavesical seg- Moreover, there are few data available regarding microves- ment that is unable to transport urine at acceptable rates. sel density at the site of obstructed ureteral endings.7 Pre- However, differentiating urinary dilatation that is obstruc- vious reports on changes in nerve supply at the site of tive and requires surgery from that representing mere ana- vesicoureteral junction obstruction are also controversial.3,5 tomical variation with no threat to renal function is still a We evaluated the apoptotic changes of myocytes in the vesi- controversial issue.2 coureteral junction of children with POMU compared to The mechanism of vesicoureteral junction obstruction is normal controls. We studied the alterations in vascular and still under investigation. Segmental changes of muscular neural elements, as well as muscular and collagenous com- components,1 the presence of a thick sleeve of muscle around ponents of obstructed ureteral endings. the distal portion of the ureter,3 increased deposition of collagen fibers4 and dysregulated neuromodulation in the juxtavesical segment of obstructed megaureters5 have been MATERIALS AND METHODS Specimens of the distal intravesical part of ureters were Submitted for publication November 21, 2006. obtained from children with POMU undergoing ureteral re- Study received local ethics committee and institutional review implantation after failed conservative treatment. The deci- board approval. sion to proceed to surgery was based on recurrent urinary * Correspondence: No. 36, 2nd Floor, 7th St., Saadat-Abad Ave., Tehran 1998714616, Iran (telephone: 9821-2208-9946; FAX: 9821- tract infections, symptoms such as flank pain, worsening 2206-9451; e-mail: [email protected]). hydronephrosis or deterioration of renal function. Mean du-

0022-5347/07/1781-0259/0 259 Vol. 178, 259-264, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.054 260 PRIMARY OBSTRUCTIVE MEGAURETERS AND MYOCYTE APOPTOSIS ration of conservative treatment in patients with POMU in 0.01 N hydrochloric acid without counterstaining. Under was 1.2 years (range 6 months to 2.1 years). Exclusion polarized light type I collagen fibers are visualized as thick, criteria were ureteral dilatation secondary to bladder or strongly birefringent, yellow-red fibers, whereas type III urethral pathology, presence of ipsilateral VUR or presence fibers are characterized as thin, weakly birefringent, green- of any other urological abnormality. ish fibers.8 Borges et al reported that after picrosirius red A total of 17 specimens were obtained from 10 males and staining collagen fibers exhibit a characteristic red-orange 6 females with POMU with a mean age of 21 months (range fluorescence when analyzed under fluorescence microscopy.9 2 months to 7 years). One 10-month-old male had bilateral The specimens were examined using light microscopy. POMU. The mode of presentation was prenatal/neonatal Color image analysis was performed using NIH Image, hydronephrosis in 8 patients, urinary tract infection and ImagePro® and Photoshop® 7.0 software. For collagen fibers urosepsis in 5, flank mass and pain in 2, and failure to thrive and ␣-actin positive muscular components the ratios of pos- in 1. itively stained areas to full thickness ureteral wall (exclud- Control samples included 19 specimens taken at autopsy ing the urothelial layer) were used for data analysis. For from age and sex matched patients with no history of uro- each specimen 4 to 5 photomicrographs were used for scor- logical disease. Control ureteral endings were obtained from ing and the mean of the scores was assigned as the final 12 male and 7 female cadavers with a mean age of 20 value for data analysis. months (range 2 months to 7 years). The cadavers were The number of vascular and neural elements were quan- autopsied within 6 hours after death to avoid lysis of body titated and expressed as the number of positively stained tissue. elements per microscopic field (100ϫ magnification), as de- Paraffin embedded specimens were cut at 5 ␮m. In situ scribed previously.8 For determination of microvessel den- detection of apoptosis was achieved with labeling of DNA sity any brown-stained endothelial cell or cluster that was strand breaks in tissue sections using TUNEL assay. The clearly separated from adjacent microvessels and connective assay was performed with a commercially available kit as elements was counted as 1 microvessel, irrespective of the described previously,8 and according to manufacturer in- presence of vessel lumen.10 structions. All TUNEL positive cells fulfilling the morpho- Differences between the 2 study groups were evaluated logical criteria for apoptosis, including cell shrinkage, nu- using the 2-tailed Student t test. Bivariate linear regression clear fragmentation and condensation, were counted (fig. 1). analyses were performed to assess the correlation between Myocyte apoptosis in ureteral sections was quantitated by different cellular and extracellular components. Pearson’s counting the number of TUNEL positive cells in 30 random correlation coefficient was calculated to find the association microscopic fields (200ϫ magnification). Apoptosis index between the variables. Data are expressed as mean Ϯ SEM, was calculated as the number of apoptotic cells divided by with statistical significance considered at p Ͻ0.05. the total number of cells counted. For immunohistochemical staining tissue sections were dewaxed and rehydrated in graded alcohol series. A nonen- RESULTS zymatic heating technique was used for antigen retrieval. Serial sections were stained using monoclonal mouse anti- The percentage of apoptotic myocytes was significantly higher human CD31 (clone JC70A), ␣-actin (clone 1A4) and neuro- in ureteral endings of patients with POMU (10.14% Ϯ 1.03%) filament protein (clone 2F11) antibodies (Dako, Carpinteria, compared to controls (2.11% Ϯ 0.21%, p Ͻ0.001). However, California) for detection of vascular elements, smooth mus- the number of CD31 positive vascular elements per micro- cle cells and nerve endings, respectively. Picrosirius red scopic field was significantly lower in children with POMU staining was used for collagen typing. Briefly, the sections compared to controls (8.18 Ϯ 1.39 vs 17.81 Ϯ 4.21, p Ͻ0.001, were stained for approximately 2 hours in 0.1% sirius red fig. 2). The obstructive ureteral endings also had fewer neu- solution in saturated picric acid, followed by rapid washing ral elements than normal specimens (12.88 Ϯ 1.20 vs 24.05 Ϯ 2.31, p Ͻ0.001, fig. 3). Table 1 outlines the correlation between myocyte apoptosis index and other cellular components. In both study groups there was a negative correlation between the number of CD31 positive vascular elements and myocyte apoptosis index. A negative correlation was also found between the number of apoptotic myocytes and neural elements in ureteral endings of children with POMU. Muscular component formed a significantly lower proportion of ureteral wall at the site of obstructed vesicoureteral junction compared to normal specimens (35.4% Ϯ 3.4% vs 57.0% Ϯ 4.0%, p Ͻ0.001, fig. 4). Expectedly, the proportion of collagen fibers in ureteral endings of patients with POMU (48.6% Ϯ 3.3%) was higher than in controls (28.5% Ϯ 3.6%, p Ͻ0.001, fig. 5). There was a negative correlation between the muscular and collagen proportions of vesicoureteral junction in the POMU (r Ϫ0.96, p Ͻ0.001) and control specimens (r Ϫ0.98, p Ͻ0.001). We found no difference between FIG. 1. TUNEL positive myocytes that fulfilled morphological criteria for apoptosis (arrow) were counted for determination of apopto- the type I-to-type III collagen ratios of POMU cases and sis index. Reduced from ϫ400. controls (fig. 5). PRIMARY OBSTRUCTIVE MEGAURETERS AND MYOCYTE APOPTOSIS 261

FIG. 3. Number of neural elements were decreased in ureteral endings of patients with POMU (A) compared to normal controls (B). CD31, reduced from ϫ100.

Various functional and histological abnormalities have been described in patients with POMU. Disproportionate development of the outer circular muscular layer vs inner longitudinal layer is suggested as a plausible etiology.1 Dixon et al found a thick muscular collar that surrounded FIG. 2. Number of vascular elements were reduced in obstructed vesicoureteral junctions (A) compared to normal controls (B). CD31, the terminal ureter and was densely innervated by norad- reduced from ϫ100. renergic neurons in some children with POMU.3 Diminution of smooth muscle component and increased proportion of connective tissue at the site of the obstructed vesicoureteral junction is another possible etiology.4,6 Increased acetylcho- Table 2 outlines the correlation between the vascular linesterase activity and increased tonic response to nor- supply of the vesicoureteral junction and cellular/extracel- adrenalin have also been reported in obstructed mega- lular components. In patients with POMU there was a pos- ureters.5,11 However, to our knowledge this study is the first itive correlation between the number of vascular and neural showing increased myocyte apoptosis and decreased vascu- elements in the ureteral endings. In both study groups the lar and neural supply at the site of the congenital vesi- higher the myocyte apoptosis index, the lower the proportion coureteral obstruction. These changes were associated with of muscular components (table 1). On the other hand, the a decreased proportion of muscular components and deposi- number of vascular elements was positively correlated with tion of collagen fibers in ureteral endings. the proportion of muscular components (table 2). The per- TUNEL assay determines DNA fragmentation, which is centage of collagen fibers per ureteral wall thickness was one of the final events in the apoptosis cascade. There are positively correlated with the percentage of apoptotic myo- several studies using this method to demonstrate apoptosis. cytes but negatively correlated with vascular supply in both However, TUNEL assay may also stain necrotic cells due to study groups. extensive DNA degradation.12 Thus, we counted only those

DISCUSSION The nature of the abnormality at the vesicoureteral junction TABLE 1. Myocyte apoptosis index in obstructed vesicoureteral junctions and normal samples in children with POMU remains controversial. Meticulous neural coordination in conjunction with interactive contrac- POMU Group Control Group tions of circular and longitudinal muscles has an important r p Value r p Value role in ureteral peristalsis and propelling of urine through Microvessels Ϫ0.74 0.001 Ϫ0.72 Ͻ0.001 the vesicoureteral junction. An adynamic ureteral ending is Nerve endings Ϫ0.60 0.010 Ϫ0.42 0.069 considered the underlying reason for functional obstruction ␣-Actin expression Ϫ0.75 Ͻ0.001 Ϫ0.60 0.006 Ͻ in patients with POMU.1 Collagen ﬁbers 0.76 0.001 0.59 0.007 262 PRIMARY OBSTRUCTIVE MEGAURETERS AND MYOCYTE APOPTOSIS

obstructed vesicoureteral junctions. The reduced vascular supply was strongly associated with an increased number of apoptotic myocytes, which suggests an etiological contribution. One may hypothesize that insufficient blood supply due to defective development of microvessels is the primary etiological factor triggering a cascade of events resulting in myocyte apoptosis and consequent fibrotic tissue substitution. The number of neural elements was also significantly decreased in obstructed ureteral endings. Decreased nerve supply is also reported in patients with VUR.15,16 However, our results are in contrast to those of Hofmann et al, who reported increased acetylcholinesterase activity in the juxtavesical segment of obstructed megaureters.11 Dixon et al also found dense noradrenergic innervation in a restrictive muscular collar surrounding the terminal ureter in children with POMU and ectopic ureteral insertion.3 The difference in neural antigens labeled for immunohistochemical detection of neural elements may explain these discrepancies. Additionally, Dixon et al reported that the aforementioned muscular collar was not exclusive to POMU cases, nor was it found in all cases of ureterovesical junction obstruction.3 It is plausible that a decreased number of neural elements in the obstructed ureteral endings is secondary to a defective blood supply and vascular development. This hypothesis is supported by the positive correlation between the number of neural and vascular elements in obstructed vesicoureteral junctions. The decreased nerve supply may also FIG. 4. Proportion of ureteral wall muscular component was signif- contribute to myocyte apoptosis. It is well known that apo- icantly lower in children with POMU (A) compared to controls (B). CD31, reduced from ϫ100. ptosis occurs in striated skeletal muscle cells after neural injuries and denervation.17 The negative correlation between the number of neural elements and myocyte apoptosis TUNEL positive cells that fulfilled the morphological crite- index in the obstructed ureteral endings supports the latter ria of apoptosis. In the present study we preferred to use hypothesis. TUNEL assay to detect the ultimately apoptotic cells. How- Previous studies have revealed that the elastic properties ever, assays for the determination of caspase activity detect and collagen composition of hollow organs may greatly in- apoptosis at earlier stages compared to other methods, since fluence their distensibility and transport capacity. Lee et al caspases are early triggering effectors in the process of ap- have extensively investigated the changes in composition of optosis.12 collagen types in megaureters.4,6 They have shown that in It is well known that cells undergoing apoptosis are re- refluxing megaureter specimens there is a marked increase moved rapidly by phagocytes without inducing inflamma- in type III collagen contents and type III-to-type I collagen tion.13 Removal of the apoptotic debris through phagocytosis ratio compared to obstructed megaureters and normal con- provokes strong fibrogenic signals, especially through gen- trols. In our series the amount of collagen fibers was signif- eration of transforming growth factor-␤.14 Thus, the empty icantly increased in POMU. However, collagen fiber compo- spaces left by dead cells are usually filled with connective sition was comparable between patients and controls, which tissue. The present data suggest that the proportion of ure- is in agreement with previous reports.4,6 teral wall muscular component decreased presumably due to Many of the cellular changes found in POMU are similar myocyte apoptosis, and these changes were concomitant to those of primary VUR. Oswald et al extensively studied with increased deposition of collagen fibers in the obstructed the microanatomical changes of primary refluxing mega- ureteral endings. The replacement of functional myocytes, ureters.18 They found increased extracellular matrix turn- which actively promote ureteral peristalsis, with connective over evidenced by increased activity of macrophages and tissue in the process of apoptotic debris phagocytosis can matrix metalloproteinases.15 These changes were concomi- contribute to the development of an adynamic vesicoureteral tant with a decrease in myelinated nerves.15 Moreover, in junction. We recently observed that a similar mechanism children with VUR the number of pacemaker interstitial may be involved in the pathogenesis of ureteropelvic junc- cells of Cajal and gap junction proteins was also decreased.16 tion obstruction.8 The present findings also provide novel Recently, Schwentner et al observed reduction of vascular evidence about possible triggers for the induction of ureteral endothelial growth factor expression and a subsequent de- myocyte apoptosis. crease in microvessel density in patients with VUR.7 Inter- Sufficient blood supply is essential in the maintenance of estingly, other studies have demonstrated that vascular en- cell survival in almost all tissues. It is well known that dothelial growth factor is a neurotrophic factor for neural ischemic injuries are associated with increased apoptosis cells.19 One can speculate that a common pathway leads to and replacement of fibrotic tissue.13 We observed that the defective development of ureteral endings in POMU and number of vascular elements is significantly decreased in primary VUR. PRIMARY OBSTRUCTIVE MEGAURETERS AND MYOCYTE APOPTOSIS 263

FIG.5.A and B, collagen appeared as characteristic red-orange fibers under fluorescent light. Amount of collagen fibers was higher in obstructed ureteral endings (A) compared to controls (B). Picrosirius red, reduced from ϫ100. C and D, using polarization microscopy, thick type I collagen fibers appeared strongly birefringent and yellow or red-colored, while thin type III collagen fibers exhibited weak birefringence and greenish color. There was no difference in collagen fiber composition between patients (C) and controls (D). Picrosirius red, reduced from ϫ400.

The specimens in this series were obtained from a sub- connective tissue seems to be the end point of this cascade, group of patients with POMU who failed conservative treat- which leads to failure of peristalsis across the obstructed ment and in whom surgical intervention was indicated to vesicoureteral junction. However, it is impossible to deter- preserve renal function and relieve symptoms. However, mine definitively the primary etiological factor in patients more than 50% of megaureters diminish with time, presum- with POMU based on the present data. These findings only ably due to maturation of the vesicoureteral junction.20 reveal the coincidence of cellular changes in vascular, neural Thus, it should be noted that the observed changes may not and muscular components of the ureteral wall, along with be found in all cases of POMU. alteration of the proportion of connective tissue. It is also theoretically possible that there is a common, as yet un- CONCLUSIONS known factor that triggers the cascade of events leading to the aforementioned cellular and structural alterations. Our findings suggest that induction of apoptosis in normal functioning myocytes and substitution of fibrotic tissue may contribute to the pathogenesis of POMU in patients eventu- Abbreviations and Acronyms ally requiring surgical intervention. There are also obvious microanatomical similarities between POMU and primary POMU ϭ primary obstructive megaureter ϭ VUR, probably due to a common etiology. In POMU defec- TUNEL terminal deoxynucleotidyl transferase tive vascular development can be the primary triggering dUTP nick-end labeling VUR ϭ vesicoureteral reflux factor for myocyte apoptosis, and reduction of neural elements and muscular components. Reduced nerve supply to obstructed ureters may also contribute to apoptotic changes. REFERENCES Subsequent replacement of functional muscular tissue with 1. Shokeir AA and Nijman RJ: Primary megaureter: current trends in diagnosis and treatment. BJU Int 2000; 86: 861. 2. Baskin LS, Zderic SA, Snyder HM and Duckett JW: Primary TABLE 2. Microvessel supply in obstructed vesicoureteral dilated megaureter: long-term followup. J Urol 1994; 152: junctions and normal samples 618. POMU Group Control Group 3. Dixon JS, Jen PY, Yeung CK and Gosling JA: The vesicoureteric junction in three cases of primary obstructive r p Value r p Value megaureter associated with ectopic ureteric insertion. Br J Nerve endings 0.65 0.004 0.33 0.155 Urol 1998; 81: 580. ␣ -Actin expression 0.64 0.006 0.63 0.004 4. Lee BR, Silver RI, Partin AW, Epstein JI and Gearhart JP: A Collagen fibers Ϫ0.66 0.004 Ϫ0.64 0.003 quantitative histologic analysis of collagen subtypes: the 264 PRIMARY OBSTRUCTIVE MEGAURETERS AND MYOCYTE APOPTOSIS

primary obstructed and refluxing megaureter of childhood. mon etiology for both entities, namely a congenital dysfunc- Urology 1998; 51: 820. tion of the vesicoureteral junction (reference 7 in article). 5. Hertle L and Nawrath H: In vitro studies on human primary These structural deficiencies probably hamper directed peri- obstructed megaureters. J Urol 1985; 133: 884. stalsis and coordinated valve function of the intravesical 6. Lee BR, Partin AW, Epstein JI, Quinlan DM, Gosling JA and ureter. However, the etiology of the aforementioned changes Gearhart JP: A quantitative histological analysis of the remains unclear, since primary dysplasia and secondary dilated ureter of childhood. J Urol 1992; 148: 1482. 7. Schwentner C, Oswald J, Lunacek A, Schlenck B, Berger AP, alterations are conceivable. Moreover, the common applica- Deibl M et al: Structural changes of the intravesical ureter bility may be impaired because only those patients with in children with vesicoureteral reflux—does ischemia have POMU requiring surgery were investigated. Hence, the mor- a role? J Urol 2006; 176: 2212. phological and functional changes may not occur in all pa- 8. Kajbafzadeh AM, Payabvash S, Salmasi AH, Monajemzadeh M tients, since POMU resolves spontaneously in most children. and Tavangar SM: Smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junc- Christian Schwentner tion obstruction. J Urol 2006; 176: 718. Department of Pediatric Urology 9. Borges LF, Taboga SR and Gutierrez PS: Simultaneous ob- Medical University servation of collagen and elastin in normal and patholog- Innsbruck, Austria ical tissues: analysis of sirius-red-stained sections by fluorescence microscopy. Cell Tissue Res 2005; 320: 551. 1. Sondell M, Sundler F and Kanje M: Vascular endothelial growth 10. Gasparini G and Harris AL: Clinical importance of the deter- factor is a neurotrophic factor which stimulates axonal out- mination of tumor angiogenesis in breast carcinoma: much growth through the flk-1 receptor. Eur J Neurosci 2000; 12: more than a new prognostic tool. J Clin Oncol 1995; 13: 765. 4243. 11. Hofmann J, Friedrich U, Hofmann B and Grabner R: Acetyl- cholinesterase activities in association with congenital mal- REPLY BY AUTHORS formation of the terminal ureter in infants and children. Z Kinderchir 1986; 41: 32. The proposal for the presence of a common etiological path- 12. Walker JA and Quirke P: Viewing apoptosis through a way as the underlying mechanism of obstructive ureter in ‘TUNEL.’ J Pathol 2001; 195: 275. ureteropelvic and vesicoureteral junction obstruction is con- 13. Thompson CB: Apoptosis in the pathogenesis and treatment of ceivable due to similar histopathological changes and clini- disease. Science 1995; 267: 1456. cal course of both diseases. However, speculation that the 14. Canbay A, Friedman S and Gores GJ: Apoptosis: the nexus of refluxing and obstructive vesicoureteral junctions result liver injury and fibrosis. Hepatology 2004; 39: 273. from a common etiology seems naïve. 15. Oswald J, Schwentner C, Brenner E, Deibl M, Fritsch H, Recent studies from Schwentner et al have renovated our Bartsch G et al: Extracellular matrix degradation and re- idea of microstructural and cellular changes in the primary duced nerve supply in refluxing ureteral endings. J Urol refluxing vesicoureteral junction. They have shown that the 2004; 172: 1099. 16. Schwentner C, Oswald J, Lunacek A, Fritsch H, Deibl M, Bar- ratio of intravesical ureteral length-to-ureteral diameter in 1 tsch G et al: Loss of interstitial cells of Cajal and gap junction neonates is lower than the level assumed previously. In protein connexin 43 at the vesicoureteral junction in children patients with primary refluxing vesicoureteral junction they with vesicoureteral reflux. J Urol 2005; 174: 1981. have found atrophic and dysplastic changes in the smooth 17. Tews DS, Goebel HH, Schneider I, Gunkel A, Stennert E and muscle layer, along with enhanced activity of macrophages and Neiss WF: DNA-fragmentation and expression of apoptosis- remodeling of extracellular matrix (references 15 and 18 in related proteins in experimentally denervated and reinner- article). According to their recent studies, the number of neural vated rat facial muscle. Neuropathol Appl Neurobiol 1997; elements and interstitial cells of Cajal, as well as microvessel 23: 141. density and the level of VEGF, are decreased in the primary 18. Oswald J, Brenner E, Schwentner C, Deibl M, Bartsch G, refluxing vesicoureteral junction (references 7 and 16 in article). Fritsch H et al: The intravesical ureter in children with vesicoureteral reflux: a morphological and immunohisto- Although most of these changes are similar to microana- chemical characterization. J Urol 2003; 170: 2423. tomical and cellular changes found in ureteropelvic and 19. Storkebaum E, Lambrechts D and Carmeliet P: VEGF: once vesicoureteral junction obstruction, many are considered to regarded as a specific angiogenic factor, now implicated in be nonspecific cellular reactions found with various other neuroprotection. Bioessays 2004; 26: 943. tissue damages as well. On the other hand, one should also 20. Hemal AK, Ansari MS, Doddamani D and Gupta NP: Symp- note the disparity between reported success rates in reim- tomatic and complicated adult and adolescent primary ob- plantation of obstructed versus refluxing megaureters, as structive megaureter—indications for surgery: analysis, well as the different collagen composition in these 2 condi- outcome, and follow-up. Urology 2003; 61: 703. tions (references 4 and 6 in article). Moreover, while the refluxing junction is usually managed medically, a large EDITORIAL COMMENT number of cases of obstructive megaureters finally require Augmented smooth muscle apoptosis and reduction of the surgery (reference 1 in article). Thus, in our opinion it is vascular and nerve supply as well as an increase in extra- more plausible that the refluxing and obstructive vesi- cellular collagen deposition are typical features of primary coureteral junctions are secondary to different etiological ureteral obstruction (reference 8 in article). However, the factors and have different clinical fates, but manifest with a correlation of microvasculature and nerve density appears comparable spectrum of cellular changes. particularly relevant, since vascular endothelial growth fac- 1. Oswald J, Brenner E, Deibl M, Fritsch H, Bartsch G and Rad- tor is an important neurotrophic factor guiding the ingrowth mayr C: Longitudinal and thickness measurement of the 1 of nerve fibers during organogenesis. Similar morphological normal distal and intravesical ureter in human fetuses. changes are seen in primary VUR, possibly implying a com- J Urol 2003; 169: 1501. Durability of a Single Successful Endoscopic Polytetrafluoroethylene Injection for Primary Vesicoureteral Reflux: 14-Year Followup Results

Selçuk Yücel, Tufan Tarcan* and Ferruh S¸ ims¸ek From the Department of Urology, Pediatric Urology Section, Akdeniz University School of Medicine, Antalya (SY) and Department of Urology, Pediatric Urology Section, Marmara University School of Medicine, Istanbul, Turkey

Purpose: We reviewed our 14-year experience with successful single endoscopic subureteral polytetrafluoroethylene injection for the treatment of primary vesicoureteral reflux in children. Materials and Methods: We retrospectively reviewed the charts of 42 patients with primary vesicoureteral reflux who were treated with a single successful subureteral polytetrafluoroethylene injection between 1989 and 1993 and followed with routine 1, 3 and 10-year voiding cystourethrography. Results: The study included 30 girls and 12 boys 2 to 14 years old (median age 6 years). Four patients were lost to followup. Of the 38 remaining patients 28 had unilateral and 10 had bilateral primary vesicoureteral reflux. Endoscopic treatment with subureteral polytetrafluoroethylene injection was performed in 48 ureters. Followup ranged from 10 to 14 years (mean 12.5 Ϯ 2.1). Voiding cystourethrography in 38 patients and 48 ureters revealed that 35 ureters (73%) remained free of reflux, whereas reflux recurred in 13 (27%) at a median of 2 years. Of these 13 ureters recurring reflux was grade I to II in 5 and grade III to V in 8. Reflux recurred in 11 of 24 ureters with grade IV to V reflux. Of the 13 recurrences 10 presented as febrile urinary tract infections and only 3 grade I recurrences were detected on voiding cystourethrography alone. No untoward effects were seen in any of these patients with injection of polytetrafluoroethylene. Conclusions: Long-term followup may be warranted after a single successful endoscopic injection for vesicoureteral reflux, particularly high grade reflux. However, followup voiding cystourethrography is unnecessary in patients presenting with febrile urinary tract infection. Key Words: vesico-ureteral reflux, endoscopy, polytetrafluoroethylene, treatment failure, follow-up studies

ince approval by the Food and Drug Administration of lution in early followup? Or are we going to reserve voiding dextranomer/hyaluronic acid copolymer for vesi- cystourethrography for urinary tract infections? If reflux has S coureteral reflux correction, there has been a world- the possibility of recurring, when should we expect it? Par- wide shift in the treatment of vesicoureteral reflux, with ents would like to know if endoscopically corrected reflux endoscopic injection now being recommended as the primary really is a lifelong correction. treatment.1 Recently, a committee assembled to update the As the meta-analysis indicates, success rates change sig- American Urological Association Pediatric Vesicoureteral nificantly after subsequent injections (85.05% vs 74.13%), Reflux Treatment Guidelines published a meta-analysis on possibly as a result of better injection placement and more the outcomes of endoscopic correction by different injectable volume injected.2 Recently, success rates have been reported agents, including PTFE, polydimethylsiloxane, collagen and to be associated with injected volume and injection tech- dextranomer.2 Although the meta-analysis clearly showed a nique, particularly in dilating reflux.9 Diamond et al re- reasonable success rate with endoscopic correction, concerns cently studied the minimal critical injection volume required regarding the durability of outcomes in the long term have to correct reflux.10 It is reasonable that recurrent injections remained unanswered. We still do not know how and how will have a higher injected volume, and although there is a long we have to follow these refluxing ureters after success- gradual volume loss with time, the critical volume can be ful endoscopic correction. reached after reinjection. To assess the long-term durability, Although there are few studies addressing the long-term we homogenized our study population into single successful durability of success after endoscopic correction,3–8 parents injections. We report our 14-year followup in ureters with must be informed of the long-term outcomes when deciding single successful endoscopic PTFE injection, with special on a treatment modality. Are we going to continue to do reference to long-term durability and morbidity. voiding cystourethrography after documenting reflux reso-

MATERIALS AND METHODS Submitted for publication October 19, 2006. Supported by Akdeniz University Scientific Research and Project We retrospectively reviewed the charts of 42 patients with Unit (SY). primary vesicoureteral reflux who were successfully treated * Correspondence: Department of Urology, Marmara University with a single subureteral PTFE injection between 1989 and School of Medicine, Tophanelioglu cad. No. 13-15, Istanbul, Turkey (telephone: 90-216-325-2052; FAX: 90-216-325-8579; e-mail: tufan@ 1993 at Marmara University. Four patients were lost to marmara.edu.tr). followup after the first year of control, and were excluded

0022-5347/07/1781-0265/0 265 Vol. 178, 265-268, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.060 266 SINGLE POLYTETRAFLUOROETHYLENE INJECTION FOR VESICOURETERAL REFLUX from the study. The study included 26 girls and 12 boys 2 to urinary tract infection during followup, of whom 10 (26%) 16 years old (median age 6 years). Of the patients 28 had were observed to have recurrent reflux. After subsequent unilateral vesicoureteral reflux and 10 had bilateral reflux. injections or open reimplantation we did not observe any None of the patients had a duplex system. febrile urinary tract infection during followup. Subureteral PTFE injection was performed in all patients Among 10 low grade (I to II) refluxing ureters only 1 by the senior author (FS) using the technique described by (10%) exhibited recurrence of reflux. Grade II vesicoureteral Puri.11 According to the international classification, reflux reflux recurrence was diagnosed at 1-year voiding cystoure- was grade I in 4 ureters (8%), grade II in 6 (13%), grade III thrography after a febrile urinary tract infection. A second in 14 (29%), grade IV in 17 (35%) and grade V in 7 (15%). PTFE injection was performed in this patient. The patient Indications for endoscopic injection were the same as for was reflux-free at 10 years following the second injection. open ureteral reimplantation in grades III to V reflux. Low Of 14 grade III refluxing ureters 1 (7%) exhibited recur- grade (I to II) reflux was treated only in patients with renal rent grade I vesicoureteral reflux after a symptomatic uri- scarring on radionuclide scan, recurrent urinary tract infec- nary tract infection at 2-year followup. A second PTFE in- tions despite antibiotic prophylaxis or contralateral high jection was performed. The patient was reflux-free at 10 grade reflux. The majority of the children were discharged years after the second injection. home on the day of the procedure. Among 17 grade IV refluxing ureters 7 (41%) displayed Antibiotic prophylaxis was continued for 12 weeks after recurrent reflux on followup. Two of these ureters exhibited endoscopic injection. Voiding cystourethrography and renal grade IV reflux on voiding cystourethrography at 2 years, pre- ultrasonography were performed at 3 months following in- ceded by a febrile urinary tract infection, and 2 ureters exhib- jection. Reflux resolution (including grade I) on cystourethrog- ited grade IV reflux at 3 years, preceded by a febrile urinary raphy at 3 months was regarded as a successful injection. After tract infection and dilatation of the upper urinary system on reflux resolution documentation voiding cystourethrography ultrasonography. Two of these patients underwent open ure- was performed at 1, 3 and 10 years of followup, in participation teral reimplantation, and 2 underwent a second PTFE injec- with a multicenter survey by Puri and Granata.5 Patients tion. These patients were reflux-free at 10 years following the were followed annually with physical examination including second injection. The remaining 3 ureters exhibited grade I arterial blood pressure, urinalysis and urine culture, and vesicoureteral reflux on followup voiding cystourethrography renal ultrasonography. Otherwise, voiding cystourethrogra- at 3 years. No further treatment was needed. On 10-year phy was done if a febrile urinary tract infection or dilatation voiding cystourethrography grade I reflux was still present in of the upper urinary system was noted. 3 of the patients, without any symptoms. Of 7 grade V refluxing ureters 4 (57%) displayed recur- RESULTS rent reflux at followup. Three ureters exhibited grade V reflux recurrence, with 1 observed at 1 year and 2 at 2 years A total of 38 patients with 48 refluxing ureters were followed after injection, preceded by a febrile urinary tract infection. for 10 to 14 years (mean 12.5 Ϯ 2.1). Of the 48 ureters with a These 3 cases were managed by open ureteral reimplanta- successful single injection 40 (83%) required less than 0.4 ml tion. One patient had a recurrence of grade III reflux at PTFE. A total of 37 children (97%) were discharged home on 5-year voiding cystourethrography, preceded by a febrile the day of the procedure. One patient was hospitalized be- urinary tract infection, and a second injection corrected the cause of urinary retention following the procedure, which reflux. The patient was reflux-free at 3 years and symptom- subsided after 1 day of urethral catheterization. free at 8 years after the second injection. As seen in the figure, voiding cystourethrography demon- Initial reflux grades, recurrence rates and recurrent re- strated absence of reflux (including grade I) in 35 of 48 flux grades are summarized in the table. No clinically unto- ureters (73%) on long-term followup. Of the 13 ureters with ward effects were reported in any patient due to the use of recurrence VUR grade was low (I to II) in 5 and high (III to PTFE as an injectable material. V) in 8. A total of 11 patients (29%) presented with febrile DISCUSSION The first injectable material for endoscopic treatment of vesicoureteral reflux was PTFE, and, therefore, it is the material with the longest followup data.11 We studied long- term outcomes in children treated at our institution with a single successful PTFE injection for reflux. We observed durable success in 35 of 48 ureters (73%) and clinically significant recurrence in 10 ureters at a mean followup of 12.5 years. Reflux recurrence was chiefly seen in the high grade (III to V) group (12 of 13 cases). Recurrent reflux was low grade (I to II) in 5 ureters and high grade (III to V) in 8. Voiding cystourethrography alone detected only grade I recurrences in 3 cases, while the remainder were preceded by a febrile urinary tract infection. The latest recurrence was observed at 5 years (median 3, see figure). There are only 5 published studies with long-term outcomes following PTFE injection,3–7 and 1 known study following dex- Durability of success by VUR grade in long-term followup tranomer/hyaluronic acid injection.8 Chertin et al reported the SINGLE POLYTETRAFLUOROETHYLENE INJECTION FOR VESICOURETERAL REFLUX 267

8 VUR Grade No. Pts No. Recurrences (%) No. Recurrences by Grade The results of Lackgren et al are comparable to our findings, since we detected only grade I reflux recurrence by I40 4 voiding cystourethrography alone. However, we disagree II 6 1 (17) 1 III 14 1 (7) 1 with the statement that most recurrences happen in the first IV 17 7 (41) 4 18 months, since we detected 11 of 13 recurrences at 2 years V 7 4 (57) 3 after injection, or later. We propose that this statement should be changed to reflect that the risk of recurrence largest population undergoing PTFE injection, with the longest significantly decreases after 3 years following endoscopic followup.6 In 1998 Puri and Granata published the results of a correction. multicenter survey of PTFE injections, in which recurrence The febrile urinary tract infection rate following endo- was seen in only 2.8% of the cases.5 However, in that study scopic correction was reported as 0.75% in a recent meta- only 7.6% of the cases were followed for more than 10 years, analysis.2 However, this result may not be exact, since, as and only 22.8% of the cases were grade IV or V reflux. In 2002 the authors stated, most studies reviewed in the meta-anal- Chertin et al reported 94% durability (367 of 389 cases) after 17 ysis were not specific regarding infection, and followups years.6 However, 65 ureters (17%) required at least 2 injections were short. Lackgren et al reported a febrile urinary tract to correct the reflux. If we subtract all ureters with multiple infection rate of 3.5% (8 of 228 patients) at up to 6 years of injections, the durability decreases to 78%. A year later these followup.8 Of these 8 recurrences 7 (88%) were grade III or authors presented their data on grades IV and V reflux with higher. This finding is similar to ours, since most recur- 11-year followup, noting only 1.2% recurrence.7 However, rences in our study (77%) were found due to febrile urinary when we scrutinized the data recurrence following single in- tract infection. jection was 2.1%. Although Puri et al did not observe distant migration Unfortunately, our results with PTFE injection were not after PTFE injection in their large patient group,3–7 our comparable to the long-term studies of Puri4,5,7,11 et al. major concern during followup was the risk of distant mi- During a mean followup of 12.5 years the overall recurrence gration of PTFE particles, as suggested by the literature.15 rate was 27%, and grade IV/V recurrence was 45%. Our overall Luckily, we have not been confronted with this complication. durability rate for successful single injection ureters is similar Based on our findings, we speculate that followup after a to that of Vereecken and Proesmans (73% vs 70%).3 single successful injection can be designed as clinical visits There can be 2 explanations for the discrepancy between for febrile urinary tract infection during the first 3 years our outcomes and those of Puri et al, namely different injection after injection, with voiding cystourethrography reserved for techniques and different injected volumes. Our injection tech- febrile cases. Similarly, Lackgren et al reported a 3.5% fe- nique is the same as that described by Puri.11 In addition, brile infection rate and a 4% recurrence of reflux.8 Unfortu- our overall short-term success rate (90%) is comparable to nately, in our study we failed to gain any insight about the meta-analysis results.2,12 We injected 0.4 ml in most possible factors decreasing the success of endoscopic correc- cases, which is comparable to the mean dose reported in the tion, such as bladder instability, gender or cystitis. However, meta-analysis (0.23 ml).2 Likewise, Puri et al indicated that our patient group was small and statistical analysis would the majority of ureters (87%) corrected with a single injec- be ineffective. tion required less than 0.3 ml PTFE.4 We believe that it is important to report a study of pri- The failure mechanism in PTFE injections was investi- mary vesicoureteral reflux with no patient younger than 1 gated by Bhatti et al, who described volume loss in 48% of year and no recurrent injections, to assess the long-term cases and mound displacement in 35%.13 Diamond et al durability of reflux treatment. Our experience is that chil- agreed with these mechanisms, although they also identified dren who are reflux-free after a single endoscopic injection mound extrusion.10 Based on pre-injection and post-injec- are more prone to be lost to followup. Parents of such chil- tion photographs comparing 4 different agents, we also ob- dren should especially be warned about the possibility of served the failure mechanisms to be volume loss and mound recurrence in the long term, and encouraged to keep up with displacement.14 It is noteworthy that all of the mound dis- regular visits to the pediatrician. placements in failed cases were detected in the short term. However, it is reasonable to suspect the same failure mech- CONCLUSIONS anism in the long term. Higher injection volumes, as stated Single successful injection does not guarantee lifelong suc- by Kirsch et al, may affect the outcome in the long term as cess, especially in high grade vesicoureteral reflux. How- well as the short term.9 ever, recurrence can be detected based on febrile urinary The only known long-term study of dextranomer/hyal- tract infections, and voiding cystourethrography may be re- uronic acid copolymer was reported by Lackgren et al, who served for those cases. followed 334 ureters (grade III to IV VUR in 94%) for 2 to 7.5 years (mean 5).8 Of 162 ureters with a single successful injection grade III or higher reflux recurred in 14 (9%). Our recurrence of grade III and higher reflux was 17%. It is Abbreviations and Acronyms noteworthy that 77 ureters were studied with voiding cys- PTFE ϭ polytetrafluoroethylene tourethrography during 2 to 5 years of followup. Reflux VUR ϭ vesicoureteral reflux resolution was durable in 39 of 45 ureters (87%) in the long term. According to Lackgren et al, if there is no reflux at 12 REFERENCES to 18 months, there is little risk of recurrence in the long 8 term. Interestingly, 10 recurrences were noted at 2 and 3 1. Stenberg A, Hensle TW and Lackgren G: Vesicoureteral reflux: years in our study. a new treatment algorithm. Curr Urol Rep 2002; 3: 107. 268 SINGLE POLYTETRAFLUOROETHYLENE INJECTION FOR VESICOURETERAL REFLUX

2. Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, worthy that the median patient age for initial treatment in Hurwitz R et al: Endoscopic therapy for vesicoureteral re- this study was 6 years. The durability reported may not be flux: a meta-analysis. I. Reflux resolution and urinary tract applicable to children treated at earlier ages. It would be infection. J Urol 2006; 175: 716. useful to report any differences in durability between age 3. Vereecken RL and Proesmans W: Results of endoscopic treat- groups. ment for vesico-ureteric reflux. Eur Urol 1995; 27: 76. 4. Puri P, Palanimuthu M and Dass L: Endoscopic treatment of Information regarding the patients with recurrent reflux primary vesicoureteric reflux in infants by subureteric in- would be helpful—including the presence of voiding dysfunc- jection of polytetrafluoroethylene. A 9-year follow-up. Eur tion, volume of PTFE remaining (estimated by bladder ul- Urol 1995; 27: 67. trasound) and location of the PTFE. Our experience with 5. Puri P and Granata C: Multicenter survey of endoscopic treat- dextranomer/hyaluronic acid indicates durability with no ment of vesicoureteral reflux using polytetrafluoroethylene. significant loss of injected volume measured sonographically J Urol 1998; 160: 1007. for at least 3 years.1 We recognize that radiographic recur- 6. Chertin B, Colhoun E, Velayudham M and Puri P: Endoscopic rence is possible. However, given the 5% clinical recurrence treatment of vesicoureteral reflux: 11 to 17 years of fol- rate (despite normal voiding cystourethrogram in many lowup. J Urol 2002; 167: 1443. cases), we agree that postoperative voiding cystourethro- 7. Chertin B, De Caluwe D and Puri P: Endoscopic treatment of primary grades IV and V vesicoureteral reflux in children grams may be deferred in the majority of children treated with subureteral injection of polytetrafluoroethylene. endoscopically. A minimum followup of 2 years, particularly J Urol 2003; 169: 1847. when patients are treated at a younger age, seems prudent. 8. Lackgren G, Wahlin N, Skoldenberg E and Stenberg A: Long- I have come to believe that the vast majority of endoscopic term followup of children treated with dextranomer/hyal- failures are technical errors relating primarily to the agents uronic acid copolymer for vesicoureteral reflux. J Urol 2001; used, mode of implantation and, most importantly, means of 166: 1887. determining the end point of injection (ie volume used and 9. Kirsch AJ, Perez-Brayfield M, Smith EA and Scherz HC: The loss of hydrodistention following implantation). One may modified STING procedure to correct vesicoureteral reflux: anticipate lower success rates in historical trials, and we improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413. should counsel families as to the high modern success of 10. Diamond DA, Caldamone AA, Bauer SB and Retik AB: Mech- endoscopic treatment in the era of improved techniques and 2 anisms of failure of endoscopic treatment of vesicoureteral agents (reference 9 in article). reflux based on endoscopic anatomy. J Urol 2003; 170: Andrew J. Kirsch 1556. 11. Puri P: Endoscopic correction of primary vesicoureteric reflux Department of Urology by subureteric injection of polytetrafluoroethylene. Lancet Children’s Healthcare of Atlanta 1990; 335: 1320. Emory University School of Medicine 12. Simsek F, Dillioglugil O, Ilker Y and Akdas A: Correction of Atlanta, Georgia primary and secondary vesicoureteral reflux by subureteric Teflon injection. Int Urol Nephrol 1995; 27: 51. 1. McMann LP, Scherz HC and Kirsch AJ: Long-term preservation 13. Bhatti HA, Khattak H and Boston VE: Efficacy and causes of of dextranomer/hyaluronic acid copolymer implants after en- failure of endoscopic subureteric injection of Teflon in the doscopic treatment of vesicoureteral reflux in children: a treatment of primary vesicoureteric reflux. Br J Urol 1993; sonographic volumetric analysis. J Urol 2007; 177: 316. 71: 221. 2. Yu RN and Roth DR: Treatment of vesicoureteral reflux using 14. Yucel S, Ucar M, Guntekin E, Kukul E, Melikoglu M and endoscopic injection of nonanimal stabilized hyaluronic acid/ Baykara M: The effect of location of the ureteric orifice on dextranomer gel: initial experience in pediatric patients by a the efficacy of endoscopic injection to correct vesico-ureteric single surgeon. Pediatrics 2006; 118: 698. reflux. BJU Int 2005; 95: 1314. 15. Aragona F, D’Urso L, Scremin E, Salmaso R and Glazel GP: Polytetrafluoroethylene giant granuloma and adenopathy: REPLY BY AUTHORS long-term complications following subureteral polytetra- Although endoscopic correction of VUR has been practiced in fluoroethylene injection for the treatment of vesicoureteral pediatric urology since the 1980s, there are many unknowns reflux in children. J Urol 1997; 158: 1539. for every aspect of this surgical modality. Unfortunately, we are still far from defining the ideal patient, the ideal injected EDITORIAL COMMENT volume and even the ideal injection technique for the best A scant body of knowledge exists regarding the durability of outcome. Treatment failure does not necessarily correspond endoscopic treatment of vesicoureteral reflux. Although to mound loss detected on ultrasound since even a small PTFE is seldom used today, the authors should be com- shift of the mound may result in failure. Although endo- mended for the detail and length of followup that is provided scopic correction has greatly decreased the anxiety of par- in this article. ents they should be warned about the risk of reflux recur- The low injected volumes and use of PTFE are limitations rence at least within the first 3 years of therapy. Long-term of this study that are not directly applicable to contemporary studies on dextranomer/hyaluronic acid are needed to con- management using dextranomer/hyaluronic acid. It is note- firm durability. Vesicoscopic Cross-Trigonal Ureteral Reimplantation: A Minimally Invasive Option for Repair of Vesicoureteral Reflux

Stephen J. Canon,* Venkata R. Jayanthi and Ashay S. Patel From the Section of Urology, Columbus Children’s Hospital, Ohio State University, Columbus, Ohio

Purpose: Cross-trigonal ureteral reimplantation is a commonly performed procedure for the correction of vesicoureteral reflux. Most previously described laparoscopic techniques have used an extravesical approach. A “vesicoscopic” technique is analogous to standard open cross-trigonal repair in principle, except that 3 ports with insufflation of the bladder are used to perform the ureteral reimplantation. Materials and Methods: A retrospective review was performed of patients treated for primary vesicoureteral reflux with either vesicoscopic or open ureteral reimplantation. For patients with vesicoscopic reimplantationa5mmport is placed in the dome of the bladder and 2, 3 mm ports are placed laterally. The ureters are mobilized transvesically, cross-trigonal submucosal tunnels are made and the ureters are sutured in place with intracorporeal suturing. The bladder ports are closed and a urethral catheter is left indwelling for 36 hours. Among the open reimplantation group 38 patients underwent cross-trigonal ureteral reimplantation, 2 underwent extravesical ureteral reimplantation and 2 were excluded due to insufficient records. Followup imaging for both groups included ultrasonography at 1 month and voiding cystography at 3 months postoperatively. Results: A total of 52 consecutive children underwent vesicoscopic ureteral reimplantation with 1 patient converted to open intravesical reimplantation, and 40 consecutive controls underwent open ureteral reimplantation. Postoperative vesicoureteral reflux resolution rates for the vesicoscopic and open groups were 91% (42 of 46 patients) and 97% (31 of 32 patients), respectively. Mean patient age and mean maximal grade of vesicoureteral reflux in the vesicoscopic and open groups were 5.7 and 4.0 years (p ϭ 0.001), and 2.8 and 3.2 (p ϭ 0.036), respectively. Mean operative times for vesicoscopic and open procedures were 199 and 92 minutes, respectively (p ϭ 0.001). While the average length of hospital stay of 2 days was similar between the groups (p ϭ 0.122), less oral and intravenous analgesia was needed postoperatively in the vesicoscopic group (p ϭ 0.001 and p ϭ 0.005, respectively). Complications of vesicoscopic ureteral reimplantation included urinary leakage in 1 child, bladder stones in 1 and bilateral ureteral obstruction in 1. There were no complications in the open group. Conclusions: There is an ever increasing trend toward minimally invasive surgery. Our preliminary results indicate that vesicoscopic ureteral reimplantation is an effective procedure with minimal morbidity. Although success rates for vesicoureteral reflux resolution were slightly lower in the vesicoscopic group in this study, the favorable results of other series and the improvement in postoperative discomfort observed here suggest that this technique may be a reasonable option in the management of vesicoureteral reflux. Further refinement of the technique and critical analysis of the long-term outcomes are needed to understand fully its place in the treatment of vesicoureteral reflux. Key Words: vesico-ureteral reflux, ureter, laparoscopy, replantation, cystostomy

he options for surgical management of VUR have ex- novel technique of vesicoscopic cross-trigonal ureteral reim- 4 panded in recent years with the application of dextra- plantation under CO2 pneumovesicum. That series demon- T nomer/hyaluronic acid injection and the introduction strated excellent results, with 96% of 16 patients having of laparoscopic extravesical ureteral reimplantation. Recent resolution of reﬂux. The aim of this study was to describe our studies aimed at determining parental preferences have initial experience with VR in a larger group of children, and shown that parents are more apt to choose minimally to compare the outcomes to a control group undergoing OR. invasive techniques to treat VUR when intervention is necessary.1,2 Gill et al originally described a technique of vesicoscopic MATERIALS AND METHODS cross-trigonal ureteral reimplantation using glycine irrigation in a small series of patients, with 2 of 3 exhibiting We retrospectively reviewed the records of all children un- resolution of VUR.3 Yeung et al subsequently developed a dergoing correction of reﬂux via a vesicoscopic approach at our institution. A control group of consecutive patients with a history of primary VUR and OR was reviewed for comparison. Indications for surgery for both groups included break- Submitted for publication October 21, 2006. through urinary tract infections during antibiotic prophy- * Correspondence: Section of Urology, Columbus Children’s Hos- pital, 700 Children’s Dr., Columbus, Ohio 43205 (e-mail: canons@ laxis, persistent VUR after observation with medical chi.osu.edu). treatment for 4 to 5 years, especially in association with

0022-5347/07/1781-0269/0 269 Vol. 178, 269-273, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.059 270 VESICOSCOPIC CROSS-TRIGONAL URETERAL REIMPLANTATION signiﬁcant renal scarring, and/or persistent VUR after injection therapy. Families were given the options of dextranomer/hyaluronic acid injection, open reimplantation and vesicoscopic reimplantation. The VR technique is similar to that described by Yeung et al,4 with minor variations.

Positioning The VR procedure is performed with the patient in the standard dorsal lithotomy position, with the perineum and abdomen in the sterile ﬁeld. This approach allows access to the urethra, as needed, throughout the operation. Careful positioning and padding are ensured to prevent nerve palsy.

Bladder Wall Fixation and Port Placement

Cystoscopy using CO2 bladder distention filled to 10 to 15 mm Hg is performed to assess the anatomy and to allow for FIG. 2. Bilateral procedure. A, ureteral dissection is performed with hook electrode at low power setting. B, as in open repair, ureter is percutaneous fixation of the bladder to the anterior abdom- freed until enough length is gained to transpose to other side. C, left inal wall. Sequentially, at the dome and the lateral walls an ureter has been placed in its submucosal tunnel with neomeatus to 18 gauge spinal needle is passed into the bladder, through be placed near original location of right meatus. D, completed repair which a 2-zero polydioxanone suture is passed. A stone bas- before removal of ureteral catheters. ket is then placed through an adjacent puncture to snare the suture and extract it. The sutures are then tied, fixing the anterior bladder wall to the abdomen.A5mmport is placed hiatus. The feeding tubes are passed through the tunnels to in the dome and 3 mm ports are placed laterally. A 30-degree aid in transposition of the ureters (fig. 2, C). The ureter is lens is placed through the dome port and vesicoscopy is fixed into position with 5-zero polydioxanone interrupted performed (fig. 1). sutures (fig. 2, D). The remaining mucosal defects are closed with absorbable suture, and the feeding tubes are removed. Ureteral Dissection Feeding tubes (3.5Fr) are placed through the urethra into Bladder Port Closure the bladder, passed up each orifice and fixed in place with To maintain the pathway through the incision into the blad- 5-zero polydioxanone suture. The affected ureters are then der, a feeding tube is placed through each tract before re- mobilized with a hook electrode at a low power setting, or moval of the port. By passing spinal needles through the with a combination of blunt and sharp dissection using scis- incisions and avoiding the fascia, each bladder port is closed sors or graspers (fig. 2, A). After sufficient ureteral mobili- in a manner analogous to the abdominal wall fixation. After zation the defect in the detrusor muscle is closed with inter- placing all bladder sutures a Foley catheter is inserted for rupted 4-zero polydioxanone suture (fig. 2, B). decompression. The original bladder-anterior abdominal wall fixation sutures are removed, allowing the bladder to fall away from the abdominal wall. The bladder port closure Tunnel Creation sutures are then carefully tied, and the skin incisions are Cross-trigonal tunneling is then performed with a combina- subsequently closed. tion of sharp and blunt dissection in the submucosal plane. Postoperatively, all patients in both groups were given Maryland graspers are used to elevate the mucosa, and fine intravenous ketorolac for 24 hours unless contraindicated. scissors are used to initiate and develop the submucosal Acetaminophen with codeine (1 mg/kg every 4 hours), intra- plane from either direction (fig. 3). The length of tunnel created spans from the initial hiatus across to the opposite

FIG. 3. Tunnel creation. Lifting mucosa allows submucosal plane to be identified. Tunnel is then created using sharp and blunt dissec- FIG. 1. Port placement in vesicoscopy tion. VESICOSCOPIC CROSS-TRIGONAL URETERAL REIMPLANTATION 271 venous morphine (0.1 mg/kg every 4 hours) and oral oxy- The VR and OR groups were compared for VUR resolu- butynin were given as needed based on patient request in tion, excluding the single patient with open conversion. Of both groups. Bladder catheters were left indwelling until the the 51 patients in the VR group 46 underwent postoperative morning of postoperative day 1 in the OR group and for 36 cystography, which showed VUR resolution in 42 (91%). Two hours in the VR group. On discontinuation of the catheter of these 42 patients had transient VUR initially, which and tolerance of a regular diet patients were discharged resolved spontaneously on subsequent cystography. Of the home. Renal ultrasound and voiding cystography were per- 40 patients in the OR group 32 underwent postoperative formed at 1 and 3 months postoperatively, respectively. cystography, which demonstrated VUR resolution in 31 (97%). Chi-square and logistic regression analysis control- Statistics ling for weight and age was used to compare treatment SPSS® for Windows version 13 was used to perform statis- outcomes, and no significant differences in VUR resolution tical analysis of the VR and OR groups. Chi-square and were found between the 2 groups. logistic regression analysis were used to compare VUR out- Student’s t test was used to compare maximum VUR comes. Student’s t test was used to compare results for grade, LOS, postoperative narcotic dose requirements (oral maximum VUR grade, LOS, postoperative narcotic require- codeine and intravenous morphine), postoperative anticho- ments, oxybutynin requirements, patient weight and age, linergic dose requirements (oxybutynin), patient weight and and total operative time (see table). age, and total operative time (see table). No significant differences in LOS or oxybutynin use were noted between the 2 RESULTS groups. Average maximum reflux grade was higher in the control group, and weight and age were higher in the vesi- The VR group was comprised of 45 girls and 7 boys, with an coscopic group. While the average operative time for VR average age of 5.7 years (range 1 to 18) and an average (3.3 hours) was longer than for OR (1.5 hours, p ϭ 0.001), followup of 11 months. These 52 patients underwent at- patients in the OR group required more postoperative oral tempted VR between October 2004 and January 2006. Of and intravenous analgesics than those undergoing VR (p these patients 13 underwent unilateral reimplantation and ϭ 0.001 and p ϭ 0.005, respectively). 38 underwent bilateral reimplantation. There was 1 open Although no major intraoperative complications occurred conversion due to equipment malfunction and poor port in either group, minor intraoperative complications were placement. A total of 10 patients had failed subureteral encountered in the VR group. Pneumoperitoneum occurred dextranomer/hyaluronic acid injection. At the time of the on occasion, and was easily treated with transumbilical procedure 28 patients had bilateral VUR and 24 had unilat- Veress needle placement. Also, proximal migration of the eral VUR. Of the 24 patients with unilateral VUR 11 under- feeding tube occurred in 3 patients during VR, necessitating went bilateral ureteral reimplantation (8 had previous con- immediate flexible ureteroscopy for retrieval. This problem tralateral VUR, 2 had unfavorable anatomy and 1 had was attributed to inadequate fixation of the feeding tube to bilateral renal scarring on dimercapto-succinic acid scan). the ureteral orifice, and none of these 3 patients had persis- None of the patients had a ureteral stent left indwelling tent VUR or any other postoperative complications. postoperatively. There were no major complications in the control group. The control group was comprised of 42 consecutive pa- Of 51 patients in the VR group 3 (6%) had postoperative tients with a history of primary VUR who underwent OR complications. The initial patient in the series had extra- between July 2003 and June 2004. Two patients were ex- peritoneal urinary leakage at 1 week postoperatively. This cluded from analysis because of insufficient records for ad- complication occurred before initiation of the port closure equate comparison. The group was comprised of 31 girls and technique. 9 boys, with an average age of 4 years and an average One child in the VR group had bladder stones, which followup of 28 months. Two patients underwent extravesical passed spontaneously. Although stone analysis revealed no unilateral reimplantation, and the remainder underwent nidus, excessive suture tags may have contributed, and we unilateral (6 patients) or bilateral (32) intravesical cross- have since made an effort to minimize suture tags. trigonal ureteral reimplantation. A total of 17 patients had Finally, 1 patient in the VR group was hospitalized else- unilateral VUR and 23 had bilateral VUR. Of the 17 patients where at 1 month postoperatively for bilateral ureteral ob- with unilateral VUR 9 underwent bilateral intravesical ure- struction with acute renal failure. After temporary dialysis teral reimplantation due to a history of bilateral VUR or and bilateral nephrostomy placement renal function re- concerning contralateral anatomical findings. turned to normal. We suspect that this child may have had leakage through the tunnels, with obstruction due to extrinsic compression from the retrovesical urinomas that had developed. Subsequent reconstruction was performed else- Statistical comparison of OR and VR where. OR (40 pts) VR (51 pts) Cystoscopy was performed in 3 patients with persistent Mean SD Mean SD p Value VUR after VR. One patient had no evidence of intramural ureter crossing the trigone and 2 patients had ureterovesical Max reflux grade 3.2 0.9 2.8 0.7 0.036 No. days hospitalized 2.0 0.8 2.1 0.5 0.122 fistulas. No. codeine doses (1 mg/kg) 3.3 1.9 2.1 1.9 0.001 No. morphine doses (0.1 mg/kg) 2.2 2.1 1.1 1.5 0.005 No. oxybutynin doses (0.2 mg/kg) 0.8 1.3 1.1 2.0 0.370 DISCUSSION Pt wt (kg) 19.2 11.6 22.1 8.1 0.003 Pt age (yrs) 4.0 3.3 5.7 3.1 0.001 Ureteral reimplantation has proved to be effective in the Total operative time (hrs) 1.5 0.6 3.3 0.7 0.001 treatment of VUR, with few major complications. However, 272 VESICOSCOPIC CROSS-TRIGONAL URETERAL REIMPLANTATION minor complications following these procedures, such as he- imperative that great care be taken during dissection and maturia and bladder irritability, can greatly affect the post- mobilization of the affected ureters. A low power setting on operative course. With the advent of laparoscopic urological the hook electrode and liberal sharp scissors dissection of surgery there exists the possibility of reproducing open ure- the periureteral tissue may help decrease the likelihood of teral reimplantation with less postoperative pain. Conse- cautery injury, as we have had no further cases of persistent quently, some urologists have applied laparoscopic tech- VUR since instituting this change. niques to ureteral reimplantation in an attempt to improve on the current options in the management of VUR. Although there was no discernible statistical difference in CONCLUSIONS VUR resolution between the VR and open groups in our Our preliminary results indicate that VR is an effective study, the results were not as favorable in VR as in open procedure involving less pain compared to open transvesical surgery in this and other studies of open intravesical ure- repair. To our knowledge this series of vesicoscopic ureteral teral reimplantation.5–7 However, after using a similar tech- reimplantation is the first to compare results to a control nique Yeung et al observed results equivalent to OR (96% group undergoing open ureteral reimplantation. The lower VUR resolution) in a smaller series in children.4 Also, in a mean age and the higher preoperative VUR grade in the series of 50 patients with VR (6 months to 14 years old) control group are likely reflective of our bias toward per- Steyaert and Valla reported VUR resolution in 40 of 41 forming OR in small children and in children with high patients (98%) with followup.8 We believe that the technique grade VUR. These differences may have an impact on the of creating cross-trigonal tunnels is the same as that of OR outcomes observed, and are certainly limitations to the but that the tools and exposure are slightly different. Errors study. Nevertheless, significant differences in narcotic re- with our execution of this technique likely caused decreased quirements and total OR time were observed in this series. success compared to other series. With increasing experi- While the rate of VUR resolution for VR in this series is ence we expect that VUR resolution rates will be identical to not as high as that of OR, the favorable results of other those of open ureteral reimplantation. series and the reduction in observed postoperative pain war- Although this study is retrospective and no validated rant consideration of this technique in the management of postoperative pain questionnaire was used, there was a sta- VUR. Further refinement of the technique and critical anal- tistically significant difference in the amount of narcotic ysis of the long-term outcomes are needed to understand medications taken by the 2 groups. Significance was ob- fully its place in the treatment of VUR. As with any new served for the number of doses of oral and intravenous procedure, complications not typically encountered with analgesics administered on an as needed basis (p ϭ 0.001 standard techniques occurred. However, there is a steep and p ϭ 0.005, respectively). However, there was no statis- learning curve, and we suspect that with greater experience tical difference between the 2 groups regarding the amount the occurrence of such complications should be low. of anticholinergic medication (oxybutynin) taken postoperatively (see table). We believe that elimination of the anterior cystotomy and placement of an intravesical retractor through the VR decreases postoperative bladder irritability. Abbreviations and Acronyms Operative times were clearly longer in the VR group in this LOS ϭ length of stay study (p ϭ 0.001). We analyzed the trend of operative times OR ϭ open ureteral reimplantation with increased experience. However, no substantial improve- VR ϭ vesicoscopic ureteral reimplantation ment was noted, which is likely due to inclusion of physicians VUR ϭ vesicoureteral reflux in training during certain portions of the procedure in the latter half of the study. Factors unique to this procedure that make it challenging include a small working space, intracor- REFERENCES poreal suturing, and dissection and tunneling of the ureters. Surgeon baseline laparoscopic skills and experience should 1. Ogan K, Pohl HG, Carlson D, Belman AB and Rushton HG: influence the slope of the learning curve for this technique. Parental preferences in the management of vesicoureteral Subjective improvement in ease of the procedure was noted reflux. J Urol 2001; 166: 240. 2. Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M and after 15 to 20 cases, although certain aspects of the technique Caione P: Treatment of vesico-ureteric reflux: a new algo- are constantly being modified and improved. rithm based on parental preference. BJU Int 2003; 92: 285. There was no statistically significant difference in hospital 3. Gill IS, Ponsky LE, Desai M, Kay R and Ross JH: Laparoscopic stay between the 2 groups studied (p ϭ 0.122). Furthermore, cross-trigonal Cohen ureteroneocystostomy: novel tech- LOS in the OR group was comparable to other studies of open nique. J Urol 2001; 166: 1811. ureteral reimplantation.5,9 We believe that this technique will 4. Yeung CK, Sihoe JD and Borzi PA: Endoscopic cross-trigonal eventually require only overnight observation, and we ac- ureteral reimplantation under carbon dioxide bladder insuf- knowledge our hesitancy to shorten the hospital stay due to the flation: a novel technique. J Endourol 2005; 19: 295. newness of the procedure and unknown expectations for the 5. McCool AC and Joseph DB: Postoperative hospitalization of postoperative course. The main limiting factor for hospitaliza- children undergoing cross-trigonal ureteroneocystostomy. J Urol 1995; 154: 794. tion involves removal of the Foley catheter, not pain control. 6. Burbige K: Ureteral reimplantation: a comparison of results There were 3 patients in the study who had the Foley removed with the cross-trigonal and Politano-Leadbetter techniques on postoperative day 1, with no subsequent problems. in 120 patients. J Urol 1991; 146: 1352. Cystoscopic examination of our treatment failures 7. Kennelly MJ, Bloom DA, Ritchey ML and Panzl AC: Outcome showed that persistent VUR was most likely due to electri- analysis of bilateral Cohen cross-trigonal ureteroneocystos- cal/ischemic injury of the ureter during mobilization. It is tomy. Urology 1995; 46: 393. VESICOSCOPIC CROSS-TRIGONAL URETERAL REIMPLANTATION 273

8. Steyaert H and Valla JS: Minimally invasive urologic surgery in even a valid option for treating vesicoureteral reflux in the children: an overview of what can be done. Eur J Pediatr near future. Surg 2005; 15: 307. 9. Miller OF, Bloom TL, Smith LJ, McAleer IM, Kaplan GW and Ricardo González Kolon TF: Early hospital discharge for intravesical ure- Department of Surgery, Division of Pediatric Urology teroneocystostomy. J Urol 2002; 167: 2556. Alfred I. duPont Hospital for Children Wilmington, Delaware EDITORIAL COMMENT REPLY BY AUTHORS As laparoscopic surgery in pediatric urology gains momen- The only way to know the extent to which laparoscopic tech- tum, it is appropriate to pause periodically to review the niques can be applied to pediatric reconstructive surgery is to results and compare them to those of well established open push the limits and objectively review outcomes. As with any procedures, as the authors of this study have done. The new technique or procedure one must objectively review out- theoretical advantages of laparoscopic surgery include bet- comes to assess what good and what bad might have occurred. ter cosmetic results, shorter hospitalization, decreased an- Evaluation of our cases with persistent refux suggested that algesic requirement, faster recovery, and in some cases more the technique of ureteral dissection might have been subopti- satisfactory operations resulting from better visualization mal. However, modifications to the dissection technique have and greater magnification. These theoretical advantages are improved outcome such that there have been no further cases not always easy to demonstrate in the pediatric population. of persistent reflux in the subsequent 30 patients tested. Pres- It is clear that at present laparoscopic surgery is superior ently we have a 94% rate of reflux resolution and can state that to open surgery for orchiopexy of intra-abdominal or peeping vesicoscopic reimplantation has a success rate nearly equiva- testes, and for pyeloplasty in older children. I also use lapa- lent to open repair. The length of tunnel that can be created is roscopy for primary or redo pyeloplasties in infants and a not a major issue, since even with open surgery there is no toddlers, partial nephrectomy for duplication anomalies and need to create a tunnel that extends past the contralateral ipsilateral ureteroureterostomy, and in cases when trans- hiatus. Indeed our present success rate would suggest that ureteroureterostomy, appendicovesicostomy or appendi- tunnel length creation is a nonissue. cocecostomy is required as an isolated procedure. In most of Admittedly, no validated pain scale was used in this retro- these cases laparoscopic surgery yields better cosmetic respective review. However, all patients had the same postoper- sults with equal or better outcomes compared to open sur- ative protocol with scheduled doses of ketorolac and with nar- gery. This outcome may justify the longer operating time. In cotics reserved for breakthrough pain. Thus, the documented our experience it has been difficult to determine a clear decreased need for narcotics in the vesicoscopic group is sug- advantage as to the length of hospitalization and analgesic gestive of the procedure leading to less pain. Indeed the mother requirement. of a recent patient, who had undergone open unilateral repair With this background in mind the present report leaves 3 years previously and subsequent contralateral vesicoscopic me unconvinced of the wisdom of pursuing cross-trigonal repair for new onset reflux and recurrent pyelonephritis, no- ureteroneocystostomy in children. I have several concerns. ticed the marked decrease in pain and recovery time after the Even in this series, the largest published to date, the results second procedure. are inferior to those of open surgery. In my opinion 4 cases of Every procedure has a learning curve during which there persistent reflux and 1 bilateral ureteral obstruction are may be unexpected complications and problems. Indeed, unacceptable in a series of fewer than 50 cases. I am skep- laparoscopic cholecystectomy, early in its development, had tical about the statement that the results will improve with an increased complication rate, such as bile duct injury, greater experience. The problem of creating a tunnel that compared to open cholecystectomy. Recognition of this po- extends beyond the original point of entrance of the ureter tential led to modifications to the procedure such that biliary on the opposite side is intrinsic to the technique and one of injury is now rare and laparoscopic cholecystectomy is the the reasons why I have abandoned it. New instrumentation standard of care. will have to be developed to solve this problem. It would Open surgery for reflux works well, especially after de- have been useful if the authors had provided a chart outlin- cades of refinement, and it is hard to improve something ing the surgical times in relation to increasing experience. In that has already been nearly perfected. Standard surgery this type of procedure surgical time is a good indicator of has little risk, a low complication rate and a high success technical ease. rate and can be performed through a relatively small inci- Also, it is difficult to improve the cosmetic appearance of sion. So why laparoscopy? As we demonstrated, a vesico- a well healed Pfannenstiel incision. Certainly, the scars of scopic approach leads to less pain. Parents are much more the 2 lower quadrant port sites are not necessarily better. accepting of surgery, in general, when it can be done in a The lower use of analgesics in this series is not convincing. minimally invasive manner. Vesicoscopic reimplantation, No validated pain scale was used, the doses of ketorolac although difficult to learn, can be a wonderful tool for resi- were not taken into account and in the absence of a strict dent or fellow education, forcing one to master complex protocol for analgesic administration that is not controlled dissection and suturing techniques. by the surgeon results are likely to be biased. What is best for the patient is not always best for the Nonetheless, I would like to thank and congratulate the surgeon. The improved postoperative course in these chil- authors for this report. I admire the effort they have made to dren can be a strong motivating factor in learning an admit- master this technically demanding procedure and the hon- tedly difficult technique. Our extended data suggest that esty of their reporting. However, for the reasons outlined vesicoscopic ureteral reimplantation is a valid and effective herein, I doubt that this operation will become standard or method for the correction of reflux. Kidney Transplantation in Children With Augmentation Cystoplasty

Abbas Basiri,* Hassan Otoukesh, Nasser Simforoosh, Rozita Hosseini and Farhat Farrokhi From the Department of Urology (AB, NS, RH) and Department of Kidney Transplantation (HO), Shaheed Labbaﬁnejad Medical Center, and Urology and Nephrology Research Center (FF), Shaheed Beheshti University of Medical Sciences, Tehran, Iran

Purpose: Treatment of children with end stage renal disease, especially those with significant bladder dysfunction, is difficult. A high pressure and low capacity bladder is a major risk factor for a transplanted kidney. Cystoplasty can protect the kidney allograft by reducing the intravesical pressure and creating an appropriate capacity. The aim of this study was to evaluate the outcome of kidney transplantation in children with and without prior cystoplasty. Materials and Methods: A total of 43 children with bladder dysfunction in urgent need of cystoplasty were enrolled in the study and were compared to a control group with regard to acute and chronic rejection rates, survival of the transplanted kidney, surgical complications and febrile urinary tract infection. Results: The rates of febrile urinary tract infection and chronic rejection were significantly higher in patients with prior cystoplasty (p Ͻ0.001 and p ϭ 0.004, respectively). Also, graft loss was much more frequent in these patients (34.9% vs 20.9%), although this difference was not statistically significant. In patients with prior cystoplasty graft survival rates were 92%, 73%, 58% and 45% at postoperative years 1, 3, 5 and 7, respectively. In the control group these rates were 94%, 87%, 81% and 75%, respectively (p ϭ 0.007). Conclusions: Based on our findings, the survival rate of the kidney is significantly lower in children with prior cystoplasty, possibly due to the higher prevalence of chronic rejection and febrile urinary tract infection in this group. Key Words: kidney transplantation; urinary bladder, neurogenic; kidney failure, chronic; postoperative complications

nomalies of the lower urinary tract (congenital or tests, including cystometrography, uroflowmetry and flow acquired) account for 20% to 30% of pediatric chronic electromyography. In this retrospective study we reviewed A renal failure cases.1,2 In children with ESRD, espe- the hospital records of all patients younger than 18 years cially those with bladder dysfunction, treatment is difficult. with ESRD and a diagnosis of bladder dysfunction who A high pressure and low capacity bladder is a significant risk received a kidney transplant between 1985 and 2004. We factor for the transplanted kidney. compared these patients to a control group without bladder Cystoplasty was first performed in a child in 1982.3 Since dysfunction who also underwent pediatric kidney transplan- then, several studies have evaluated kidney transplantation tation. Acute rejection episodes, CR, graft survival, surgical in relation to cystoplasty in children.4–11 Some authors be- complications and febrile UTIs were assessed in the 2 lieve that cystoplasty will protect the kidney allograft. In groups. Overall, 43 subjects (group 1) and 86 controls (group contrast, some studies have shown that the graft survival 2) were evaluated. The patients in group 2 were matched rate in children with cystoplasty is unfavorable and the with those in group 1 for age, sex, time of the transplanta- frequency of graft loss is high.12,13 The current knowledge is tion and surgical team. based on studies and treatment of a limited number of Children with neurogenic bladder underwent augmenta- patients with a wide variety of lower urinary tract abnor- tion cystoplasty using ileum, colon and, in rare cases, stom- malities. We evaluated the outcomes of kidney transplanta- ach. In ileal cystoplasty a 40 to 50 cm segment of terminal tion in children with neurogenic bladder who underwent ileum was dissected, and in colon cystoplasty a 25 cm seg- augmentation cystoplasty and compared them to a control ment of sigmoid colon with its vascular pedicle was selected. group of children with normal bladder function undergoing The selected segment was detubularized and placed as a cup kidney transplantation. on the native bladder and fixed with 2-zero polyglactin sutures. For kidney transplantation the renal artery and vein MATERIALS AND METHODS were anastomosed to the iliac vessels, and the ureter of the graft was anastomosed to the augmented part of the bladder All patients younger than 18 years who are candidates for directly. The ureter was anastomosed to an area without kidney transplantation at our center undergo a thorough pouch vessels (mesentery of the intestine) using the antire- investigation for lower urinary tract disorders based on his- flux principle (Bricker technique). A ureteral catheter was tory, physical examination and voiding cystourethrography. placed for 4 weeks in all patients and then removed by Patients with bladder dysfunction undergo urodynamic cystoscopy. All of the children in the cystoplasty group had acceptable urine output, and there was no need for patient education or treatments such as recycling. Submitted for publication November 26, 2006. * Correspondence: No. 44, 9th Boustan, Pasdaran, Tehran 16666, Prednisolone was started with a loading dose of 250 mg Iran (telephone, FAX: 0098-2256-7282; e-mail: [email protected]). daily for 3 days, which was gradually reduced to 200 mg,

0022-5347/07/1781-0274/0 274 Vol. 178, 274-277, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.049 KIDNEY TRANSPLANTATION AFTER AUGMENTATION CYSTOPLASTY 275

RESULTS TABLE 1. Medical complications in cystoplasty and control groups A total of 300 kidney transplantations were performed in Cystoplasty Group Control Group children at the Shaheed Labbafinejad Medical Center be- Complications (No. pts/%) (No. pts/%) p Value tween 1985 and 2004. Among these children 43 with neuro- Febrile UTI 15/34.9 3/3.5 Ͻ0.001 genic spastic bladder, characterized by a low capacity, high Acute rejection 23/53.5 40/46.5 0.46 pressure bladder with dyssynergia of the external sphincter Chronic rejection 25/58.1 27/31.4 0.004 Graft loss 15/34.9 18/20.9 0.08 (confirmed by urodynamic study), underwent cystoplasty and kidney transplantation (group 1). In this group cystoplasty was performed using ileum in 29 patients (67.4%), 150 mg, 100 mg and 60 mg during the following 4 days. colon in 8 (18.6%) and stomach in 2 (4.7%), with data miss- The dose of prednisolone was then tapered to at least 0.15 ing in 4 patients. mg/kg approximately 6 months postoperatively. Cyclospor- A total of 86 children with ESRD with a normal urinary ine was started at a loading dose of 10 mg/kg daily, and the tract and prior kidney transplantation were considered as continuation of treatment was adjusted according to serum controls (group 2). Mean patient ages were 11.90 Ϯ 2.77 levels. Mycophenolate mofetil has been used instead of aza- years and 11.60 Ϯ 3.17 years in groups 1 and 2, respectively thioprine at our center since 1997. Mycophenolate was ad- (p ϭ 0.57), and female-to-male ratios were 12:31 and 26:60, ministered at a dose of 1,200 mg/m2 daily. All patients respectively (p ϭ 0.87). Mean followup was 3.11 years received appropriate antibiotics for prophylaxis. Acute rejec- (37.3 Ϯ 30.2 months) in group 1 and 4.20 years (40.4 Ϯ 34.1 tion was treated with pulse corticosteroid at a dose of 250 to months) in group 2 (p ϭ 0.03). 500 mg daily for 3 to 7 days. Cases resistant to treatment The frequency of UTIs, AR, CR and graft loss in both with pulse corticosteroid were treated with antithymocyte groups is outlined in table 1. Of the patients with AR 2 were globulin for 14 days. resistant to pulse steroid therapy (1 in group 1 and 1 in Data including age at transplantation, underlying kidney group 2). The frequency of febrile UTIs and CR was signifi- disease, frequency of febrile UTI and urological complica- cantly higher in group 1 (p Ͻ0.001 and p ϭ 0.004, respec- tions after kidney transplantation were assessed. Graft loss tively). The rate of graft loss, although higher in group 1, did was defined as impairment of the kidney allograft requiring not differ significantly between the groups (p ϭ 0.08). Sur- dialysis or retransplantation, or death due to diseases re- gical complications were noted in 4 patients, with pouch lated to transplantation. To assess the growth pattern of the rupture in 2, anastomosis leak in 1 and ureterovesical ste- transplanted children, we calculated the HSDS in both nosis in 1. However, these complications were not responsi- groups before transplantation, and at 1, 2 and 5 years after- ble for graft loss in any patient. ward.14 The 1, 3, 5 and 7-year survival rates of the transplanted The qualitative and quantitative variables were analyzed kidney were 92%, 73%, 58% and 45%, respectively, in group by chi-square and Student’s t tests, respectively. For analy- 1, and 94%, 87%, 81% and 75%, respectively, in group 2 (see sis of the survival rate the Kaplan-Meier method and log figure). Statistically, the survival rates at 5 and 7 years were rank test were used to compare the 2 groups. A p value of better in group 2 (p ϭ 0.007). None of the patients lost the less than 0.05 was considered statistically significant. transplanted kidney within the period of the febrile UTI.

Graft survival curves for pediatric kidney recipients with prior cystoplasty compared to those without urinary tract abnormalities (controls). 276 KIDNEY TRANSPLANTATION AFTER AUGMENTATION CYSTOPLASTY

TABLE 2. Survival and complications following renal transplantation with prior cystoplasty References No. Pts Subgroups Complications

McInerney et al16 8 Nonanalytical, augmentation Dry cystoplasty (1), mucus production pyocystis ϩ cystoplasty necrosis (1) Koo et al5 18 Nonanalytical Ureteral obstruction (2), stomal stenosis (1), Mitrofanoff stomal incontinence (1) Hatch et al4 17 Nonanalytical UTI (12), stomal stenosis (1), urine leak (1), stone (1) Rigamonti et al19,* 17 Augmentation, control Ureteral obstruction (2), anastomosis leak (1) DeFoor et al17 20 Nonanalytical, augmentation Graft loss (4), lymphocele (1), stone (1) Aki et al15 3 Nonanalytical, augmentation None * Graft survival was approximately 80% at 8 years.

Before transplantation the HSDS was Ϫ2.9 and Ϫ3.7 in and surgical complications in children undergoing cysto- groups 1 and 2, respectively. At 1, 3 and 5 years after trans- plasty in studies performed without a control group and with plantation the HSDS in group 1 vs group 2 was Ϫ2.4 vs Ϫ2.7, sample sizes less than 20 (table 2).4,5,15–17 Ϫ2.9 vs Ϫ3.1, and Ϫ3.6 vs Ϫ3.4, respectively (p ϭ 0.12). In our study the frequency of febrile UTI was signifi- We also evaluated the type of cystoplasty and its effect on cantly higher in patients with prior cystoplasty (34.9% vs the outcome and complications of transplantation. Compli- 3.5%). This high prevalence may be associated with the cations were assessed during a median followup of 12.2 higher frequency of CR and graft loss in this group. More months for patients with colon cystoplasty and 45.4 months studies are needed to evaluate this finding. We recommend for patients with ileal cystoplasty. The frequency of UTI was an intensive prevention and treatment program for UTI. 25% in cystoplasty operations using colon and 41.4% in This approach may result in better graft outcomes in chil- those using ileum (p ϭ 0.68). Chronic rejection was seen in dren with prior cystoplasty. 37.5% of the patients with a colon cystoplasty and in 62.1% We performed cystoplasty mainly using ileum. We used of those with an ileum cystoplasty (p ϭ 0.25). In addition, stomach in only 2 of our primary cases and discontinued its there was no difference in the frequency of AR in these 2 use due to complications. The few cases of cystoplasty using groups (75% vs 51.7%, respectively, p ϭ 0.42). Graft loss was colon in our series involved slightly fewer complications seen in 37.5% of the patients with a colon cystoplasty and in than in the ileal group. However, the limited number of 31% of those with an ileum cystoplasty (p ϭ 0.73). patients, different followup durations and other factors influencing medical complications in our study preclude any DISCUSSION distinct conclusion with regard to the use of ileum vs colon. The first kidney transplantation was performed in homozy- gous twins in 1952. Transplantation was performed in pa- CONCLUSIONS tients with ESRD with bladder dysfunction 12 years later. To preserve the transplanted kidney in these patients, the Overall, intensive care for children with ESRD can make surgeons had to turn the bladder into a high capacity, low kidney transplantation with augmentation cystoplasty a pressure reservoir. Cystoplasty is one of the options for this safe procedure. Thus, children with bladder abnormalities purpose but it puts the patient at risk for infection. can benefit from transplantation and have a growth pattern In 1982 Marshall et al performed cystoplasty for the first comparable to that of other children with kidney trans- time in a patient after kidney transplantation.3 The first plants. Further investigation is warranted to improve the report of kidney transplant in a child after cystoplasty was surgical treatment of ESRD in children with neurogenic published in 1984. To date, a limited number of studies have bladder. been performed in children with cystoplasty, and the sample sizes are small. These studies are nonanalytical and descriptive, and include patients with a wide range of lower urinary Abbreviations and Acronyms 4,5,15–18 tract abnormalities. AR ϭ acute rejection In a limited case-control study by Rigamonti et al 17 CR ϭ chronic rejection patients with cystoplasty before transplantation were eval- ESRD ϭ end stage renal disease uated regarding surgical and medical complications.19 Sur- HSDS ϭ height standard deviation scores gical complications included ureterovesical junction stenosis UTI ϭ urinary tract infection in 2 cases and urine leakage from the ureter to the neoblad- der anastomosis site in 1. The sole medical complication was formation of a calculus in 1 patient. Pyelonephritis and REFERENCES metabolic acidosis were not observed in these patients. The graft survival rate was approximately 80% at 8 years, which 1. United States Renal Data System. Annual Data Report. Avail- is comparable to that in patients with medical causes of able at: http://www.usrds.org/adr.htm. renal failure. 2. Crowe A, Cairns HS, Wood S, Rudge CJ, Woodhouse CR and Neild GH: Renal transplantation following renal failure We compared survival rates of the transplanted kidneys due to urological disorders. Nephrol Dial Transplant 1998; in the prior cystoplasty and control groups, and discovered 13: 2065. that the long-term survival rates (at 5 and 7 years) were 3. Marshall FF, Smolev JK, Spees EK, Jeffs RD and Burdick JF: significantly lower in the cystoplasty group. This finding The urological evaluation and management of patients with may be due to the significantly higher frequency of chronic congenital lower urinary tract anomalies prior to renal rejection in these patients. Others have reported medical transplantation. J Urol 1982; 127: 1078. KIDNEY TRANSPLANTATION AFTER AUGMENTATION CYSTOPLASTY 277

4. Hatch DA, Koyle MA, Baskin LS, Zaontz MR, Burns MW, Tarry 19. Rigamonti W, Capizzi A, Mazzariol C, Milani C, Zanon GF, WF et al: Kidney transplantation in children with urinary Fusaro F et al: Kidney transplantation in children with diversion or bladder augmentation. J Urol 2001; 165: 2265. augmentation cystoplasty. BJU Int, suppl., 2002; 89: 68, 5. Koo HP, Bunchman TE, Flynn JT, Punch JD, Schwartz AC and abstract. Bloom DA: Renal transplantation in children with severe lower urinary tract dysfunction. J Urol 1999; 161: 240. EDITORIAL COMMENT 6. Sheldon CA, Gonzalez R, Burns MW, Gilbert A, Buson H and Mitchell ME: Renal transplantation into the dysfunctional The authors report their experience with renal transplanta- bladder: the role of adjunctive bladder reconstruction. tion in children with augmentation cystoplasty. One should J Urol 1994; 152: 972. be careful in reading the conclusions of this study, which do 7. Fontaine E, Gagnadoux MF, Niaudet P, Broyer M and Beurton not correspond to those of recent similar studies in children 1,2 D: Renal transplantation in children with augmentation and adults (references 18 and 19 in article). These studies cystoplasty: long-term results. J Urol 1998; 159: 2110. demonstrate a graft survival comparable to that in trans- 8. Zaragoza MR, Ritchey ML, Bloom DA and McGuire EJ: En- plant patients with a normal lower urinary tract. terocystoplasty in renal transplantation candidates: urody- It is difficult to accept a direct refluxing ureterointestinal namic evaluation and outcome. J Urol 1993; 150: 1463. anastomosis in transplanted children with potentially in- 9. Barnett MG, Bruskewitz RC, Belzer FO, Sollinger HW and fected augmentations, since this situation may lead to a Uehling DT: Ileocecocystoplasty bladder augmentation and dangerous reflux nephropathy even in grafts obtained from renal transplantation. J Urol 1987; 138: 855. adults.3 Furthermore, augmentation cystoplasty will not 10. Thomalla JV, Mitchell ME, Leapman SB and Filo RS: Renal treat external sphincter dyssynergia in all children, as retransplantation into the reconstructed bladder. J Urol ported by the authors. If dyssynergia is left untreated, and if 1989; 141: 265. it is accompanied by refluxing ureterointestinal anastomosis 11. Nahas WC, Mazzucchi E, Antonopoulos I, David-Neto E, Ianhez in potentially infected pouches as reported in this study, one LE, Sabbaga E et al: Kidney transplantation in patients may find an explanation as to why graft survival in this with bladder augmentation: surgical outcome and urody- study group was inferior to that reported in recent studies. namic follow-up. Transplant Proc 1997; 29: 157. 12. Alfrey EJ, Salvatierra O Jr, Tanney DC, Mak R, Scandling JD, Some additional points need to be addressed by the au- Dafoe DC et al: Bladder augmentation can be problematic thors. These include discussion of the use of clean intermit- with renal failure and transplantation. Pediatr Nephrol tent catheterization and/or detrusor relaxants after trans- 1997; 11: 672. plantation, the need for native nephrectomy, the time 13. Thomalla JV: Augmentation of the bladder in preparation interval between augmentation and transplantation, and for renal transplantation. Surg Gynecol Obstet 1990; the need for prophylactic antimicrobials (such as sulfame- 170: 349. thoxazole trimethoprim) for some period after transplanta- 14. Sorva R, Lankinen S, Tolppanen EM and Perheentupa J: Vari- tion, as well as a description of how the pouches were dealt ation of growth in height and weight of children. II. After with in the interim. infancy. Acta Paediatr Scand 1990; 79: 498. 15. Aki FT, Besbas N, Ozcan O, Bakkaloglu A, Erkan I, Bakkaloglu Bedeir Ali-El-Dein M et al: Renal transplantation in children with augmentation Urology Department enterocystoplasty. Transplant Proc 2006; 38: 554. 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Transplant 3. Howie AJ, Buist LJ and Coulthard MG: Reflux nephropathy in Proc 2004; 36: 2968. transplants. Pediatr Nephrol 2002; 17: 485. Outcomes of Delayed Hypospadias Repair: Implications for Decision Making

Jennifer L. Dodson,*,† Andrew D. Baird, Linda A. Baker, Steven G. Docimo and Ranjiv I. Mathews From the Departments of Urology, Johns Hopkins University, Baltimore, Maryland (JLD, RIM), Royal Liverpool University Hospital, Liverpool, England (ADB), University of Texas Southwestern, Dallas, Texas (LAB), and University of Pittsburgh, Pittsburgh, Pennsylvania (SGD)

Purpose: The current American Academy of Pediatrics recommendation is to perform hypospadias repair at age 6 to 12 months. Primary hypospadias repair at adolescence or beyond is uncommon, and there is little reported about the postoperative course of such patients. We report the outcomes for a series of patients who underwent primary hypospadias repair at age 10 years or older. Materials and Methods: We identified patients seen at our institution between 1979 and 2002 who underwent primary hypospadias repair at age 10 years or older. Electronic and paper charts were abstracted for baseline demographics, degree of hypospadias, surgical technique, complications and reoperation. Results: A total of 31 patients were identified, with a median available followup of 14 months. Median patient age at first hypospadias surgery was 13 years. The location of the urethral meatus was distal in 19 patients, mid shaft in 7, proximal in 4 and undetermined in 1. A variety of techniques were used, including meatal advancement and glanuloplasty, meatal based flaps, island onlay flaps, Snodgrass repair and staged procedures. Complications were noted in 48% of patients (15 of 31), including fistula (10), stricture (4), hematoma (2) and other complications (2). Conclusions: Although retrospective in nature, these data suggest that delay of primary hypospadias repair into the teen years or beyond may result in more complications than currently accepted for infant hypospadias repair. Key Words: hypospadias, outcome assessment (health care), postoperative complications, urologic surgical procedures

ypospadias is a congenital malformation of the penis Several factors should be considered when deciding on caused by the incomplete tubularization of the ure- the timing of genital surgery, including hypospadias repair. H thral folds during embryonic development. The inci- Based on the developmental, psychological, anesthetic and dence is approximately 1 in 300 live male births, making it surgical factors involved in this decision, the current recom- one of the most common congenital anomalies.1 In addition, mendation of the American Academy of Pediatrics and there has been concern that the incidence of hypospadias is European experts is to perform hypospadias surgery at age increasing in the United States and Europe.1,2 The hallmark 6 to 12 months.3,4 Others have suggested that some types of abnormality is a urethral meatus that is abnormally located genital surgery be delayed until the patient reaches the age on the ventral surface of the penis. The phenotype ranges of consent.5,6 from a distal glanular meatus to a proximal perineal me- It is unknown whether surgical outcomes for delayed atus. Associated defects include a dorsal hood prepuce, ven- hypospadias repair are comparable to those performed in tral angulation or chordee and, in more severe cases, biﬁd the ﬁrst year of life. We performed a retrospective study of scrotum and genital ambiguity. primary hypospadias repair in patients 10 years and older. Hypospadias surgery presents a challenge and histori- The age of 10 was chosen to include all peripubertal and cally has been recommended for 3 reasons, namely improved postpubertal males. The number of postoperative complica- voiding, sexual function and cosmesis. The surgical goals tions and reoperations was determined and compared to include a cosmetically normal penis and urethral meatus, a accepted complication rates for infants undergoing primary straight penis during erection, a normal urinary stream and hypospadias repair. normal fertility with improved semen delivery.

MATERIALS AND METHODS Submitted for publication November 15, 2006. Study received institutional review board approval. The population was drawn from a tertiary pediatric urology Presented at annual meeting of American Urological Association, San Francisco, California, May 8–13, 2004. referral center. Using billing records from 1979 to 2002, we * Correspondence: Department of Urology, Marburg 1, Johns identiﬁed all patients 10 years or older who underwent Hopkins Hospital, 600 N. Wolfe St., Baltimore, Maryland 21287- initial surgical repair of hypospadias at or after age 10, and 2101 (telephone: 410-502-1810; FAX: 410-955-0833; e-mail: jdodson@ who had at least 1 month of followup. Paper and electronic jhmi.edu). † Supported by Grant 5 K12 HD049104-02, National Institutes of charts were reviewed to verify that the underlying diagnosis Health. was hypospadias, and that the ﬁrst repair was done at or

0022-5347/07/1781-0278/0 278 Vol. 178, 278-281, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.055 OUTCOMES OF DELAYED HYPOSPADIAS REPAIR 279 after age 10 years. Charts were also abstracted for demo- TABLE 2. Patients with no complications of primary hypospadias graphics, location of meatus, surgical technique, surgical surgery performed after age 10 years complications, reoperations and long-term results when Meatus Repair Mos available. A medical history abstraction form was used, and Pt No. Age* Yr Location Technique Followup† data were abstracted by 2 reviewers. Statistical analysis was performed using Intercooled Stata® 8.2 statistical soft- 1 10 1983 Glanular Ombredanne 76 2 44 1990 Subglanular Onlay flap 108 ware. 3 14 1981 Coronal MAGPI 2 4 14 2001 Coronal Snodgrass 12 5 10 1995 Subcoronal Flip-flap 96 RESULTS 6 11 1985 Subcoronal MAGPI 1 7 12 1985 Distal shaft MAGPI 1 A total of 31 patients were identified who fulfilled inclu- 8 23 1988 Distal shaft Staged 14 sion requirements, with a median available followup of 14 9 11 1985 Distal shaft MAGPI 2 10 11 1991 Distal shaft Staged 46 months (range 1 to 288). Median patient age at first hypo- 11 35 1991 Distal shaft Flip-flap 9 spadias surgery was 13 years (range 10 to 62). Of the sub- 12 13 1993 Mid shaft Island onlay 3 13 12 1995 Mid shaft Unknown 4 jects 71% were white and 26% were black. 14 17 1995 Mid shaft Staged 30 The location of the urethral meatus was distal shaft in 9 15 11 1980 Mid shaft Tube graft 5 patients, coronal in 8, mid shaft in 7, penoscrotal in 3, 16 13 1984 Penoscrotal Staged 3 glanular in 2, perineal in 1 and undetermined in 1. A variety * Mean 16.3 years, median 12.5 years. of techniques were used, including meatal based flaps (7 † Mean 25.8 months, median 7 months. patients), MAGPI (5), island onlay flaps (5), staged procedures (5), Snodgrass repair (2) and others (7). There were no recorded complications in 16 cases (52%). such as cleft lip and palate, aortic coarctation, seizure dis- Postoperative complications were noted in the remaining 15 order, Down syndrome and prematurity. patients (48%, 95% confidence interval 30–67, binomial, exact). Table 1 outlines the complications observed, location DISCUSSION of the meatus at first repair, surgical technique used and number of repeat procedures needed. Complications in- In this retrospective study of 31 patients undergoing initial cluded 10 fistulas (32% of patients), 4 strictures (13%), 2 hypospadias repair after age 10 years more complications hematomas (6%), 1 loss of repair (3%) and 1 urethral web were observed than was expected based on reported compli- causing spraying of stream (3%). cation rates for infants. The proportion of patients who ex- Among the group experiencing complications the median perience complications after undergoing hypospadias repair age at initial hypospadias surgery was 13 years (mean 17.9) as an infant is reportedly 2% to 15%.7-9 However, this rate and median followup was 24 months (48.6). For the group varies depending on the degree of hypospadias and the sur- with no reported complications the median age at initial gical technique used. The most commonly reported compli- hypospadias surgery was 12.5 years (mean 16.3) and median cations in this population include fistula, stricture and followup was 7 months (mean 25.8, table 2). wound breakdown. However, in most series the success Although it was difficult to determine retrospectively the rates after 1 repeat procedure are greater than 90%.10 reason for delay of initial surgery in many cases, a possible The observation of an increased number of postoperative reason was identified in 13 individuals. The family either complications in older patients has been reported previ- was advised to wait or did not seek urological care until later ously. Hensle et al published their findings concerning long- in life in 7 patients, circumcision was performed at birth in term results and complications of hypospadias repair in 42 3 (possibly contributing to the delay in repair of hypospa- adults.11 Overall, 52.3% of men had postoperative complica- dias) and the presence of medical co-morbidities was a likely tions. However, the final long-term success rate after sec- cause of delay in 4, including other congenital abnormalities ondary surgery was 88.1%. This study included patients who

TABLE 1. Patients with complications of primary hypospadias surgery performed after age 10 years Pt No. Age* Yr Meatus Location Repair Technique Mos Followup† Complications Repeat Procedures

1 11 1987 Coronal Flip-flap 108 Other 0 2 10 1983 Subcoronal Ombredanne 2 Fistula 0 3 62 1998 Subcoronal Snodgrass 24 Fistula, stricture 1 4 12 1980 Subcoronal MAGPI 19 Other 1 5 10 1994 Distal shaft Island onlay 12 Fistula 1 6 14 1992 Distal shaft Unknown 12 Fistula 1 7 15 2001 Distal shaft Flip-flap 7 Hematoma, fistula 2 8 18 1995 Distal shaft Unknown 24 Fistula, stricture 2 9 12 1985 Mid shaft Ombredanne 2.5 Fistula 0 10 11 1995 Mid shaft Island onlay 18 Fistula 2 11 13 1991 Mid shaft Tube graft 24 Fistula 1 12 15 1994 Penoscrotal Island onlay 32 Hematoma 1 13 21 1991 Penoscrotal Staged 132 Stricture 1 14 32 1981 Perineal Tube graft 288 Stricture 1 15 12 1999 Unknown Unknown 24 Fistula 1 * Mean 17.9 years, median 13 years. † Mean 48.6 months, median 24 months. 280 OUTCOMES OF DELAYED HYPOSPADIAS REPAIR had undergone multiple previous repairs beginning in child- had the initial hypospadias repair delayed for a reason that hood. Of the 8 patients in the series who underwent primary was causally related to the development of a complication. repair in adulthood 3 (37.5%) had complications, including For example children with medical co-morbidities such as fistula and skin flap loss. prematurity or congenital abnormalities might be at higher In a retrospective series by Marrocco et al of 693 patients risk for complications after hypospadias surgery. Parental undergoing primary hypospadias repair an increased num- factors such as socioeconomic status may also have delayed ber of complications was seen in patients older than 12 surgery and affected surgical outcomes. months (18.7%) and among those who underwent surgery at The followup varies among patients, which also intro- puberty or later (14.9%) compared to patients younger than duces bias. Median followup in patients without a reported 12 12 months (3.4%). Another study reported in 2005 by complication was 7 months, compared to 24 months in the Nuininga et al showed a 54% long-term complication rate group with complications. If more followup information had among 126 patients who underwent primary hypospadias 13 been available, we probably would have observed an even repair at a mean age of 7 years (range 1 to 14). higher number of postoperative complications. Conversely, There is also evidence in the literature that primary it is also possible that if patients are doing well after sur- hypospadias repair may have reasonably good success in gery, they may not return for followup. The issue of varying adults. A retrospective series of 59 patients who underwent length of followup may be less important if most complica- initial hypospadias repair in adulthood (age 20 to 27 years) tions occur in the immediate postoperative period. demonstrated that 10.1% had a postoperative complica- Despite these limitations, our results suggest that age at tion.14 In addition, Sharma reported on 13 patients 18 to 26 years old who underwent primary hypospadias repair with a first repair may be a factor in hypospadias surgery success. tubularized incised plate urethroplasty.15 One of these pa- Our findings are compatible with the current American tients had a fistula, which closed spontaneously, and the Academy of Pediatrics recommendations, which, based on a author concluded that the frequency of complications was no review of psychological, anesthetic and surgical factors, sup- different than that in children. port completion of primary hypospadias repair at age 6 to 12 3 Treatment of the older patient either with primary hypo- months if possible. spadias repair or for a complication of hypospadias repair is challenging. Although 1-stage repairs are currently most widely used, some authors have recommended 2-stage re- CONCLUSIONS pairs for primary or salvage surgery.16 If a recurrent stricture has formed after initial hypospadias repair, one should Among the 31 individuals in this study who underwent consider evaluating the patient for balanitis xerotica oblit- delayed primary hypospadias repair at or after age 10 years erans. If balanitis xerotica obliterans is present, the patient 15 (48%) had postoperative complications. The most com- may benefit from a 2-stage repair with buccal mucosa.16 mon complications were fistula and stricture. Although ret- A biological explanation for a higher number of compli- rospective, these data suggest that delay of primary hypo- cations seen in older patients undergoing hypospadias re- spadias repair into the teen years or beyond may result in pair is unknown. While one might postulate that differences more complications than currently accepted for infant rein wound healing, vascularity or hormonal milieu may be pair. factors, there is little evidence to support these mechanisms. Postoperative care is recognized as an important factor in hypospadias surgery success. In postpubertal males the Abbreviations and Acronyms amount of urethral secretions produced by the intraurethral ϭ glands increases and may provide an environment that pro- MAGPI meatal advancement and glanuloplasty motes infection.14 Erections in the postoperative period may also disrupt the surgical repair, and lead to hematoma and 14,17 wound breakdown. REFERENCES The major limitations of our study include the retrospective, observational nature of the chart review and the lack of 1. Paulozzi LJ, Erickson JD and Jackson RJ: Hypospadias trends a control group during the same period. Also, since this was in two US surveillance systems. Pediatrics 1997; 100: 831. a case series at a single center, our findings may have 2. Dolk H: Rise in prevalence of hypospadias. Lancet 1998; 351: limited generalizability to other groups of adolescent and 770. adult males with hypospadias. The group reported here is 3. Timing of elective surgery on the genitalia of male children heterogeneous with respect to age, location of meatus and with particular reference to the risks, benefits, and psycho- surgical repair used. The operations were performed during logical effects of surgery and anesthesia. American Acad- a 22-year period. Surgical techniques for hypospadias repair emy of Pediatrics. Pediatrics 1996; 97: 590. 4. Manzoni G, Bracka A, Palminteri E and Marrocco G: Hypo- have evolved significantly with time. In addition, since these spadias surgery: when, what and by whom? BJU Int 2004; cases reflect a tertiary referral center practice of pediatric 94: 1188. urology, the complexity of cases may not be reflective of the 5. Diamond M: Pediatric management of ambiguous and trauma- general population. tized genitalia. J Urol 1999; 162: 1021. There are a number of confounding factors, including 6. Lightfoot-Klein H, Chase C, Hammond T and Goldman R: severity of hypospadias, surgical technique used, postoper- Genital surgery on children below the age of consent. In: ative management and co-morbidities, which may be asso- Psychological Perspectives on Human Sexuality. Edited by ciated with the risk of postoperative complications. In addi- L Szuchman and F Muscarella. New York: John Wiley and tion, it is possible that some of the individuals in this series Sons 2000; chapt 12, pp 440–479. OUTCOMES OF DELAYED HYPOSPADIAS REPAIR 281

7. Cheng EY, Vemulapalli SN, Kropp BP, Pope JC 4th, Furness 12. Marrocco G, Vallasciani S, Fiocca G and Calisti A: Hypospa- PD 3rd, Kaplan WE et al: Snodgrass hypospadias repair dias surgery: a 10-year review. Pediatr Surg Int 2004; 20: with vascularized dartos ﬂap: the perfect repair for virgin 200. cases of hypospadias? J Urol 2002; 168: 1723. 13. Nuininga JE, De Gier RP, Verschuren R and Feitz WF: Long- 8. Minevich E, Pecha BR, Wacksman J and Sheldon CA: Mathieu term outcome of different types of 1-stage hypospadias re- hypospadias repair: experience in 202 patients. J Urol pair. J Urol 2005; 174: 1544. 1999; 162: 2141. 14. Senkul T, Karademir K, Iseri C, Erden D, Baykal K and 9. Snodgrass W, Koyle M, Manzoni G, Hurwitz R, Caldamone A Adayener C: Hypospadias in adults. Urology 2002; 60: and Ehrlich R: Tubularized incised plate hypospadias re- 1059. pair for proximal hypospadias. J Urol 1998; 159: 2129. 15. Sharma G: Tubularized-incised plate urethroplasty in adults. 10. Uygur MC, Unal D, Tan MO, Germiyanoglu C and Erol D: BJU Int 2005; 95: 374. Factors affecting outcome of one-stage anterior hypospa- 16. Bracka A: Hypospadias repair: the two-stage alternative. Br J dias repair: analysis of 422 cases. Pediatr Surg Int 2002; 18: Urol, suppl., 1995; 76: 31. 142. 17. Grobbelaar AO, Laing JH, Harrison DH and Sanders R: Hy- 11. Hensle TW, Tennenbaum SY, Reiley EA and Pollard J: Hypo- pospadias repair: the inﬂuence of postoperative care and a spadias repair in adults: adventures and misadventures. patient factor on surgical morbidity. Ann Plast Surg 1996; J Urol 2001; 165: 77. 37: 612. Urological Survey

PEDIATRIC UROLOGY

Dysfunctional Elimination Syndrome is a Negative Predictor for Vesicoureteral Reflux J. Colen, S. G. Docimo, K. Stanitski, D. D. Sweeney, B. Wise, P. Brandt and H.-Y. Wu, Department of Pediatric Urology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania J Pediatr Urol 2006; 2: 312–315. Purpose: We investigated the likelihood of finding vesicoureteral reflux (VUR) in patients with urinary tract infections (UTIs), accompanied by fever or dysfunctional elimination syndrome (DES). Materials and Methods: Two hundred consecutive voiding cystourethrograms performed in 1997–2002 for a diagnosis of UTI were reviewed. Fever, DES, and the grade and laterality of VUR were recorded. Patients were stratified into two groups by age to allow for assessment of DES symptoms in the older patient population: Ͻ2 years (n ϭ 68) and Ն2 years (n ϭ 132). Ratios were compared using a two-tailed Fisher’s exact test. Results: Of the children Ն 2 years old, 64/132 (48%) had VUR. Patients who were non-febrile with DES were less likely than patients who were febrile without DES to have VUR [12/34 (35%) vs 23/34 (68%), P ϭ 0.02], whereas the risk of dilating VUR [5/34 (15%) vs 11/34 (32%), P ϭ 0.15] and bilateral VUR [4/34 (12%) vs 11/34 (32%), P ϭ 0.08] was not statistically different. In febrile patients, the presence of DES was associated with a lower risk of VUR [22/51 (43%) vs 23/34 (68%), P ϭ 0.03] and dilating VUR [5/51 (10%) vs 11/34 (32%), P ϭ 0.01], but not bilateral VUR [8/51 (16%) vs 11/34 (32%), P ϭ 0.11]. Conclusions: Children with non-febrile UTI and DES have a significantly lower risk of having VUR compared to children with febrile UTI and no DES. Among children with a history of UTI, DES is a negative predictor for VUR. Editorial Comment: This is a retrospective study in which children referred for voiding cystourethrogram were segregated into 2 groups based on the Toronto scoring system for DES.1 These patients had been referred by pediatricians for voiding cystourethrograms following UTI. The authors found that children with nonfebrile UTI and DES have a lower risk of VUR on voiding cystourethrogram (VCUG) versus those with febrile UTI without DES. Among children with a history of UTI DES was a negative predictor for VUR. This study suggests, but did not examine the widely held belief, that children with DES without VUR are more likely to have UTI than those without DES. These data, taken together with previous reports showing that children with DES and VUR are at greater risk for breakthrough UTI,2,3 suggest that DES and vesicoureteral reflux are just 2 (of many) components important to the development of urinary tract infection and renal scarring. I agree with the authors that boys and girls with DES, UTI and no fever can initially be treated without VCUG. Nevertheless, this report reminds us that 35% of these children will have VUR. In these cases I prefer to test for VUR after managing DES, and reserve VCUG for instances of recurrent UTI. Douglas A. Canning, M.D.

1. Farhat W, Bagli DJ, Capolicchio G, O’Reilly S, Merguerian PA, Khoury A et al: The dysfunctional voiding scoring system: quantitative standardization of dysfunctional voiding symptoms in children. J Urol 2000; 164: 1011. 2. Koff SA, Wagner TT and Jayanthi VR: The relationship among dysfunctional elimination syndromes, primary vesicoureteral reﬂux and urinary tract infections in children. J Urol 1998; 160: 1019. 3. Chen JJ, Mao W, Homayoon K and Steinhardt GF: A multivariate analysis of dysfunctional elimination syndrome, and its relationships with gender, urinary tract infection and vesicoureteral reﬂux in children. J Urol 2004; 171; 1907.

Association of Elimination Dysfunction and Body Mass Index E. Erdem, A. Lin, B. A. Kogan and P. J. Feustel, Albany Medical College, Albany College of Pharmacy, Center for Neuroscience and Neuropharmacology, Albany, New York, and Mersin University, Mersin, Turkey J Pediatr Urol 2006; 2: 364–367.

0022-5347/07/1781-0282/0 282 Vol. 178, 282-283, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.078 PEDIATRIC UROLOGY 283

Purpose: The reported prevalence of mild and severe obesity among US children is 30% and 15%, respectively. Childhood obesity likely relates to alterations in diet that also may cause constipation. We investigated the relationship between obesity and various forms of elimination dysfunction. Materials and Methods: The data of 251 patients who were diagnosed as having elimination dysfunction were analyzed retrospectively. Each patient’s age, weight, height and diagnosis were evaluated and body mass index (BMI) was calculated. The percentile BMI was then analyzed based on diagnosis. BMI percentile Ն 85% was defined as mild obesity and BMI percentile Ն 95% was defined as severe obesity. The patients were divided into four groups based on diagnosis: constipation (n ϭ 70), enuresis ϩ constipation (n ϭ 21), daytime incontinence (n ϭ 96) and nocturnal enuresis (n ϭ 64). Results: The mean age of the patients was 9 years (range: 4–18 years). In the group with enuresis and constipation, 8/21 (38%) were mildly and 5/21 (24%) severely obese. Of patients with daytime incontinence, 36/70 (51%) were mildly and 22 (31%) severely obese, and of those with nocturnal enuresis alone, 35 (55%) were mildly and 20/64 (31%) severely obese. Conclu- sions: Of children with voiding dysfunction, 62–86% are also obese. This is almost double the rate in the normal population. These conditions may have a common etiology. Editorial Comment: No one knows the association between obesity and dysfunctional elimination. The authors note that the association of constipation and voiding dysfunction is recognized. They further note that constipation and obesity may result from poor diet, and that constipation may be associated with the attempt by the child to exercise control over his or her environment. Although these data require validation with a nonpopulation directed control, this may be the first in a series of articles that associate dysfunctional elimination with a broader problem, namely stress and the environmental effects of today’s busy lifestyle on children. Douglas A. Canning, M.D. Pathology Page

Adrenal Hemorrhage

drenal hemorrhage is relatively uncommon, but can become a significant clinical dilemma. It can be focal A or diffuse, range in size from less than 1 to 15 cm and result in up to 2 liters of blood loss.1 The susceptibility of the adrenal gland to hemorrhage has been attributed to its vascular anatomy and its role in the physiological response to stress in that any increase in adrenal venous pressure can cause hemorrhage into the gland.1 In adults adrenal hemorrhage can present as unilateral or bilateral adrenal enlargement or as a complication of adrenal venography. It has been associated with primary or metastatic carcinoma, sepsis with or without Water- house-Friderichson syndrome, coagulopathy, steroid or adrenocorticotropic hormone administration, adrenal vein thrombosis and mechanical trauma.1 Adrenal hemorrhage has also been reported in patients receiving postoperative anticoagulant therapy.2,3 Spontaneous adrenal hemorrhage has been reported in pregnancy in the ab- 4 FIG. 2. Adrenal hematoma, consisting of blood and fibrin with clus- sence of trauma or anticoagulant therapy. ters of adrenal cortical cells on right side. Adrenal enlargement due to hemorrhage may be detected on abdominal computerized tomography. Acute hemorrhage On gross and histological examination, the lesion consists of appears as a hyperintense mass with “streaky infiltration” of blood, relatively fresh or in various phases of organization, the periadrenal tissue. The radiological findings of older sometimes with necrosis of adjacent adrenal cortex and/or me- mass lesions are less specific. Subacute hemorrhage may be dulla (figs. 1 and 2). Organization of an adrenal hematoma can detected as high signal intensity on T1 and T2-weighted lead to cyst formation and dystrophic calcification in the wall of magnetic resonance imaging. Magnetic resonance imaging the cyst, which may be the only remnant findings long after the 1 is also useful for estimating the age of the lesion.1 In some episode of hemorrhage (fig. 1). instances adrenal hematoma is removed surgically because Adrenal hemorrhage may be complicated by adrenal in- a neoplastic process, either in the adrenal or in the adjacent sufficiency, infection with secondary abscess formation or kidney, cannot be confidently excluded (fig. 1). retroperitoneal hemorrhage, and may be life threatening in In neonates adrenal hemorrhage has been associated patients with associated malignancy, sepsis, history of anti- 1 with asphyxia or complicated delivery, and the bleeding is coagulant or steroid use, or major surgery. The occurrence often confined to the right adrenal gland. Adrenal hemor- of acute adrenal insufficiency is usually due to bilateral rhage may be radiographically indistinguishable from neu- adrenal hemorrhage but has been reported with unilateral 5 roblastoma complicated by hemorrhage in this age group.1 adrenal hemorrhage in patients on steroid therapy. Anastasia M. Canacci and Gregory T. MacLennan Department of Pathology University Hospitals Case Medical Center Case Western Reserve University Cleveland, Ohio

1. Lack EE: Tumors of the Adrenal Gland and Extra-Adrenal Paragan- glia. Washington, D.C.: Armed Forces Institute of Pathology 1997. 2. LaBan MM, Whitmore CE and Taylor RS: Bilateral adrenal hemorrhage after anticoagulation prophylaxis for bilateral knee arthroplasty. Am J Phys Med Rehabil 2003; 82: 418. 3. Bakaeen FG, Walkes JC and Reardon MJ: Heparin-induced throm- bocytopenia associated with bilateral adrenal hemorrhage after coronary bypass surgery. Ann Thorac Surg 2005; 79: 1388. 4. Gavrilova-Jordan L, Edmister WB, Farrell MA and Watson WJ: Spontaneous adrenal hemorrhage during pregnancy: a review of the literature and a case report of successful conservative management. Obstet Gynecol Surv 2005; 60: 191.

FIG. 1. Adrenal hematomas. A, lesion dwarfs kidney. Clinical sus- 5. Blanc PL, Forel C, Jay S and Susset V: Acute adrenal insufﬁciency picion was renal cell carcinoma. B, lesion clinically mimics during unilateral adrenal hemorrhage secondary to the anti- pheochromocytoma. phospholipid syndrome. Rev Med Interne 2006; 27: 970.

Syringocele of Cowper’s Gland Duct: An Increasingly Common Rarity

healthy 21-year-old man complained of persistent entertained in any male patient presenting with irritative or dysuria during the last 3 years with intermittent obstructive urinary symptoms, particularly when there is a A perineal and suprapubic discomfort, and intermittent complaint of persistent post-void dribbling or incontinence. urinary stream weakening. Bothersome post-void squirts of Urethrography remains the diagnostic modality of choice. urine immediately followed almost every urination. Diag- nosed with chronic prostatitis, he had been treated with Richard A. Watson, Mark A. Lassoff multiple long-term courses of antibiotics to no avail. Physi- and Ihor S. Sawczuk cal examination revealed an athletic man with normal male Department of Urology genitalia. There was poorly localized perineal discomfort but Hackensack University Medical Center no palpable mass. Rectal examination of the prostate was Hackensack/ normal. Urinalysis was within normal limits and urine cul- New Jersey Medical School ture was sterile. Ultrasound of the kidneys and bladder was University of Medicine and Dentistry of New Jersey also normal. However, retrograde urethrogram revealed the Newark, New Jersey presence of a fusiform filling defect along the ventral aspect of and the bulbar urethra (part A of figure). Urethroscopy demonstrated a superficial diverticular pocket with an elliptical open- Craig Thame ing approximately 1 cm in diameter in the mid bulbar urethra, Department of Radiology just to the left of the ventral midline (part B of figure). Simple Hackensack University Medical Center transurethral unroofing (marsupialization) of the syringocele Hackensack, New Jersey afforded prompt, dramatic relief of urinary symptoms. Syringoceles of Cowper’s gland ducts are congenital anom- REFERENCES alies. While the glands themselves are embedded within the urogenital diaphragm parallel to the membranous urethra, the 1. Bevers RFM, Abbekerk EM and Boon TA: Cowper’s syringocele: ducts empty into the mid bulbar urethra. A distinction to be symptoms, classification and treatment of an unappreciated made is whether the syringocele is open (communicates with problem. J Urol 2000; 163: 782. the lumen of the urethra) or closed.1 2. Brandes SB: Re: Cowper’s syringocele: symptoms, classification The diagnosis is best demonstrated by antegrade or ret- and treatment of an unappreciated problem (letter to the rograde urethrography.1 Urethroscopy is confirmatory. editor). J Urol 2000; 164: 1666. 3. Selli C, Nesi G, Pellegrini G, Bartoletti R, Travaglini F and Transperineal ultrasound has proven helpful in the diagno- Rizzo M: Cowper’s gland duct cyst in an adult male. Radio- sis of closed syringoceles.2 Evaluation by magnetic reso- 3 logical and clinical aspects. Scand J Urol Nephrol 1997; 31: nance has also been recommended (part C of figure). 313. Syringoceles in adult men are considered rare. However, a 4. Mansson W, Colleen S and Holmberg JT: Cystic dilatation of heightened index of suspicion can yield an impressive increase Cowper’s gland duct—an overlooked cause of urethral symp- in the detection of these lesions.1,4 This diagnosis should be toms? Scand J Urol Nephrol 1989; 23: 3.

A, retrograde urethrogram demonstrates scaphoid collection of contrast medium parallel to ventral surface of bulbar urethra. B, oval opening to syringocele lies distal to external urethral sphincter. Thin, semiopaque roof of syringocele, if pressed against wall of urethra by irrigation ﬂuid, could easily be overlooked by urologist intent on searching for abnormal pathology in prostatic urethra. C, magnetic resonance image (T2-weighted) detects residual urine (bright white, scaphoid lesion) coursing along ventral surface of bulbar urethra. Urethra itself is empty of urine in post-void view. Post-void pooling of urine in syringocele explains presenting complaint of post-void dribbling and incontinence.

0022-5347/07/1781-0285/0 285 Vol. 178, 285, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.155 Single Trocar Laparoscopic Nephrectomy Using Magnetic Anchoring and Guidance System in the Porcine Model

Ilia S. Zeltser, Richard Bergs, Raul Fernandez, Linda Baker, Robert Eberhart and Jeffrey A. Cadeddu* From the Clinical Center for Minimally Invasive Urologic Cancer Treatment, Department of Urology (ISZ, LB, JAC) and Department of Surgery (RE), University of Texas Southwestern Medical Center, Dallas and Automation and Robotics Research Institute, University of Texas Arlington (RB, RF), Arlington, Texas

Purpose: We assessed the feasibility of single keyhole laparoscopic surgery using a novel transabdominal magnetic anchoring and guidance system platform in the porcine model. Materials and Methods: A collaborative research group was formed to build a prototype system of magnetically anchored instruments for trocar-free laparoscopy. The design mandate was that the developed technology should be able to deploy into the insufﬂated abdomen through an existing 12 mm diameter trocar and then be moved into position in the peritoneum by manipulating external magnets. The magnetic anchoring and guidance system concept was advanced to a working prototype with a system of external magnetic anchors, an internal camera system and a hook cautery supported by an intra-abdominal robotic arm. This prototype system was then evaluated in vivo in a porcine laparoscopic nephrectomy model. Results: Two nonsurvival porcine laparoscopic nephrectomies were successfully completed without complications via a single 15 mm transumbilical trocar using the prototype magnetic anchoring and guidance system camera and the magnetically anchored robotic arm cauterizer. A conventional laparoscopic grasper was used for retraction through the 15 mm trocar after magnetic anchoring and guidance system deployment. The renal artery and vein were transected with a conventional Endo-GIA® stapler introduced through the 15 mm trocar. Procedure time was not recorded and blood loss was minimal. Conclusions: Single trocar laparoscopic nephrectomy using magnetically anchored instrumentation is technically feasible, demonstrating that intracorporeal instrument manipulation may overcome the limitations of current laparoscopic and robotic surgery by allowing unhindered intra-abdominal movement. This single access technique may be used with natural oriﬁce surgery approaches and it has the potential to realize incision-free intra-abdominal surgery. Key Words: kidney, nephrectomy, laparoscopy, instrumentation, swine

aparoscopic surgery uses small incisions that decrease We previously reported that a transabdominal MAGS pain, improve cosmesis and facilitate postoperative could be used to actively control an intra-abdominal endo- L recovery. However, intra-abdominal mobility and the scope and multiple working instruments introduced through working envelope of laparoscopy are limited to the fulcrum a single trocar into the abdominal cavity.1 In this study we motion of the instruments around each port site. Although assessed the feasibility of performing laparoscopic nephrec- current robot assisted laparoscopy overcomes some of these tomy via a single transabdominal trocar using the magnet- limitations by increasing df and enhancing visibility, it has ically anchored intra-abdominal camera and a prototype an even smaller working envelope and remains fundamen- robotic cauterizer in the porcine model. tally constrained by the entry incisions. To overcome the limitations imposed by fixed trocar technology we developed in prototype a novel adjunct laparo- MATERIALS AND METHODS scopic system concept, that is a moveable, lockable platform that is positioned intra-abdominally and stabilized by an Groups at the Departments of Urology and Surgery, Univer- external permanent magnet placed on the abdominal skin. sity of Texas Southwestern Medical Center, and the Auto- This platform would allow unrestricted intra-abdominal mation and Robotics Research Institute, University of Texas movement of surgical instruments and it has the potential to at Arlington formed a collaborative group to build a proto- realize the benefits of single keyhole surgery, while meeting type system of magnetically anchored instruments for tro- or exceeding the performance of current fixed trocar lapa- car-free laparoscopy. The MAGS concept was advanced to a roscopy (fig. 1). working prototype with a system of external magnetic anchors, 2 types of passive tissue retractors and an internal camera system.1 A 3 df pneumatically controlled robotic arm Submitted for publication September 14, 2006. was designed to support a hook cautery. The only design * Correspondence and requests for reprints: Department of Urol- mandate was that the developed technology should be able ogy, University of Texas Southwestern Medical Center, 5323 Harry to deploy into the insufflated abdomen through 1 existing 15 Hines Blvd., MC 9110, Dallas, Texas 75390-9110 (telephone: 214-648-2888; FAX: 214-648-8786; e-mail: Jeffrey.cadeddu@ mm diameter trocar and then moved into position in the utsouthwestern.edu). peritoneum by manipulating external magnets.

0022-5347/07/1781-0288/0 288 Vol. 178, 288-291, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.001 SINGLE TROCAR LAPAROSCOPIC NEPHRECTOMY 289

was inserted through a conventional 15 mm trocar and coupled to the external magnets. The assistant surgeon manipulated the pair of external magnets to orient the camera horizontally (yaw). By pushing the external magnets apart or together the assistant surgeon was then able to actively point the camera lens upward or downward (pitch). A Prizm Video Workstation 386 digital editing system (Pinnacle, Moun- tain View, California) was used to perform real-time digital zoom and further adjust rotation (horizon/roll correction). The camera, its enclosure and internal MAGS weigh 35 gm. A 158 mm long, pneumatically powered, 3 df robotic arm was designed to support a conventional hook cautery attach- FIG. 1. MAGS couplers, including 1 conventional trocar with 4 representative MAGS instruments and camera. A, deployment trocar. ment (fig. 3). The first joint of the robot, which raises and B, camera. C, retractors. D, robotic cauterizer. E, external magnets. lowers the arm, is capable of 50 degrees of motion. The second joint of the robot, acting as an elbow, is capable of 45 degrees of motion to the left. The arm was designed to mimic MAGS platform (external magnet and internal magnet the motions of a cauterizer operated by the surgeon right platform) coupling strength was previously determined hand. To simplify the design the arm moves from a centered across various distances of air gaps, and across ex vivo location to the left only. The third joint of the robot allows for porcine abdominal walls and commercially purchased bo- telescoping the cauterizer, enabling extension of the length 1 vine muscle of various thicknesses. Excellent coupling inde- of the arm an additional 20 mm. An off-the-shelf gaming pendent of the medium was demonstrated at distances less joystick serves as an input device to control robotic arm than 1.5 cm. However, at separation distances greater than 1.5 movement (fig. 4). The robot was deployed through the same 1 cm the magnetic attraction force decreased at a constant rate. 15 mm trocar and then anchored to the abdominal wall by an The permanent magnets that were used had a significant de- externally placed magnet. The surgeon positioned the ro- cay in magnetic force after tissue thickness reached 3.5 cm. botic arm by sliding the magnet along the abdominal wall. The prototype camera enclosure and the 3 df robotic arm The joystick was then used to activate the robotic arm to cauterizer were then designed, manufactured and evaluated accomplish tissue incision. The camera and robotic arm are in vivo in a porcine laparoscopic nephrectomy model. Unlike hardwired to their external controls. conventional laparoscopes that deliver illumination, the prototype camera was not designed with its own light source. RESULTS Therefore, a single working 12 mm trocar was modified by wrapping it in fiberoptic cables, resulting in an outer diam- Average porcine abdominal wall thickness was 1.5 cm and eter of 15 mm, after which it was coupled to a conventional the MAGS platform was sufficient to securely anchor the 1 light source. Using 100-pound domestic pigs the MAGS tissue retractors and camera. Due to its intended nonmedi- camera and robotic arm cauterizer were inserted through a cal design the camera resolution was expectedly inferior to 15 mm umbilical trocar port that was removed after the tools that of conventional laparoscopes. While the motion of the were securely held and located off site. The illuminating separate anchors provided the yaw and pitch control de- trocar was then inserted into the same incision beside the sired, the tool was cumbersome to operate since the 2 exter- camera and robotic arm control cables to introduce conven- nal magnetic platforms had to be manipulated together to tional tools. The kidney specimen was extracted through an move along the abdominal wall. The camera had a fixed extension of the single trocar incision. focus, which made positioning difficult. Although the image was poor secondary to significant lens fogging, it was ade- MAGS Instrumentation quate enough to complete the procedures. While light was A QN42H miniature camera (Elmo, Plainview, New York) sufficient for imaging, there was significant shadowing sec- was packaged in a customized aluminum enclosure attached ondary to the delivery of light not parallel to the camera. In to a pair of internal MAGS platforms (fig. 2). The camera particular the camera could be manipulated to any desired

FIG. 2. Fully deployed prototype internal camera. a, schematic. A, lens. B, magnetic anchors. b, internal view. 290 SINGLE TROCAR LAPAROSCOPIC NEPHRECTOMY

FIG. 3. Robotic arm cauterizer. a, schematic. A, hook cautery. B, magnetic anchor. b, internal view shows robotic arm dissecting kidney. location inside the peritoneum. The motion of the robotic hernia and/or internal organ damage, and it incrementally cauterizer was not always smooth and we encountered some decreases cosmesis.2,3 Cosmesis is particularly important in difficulty with telescoping of the arm. However, the robotic procedures in pediatric and sophisticated adult patients.4 arm had sufficient force to elevate and incise tissues and the Moreover, the intra-abdominal mobility and working enve- hook cautery transmitted the current flawlessly. lope are ultimately constrained by the fixed entry incisions. The 2 attempted nonsurvival porcine left laparoscopic To overcome these limitations robot assisted laparoscopy nephrectomies were successfully completed using the proto- was developed. The current master-slave device (the da type MAGS camera, light trocar and robotic cauterizer. As Vinci® system) provides 3-dimensional vision and superior such, only 1, 15 mm transabdominal trocar was necessary instrument manipulation. However, its working envelope is with the same port site used for specimen extraction. A even smaller, significantly limited by the bulky robotic arms, conventional laparoscopic tissue grasper introduced through which are prone to collision.5–7 Furthermore, movement of the light trocar was used to assist with tissue retraction. The the intra-abdominal instruments is still limited to the ful- renal artery and vein were transected with a conventional crum motion around the trocar site and multiple 8 mm laparoscopic stapler introduced through the solitary trocar. abdominal incisions are necessary. Procedure time was not recorded and blood loss was mini- Our objective was to further minimize the invasiveness of mal. No intraoperative complications were encountered. laparoscopic surgery using controlled magnetic coupling to manipulate intracorporeal surgical instruments that are de- DISCUSSION livered via a single keyhole incision in the patient. We believe that the development of magnetically controlled and The magnified video images used in laparoscopic surgery anchored intracorporeal surgical instruments introduced provide surgeons with better exposure and visualization of through a single trocar can further advance surgical practice critical structures. However, despite these benefits a num- and patient care by realizing the benefits of 1-keyhole sur- ber of limitations remain. Even routine laparoscopic ne- gery, while meeting or exceeding the performance of current phrectomy or cholecystectomy requires a minimum of 3 or 4 fixed trocar laparoscopy. small abdominal incisions. Although laparoscopic trocars In a recent report we described the feasibility of perform- may not result in a significant increase in postoperative ing porcine nephrectomy using only 2 abdominal trocars.1 pain, each working port carries morbidity risks of bleeding, Two nephrectomies were completed using the MAGS camera, a MAGS paddle-type tissue retractor, a 15 mm light trocar anda5mmconventional trocar. Tissue dissection was accomplished with conventional instrumentation and the renal vessels were transected with a conventional laparoscopic stapler introduced through the light trocar. To advance this concept further we successfully designed, manufactured and implemented instrumentation to complete 2 porcine laparoscopic nephrectomies using only 1 transumbilical trocar. The prototypes developed and the 2 porcine cases completed serve as proof of concept for this technology. However, the MAGS technology will be a significant advance only if certain objectives are achieved. 1) Instruments must retain the advantages of conventional and robotic instrumentation, while being easily repositioned when the working envelope becomes disadvantageous. 2) Surgical pain should be decreased by the elimination of most and possibly all abdominal trocars. 3) Mechanisms must be developed for a simple deployment and retrieval of intra- abdominal robots and instruments. 4) A future goal of the FIG. 4. Robotic arm joystick control MAGS platform must be to provide a local power source and SINGLE TROCAR LAPAROSCOPIC NEPHRECTOMY 291 wireless operating controls, so that the instruments are ogy may overcome the limitations of current laparoscopic completely independent of the deployment site. and robotic surgery by allowing unhindered intra-abdominal Clearly our pilot porcine experiments cannot address all movement. This single access technique may be used with of these objectives, and yet a few important observations can new natural orifice surgery approaches and it has the po- be made. The ability to deploy and position the intra-abdom- tential to accomplish the ultimate goal of minimally inva- inal prototype camera and robotic arm during surgery dem- sive, incision-free intra-abdominal surgery. onstrates the potential for this technology to use the entire insufflated abdomen as the working envelope, similar to open surgery performed through a large incision. Completion of a Abbreviations and Acronyms complex intra-abdominal procedure through a single transum- ϭ bilical trocar avoids penetration of the abdominal musculature MAGS magnetic anchoring and guidance system and, thus, could potentially result in more outpatient based operations. Also, visibly unappealing surgical scars can be eliminated or minimized using a single umbilical trocar. REFERENCES The single trocar concept can be modified to even further minimize the invasiveness of peritoneal access by com- 1. Park SBR, Eberhart R, Baker L, Fernandez R and Cadeddu pletely avoiding an anterior abdominal wall approach. Nat- JA: Trocar-less instrumentation for laparoscopy: magnetic ural orifice surgery may be the next logical step toward the positioning of intra-abdominal camera and retractor. development of truly incision-free abdominal surgery. In Unpublished data. fact, multiple reports of transgastric, transvaginal and even 2. Marcovici I: Significant abdominal wall hematoma from an transvesical approaches to the peritoneal cavity now exist.8–12 umbilical port insertion. JSLS 2001; 5: 293. 3. Lowry PS, Moon TD, D’Alessandro A and Nakada SY: Symp- Gettman et al performed 6 laparoscopic transvaginal nephrec- 13 tomatic port-site hernia associated with a non-bladed trocar tomies using conventional instruments in a porcine model. after laparoscopic live-donor nephrectomy J Endourol 2003; Completely transvaginal laparoscopic nephrectomy was per- 17: 493. formed on 1 kidney and the remaining 5 renal units required 4. Dunker MS, Stiggelbout AM, van Hogezand RA, Ringers J, only a single 5 mm abdominal trocar to facilitate visualization Griffioen G and Bemelman WA: Cosmesis and body image and dissection. However, Gettman et al noted difficulty asso- after laparoscopic-assisted and open ileocolic resection for ciated with instrument/trocar collision. The MAGS platform Crohn’s disease. Surg Endosc 1998; 12: 1334. could significantly enhance the applicability of natural orifice 5. Corcione F, Esposito C, Cuccurullo D, Settembre A, Miranda surgery by eliminating the limitations to intra-abdominal mo- N, Amato F et al: Advantages and limits of robot-assisted bility/collisions and visualization. We are currently testing the laparoscopic surgery: preliminary experience. Surg Endosc feasibility of using MAGS in this environment. 2005; 19: 117. 6. Marohn MR and Hanly EJ: Twenty-first century surgery using Before adopting this novel platform into clinical practice twenty-first century technology: surgical robotics. Curr several limitations must also be addressed. Since the cou- Surg 2004; 61: 466. pling strength of magnets decreases as a decaying exponen- 7. Gutt CN, Oniu T, Mehrabi A, Kashfi A, Schemmer P and tial with respect to the distance between the source magnet Buchler MW: Robot-assisted abdominal surgery. Br J Surg and its target, abdominal wall thickness in excess of 1.5 cm 2004; 91: 1390. limits the effectiveness of the magnetic anchoring. As a 8. Beger HG, Schwarz A and Bergmann U: Progress in gastro- result, potential clinical deployment of the currently avail- intestinal tract surgery: the impact of gastrointestinal enable prototypes would be limited to thin or pediatric pa- doscopy. Surg Endosc 2003; 17: 342. tients. To increase the coupling strength the use of alterna- 9. Kalloo AN, Singh VK, Jagannath SB, Niiyama H, Hill SL, tive technologies, such as electromagnets and magnetic Vaughn CA et al: Flexible transgastric peritoneoscopy: a focusing, may be required to optimize magnetic field shape novel approach to diagnostic and therapeutic interventions in the peritoneal cavity. Gastrointest Endosc 2004; 60: 114. and penetration. Although we did not note any skin/perito- 10. Lima E, Rolanda C, Pego JM, Henriques-Coelho T, Silva D, neal tissue damage in this study, future studies would re- Carvalho JL et al: Transvesical endoscopic peritoneoscopy: quire the evaluation of potential magnetic pressure injuries. a novel 5 mm port for intra-abdominal scarless surgery. Furthermore, we must extend and broaden the capabili- J Urol 2006; 176: 802. ties of existing prototypes to define long-term directions of 11. Park PO, Bergstrom M, Ikeda K, Fritscher-Ravens A and development. A stereoscopic, remotely controlled imaging Swain P: Experimental studies of transgastric gallbladder device that can maintain a clear field of view in the abdomen surgery: cholecystectomy and cholecystogastric anastomo- is needed and at least 2 proof of concept prototypes have sis (videos). Gastrointest Endosc 2005; 61: 601. been designed.14,15 Unlike the currently available robotic 12. Swanstrom LL, Kozarek R, Pasricha PJ, Gross S, Birkett D, systems, in vivo robots must be small, mobile and precise Park PO et al: Development of a new access device for manipulators, each engineered for a specific task, so that transgastric surgery. J Gastrointest Surg 2005; 9: 1129. 13. Gettman MT, Lotan Y, Napper CA and Cadeddu JA: Trans- multiple devices can be deployed and used simultaneously in vaginal laparoscopic nephrectomy: development and feasi- the abdomen. After these concepts are realized laparoscopic bility in the porcine model. Urology 2002; 59: 446. surgery will no longer be constrained by port incisions, view- 14. Rentschler ME, Dumpert J, Platt SR, Ahmed SI, Farritor SM ing angles or difficult reach. and Oleynikov D: Mobile in vivo camera robots provide sole visual feedback for abdominal exploration and cholecystec- CONCLUSIONS tomy. Surg Endosc 2006; 20: 135. 15. Miller A, Allen P and Fowler D: In-vivo stereoscopic imaging Single trocar laparoscopic nephrectomy using a magneti- system with 5 degrees-of-freedom for minimal access sur- cally anchored platform is technically feasible. This technol- gery. Stud Health Technol Inform 2004; 98: 234. Targeting ␤2-Microglobulin Mediated Signaling as a Novel Therapeutic Approach for Human Renal Cell Carcinoma

Takeo Nomura, Wen-Chin Huang, Seongil Seo, Haiyen E. Zhau, Hiromitsu Mimata and Leland W. K. Chung* From the Molecular Urology and Therapeutics Program, Department of Urology (TN, WCH, SS, HEZ, LWKC) and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, and Department of Oncological Science (Urology), Oita University Faculty of Medicine (TN, HM), Oita, Japan

Purpose: We previously reported that the biological functions of ␤2-microglobulin include antigen presentation and oncogenic activity. In the current study we investigated the direct role of ␤2-microglobulin in the regulation of human renal cell carcinoma cell growth and the possible apoptotic inducing effect of blocking the ␤2-microglobulin signaling pathway using an anti-␤2-microglobulin neutralizing antibody. Materials and Methods: We examined the effects of recombinant ␤2-microglobulin protein and anti-␤2-microglobulin antibody on renal cell carcinoma cell growth and apoptosis in vitro. To seek a molecular understanding of anti-␤2- microglobulin antibody induced apoptosis we analyzed alterations in the growth and survival signaling components in the phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase and c-jun N-terminal kinase mediated pathways using corresponding kinase inhibitors in SN12C cells. Results: Recombinant ␤2-microglobulin protein increased the growth of the 3 human renal cell carcinoma cell lines SN12C, Caki-1 and ACHN in a dose and time dependent manner. Treatment of SN12C, Caki-1 and ACHN cells with an anti-␤2- microglobulin polyclonal antibody strongly suppressed the growth of these cells in vitro, also in a dose and time dependent manner. The addition of recombinant ␤2-microglobulin protein or anti-␤2-microglobulin antibody increased or decreased, respectively, the anchorage independent growth of SN12C cells. The recombinant ␤2-microglobulin protein accelerated cell growth via activating phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase, and induced the phosphorylation of Bcl-xL/Bcl-2-associated death promoter. However, treatment with anti-␤2-microglobulin antibody induced cell death by inhibiting the phosphorylation of Akt and extracellular signal-regulated kinase, and activating c-jun N-terminal kinase, resulting in the induction of phosphorylation of B-cell lymphoma 2 and decreased phosphorylation of Bcl-xL/Bcl-2- associated death promoter, leading to apoptosis. Conclusions: Our results demonstrate that ␤2-microglobulin has an important role in regulating the growth and survival of renal cell carcinoma cells and anti-␤2-microglobulin antibody offers a potential novel therapy for the treatment of human renal cell carcinoma. Key Words: kidney; carcinoma, renal cell; beta 2-microglobulin

CC, the most lethal of the urological cancers, accounts advanced diseases. A better understanding of the biology of for 3% of all adult malignancies with the RCC inci- RCC cells and cell signaling pathways could aid the devel- R dence increased largely by incidental cases. Although opment of novel targeting strategies to control the growth, progress in cell and molecular biology has enhanced our progression and metastasis of human RCC. understanding of the mechanisms involved in RCC growth, In previous studies we reported that ␤2M is a growth relatively little is known of the molecular events leading to promoting and cell signaling molecule for human prostate,1 RCC development, progression and metastasis because of its breast and lung cancers (unpublished data). Inactivating the unusual biological, histopathological and molecular fea- ␤2M signaling pathway using sequence speciﬁc ␤2M siRNA tures. Moreover, current treatment regimens, including con- blocked human prostate cancer growth in vitro and induced ventional chemotherapy, radiation therapy and immuno- massive prostate cancer apoptosis in cultured cells and in therapy, fail to improve the overall survival of patients with tumor xenografts in mouse bone.1 In the current study we focused on elucidating the molecular pathways leading to ␤2M induced growth promoting and anti-␤2M polyclonal Submitted for publication September 25, 2006. antibody triggered antitumor effects in human RCC cells. Supported by Grants P01-CA98912, DAMD-17-03-02-0033, GM- ␤ 0702069 and RO1-CA108468 (LWKC). 2M forms complexes with heavy chain MHC class I * Correspondence and requests for reprints: Molecular Urology molecules and it has an important role in tumor immunity.2 and Therapeutics Program, Department of Urology and Winship Cancer cells often down-regulate HLA antigens and become Cancer Institute, Emory University School of Medicine, 1365-B Clifton Rd., Room B5101, Atlanta, Georgia 30322 (telephone: 404- immune evasive. Upon presentation of foreign peptide anti- 778-3672; FAX: 404-778-3675; e-mail: [email protected]). gen T cells actively bind and eliminate the antigen present- See Editorial on page 10. ing cells.3 RCC cells can escape from elimination by cytotoxic

0022-5347/07/1781-0292/0 292 Vol. 178, 292-300, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.007 ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER 293

T cells through the 1) reduction of expression of MHC anti- NaN3, 0.1% sodium dodecyl sulfate, 1% NP-40, 0.5% sodium gens and 2) prevention of the processing of MHC antigens by deoxycholate and 1 mM phenylmethylsulfonyl fluoride in lymphocytes.4,5 However, the biological functions of ␤2M in the presence of protease inhibitor cocktail (Roche Applied cancer cells remain largely uncertain. Our previous study Science, Indianapolis, Indiana). Samples containing equal showed that ␤2M protein over expression contributes to cell amounts of protein (30 ␮g) were electrophoresed on 8% to proliferation and its aggressive behavior in prostate cancer.1 16% tris-glycine gels (Invitrogen™) and transferred to nitro- In the current study we evaluated ␤2M as a cell growth cellulose membranes. After blocking with Tween-tris buff- regulator and therapeutic target. To our knowledge we re- ered saline containing 5% nonfat milk powder the mem- port for the first time that ␤2M stimulates RCC cell growth branes were incubated with mouse monoclonal antibody via the activation of PI3K/Akt and ERK mediated survival against Bad (Santa Cruz Biotechnology) (1:200 dilution) or signaling, and treatment with anti-␤2M antibody induces rabbit polyclonal antibodies against Akt (1:1,000 dilution), apoptosis in SN12C cells via JNK mediated death signaling phospho-Akt (Ser 473) (Cell Signaling, Danvers, Massachu- and disruption of the survival PI3K/Akt and ERK signaling setts) (1:1,000 dilution), ERK1/2 (Santa Cruz Biotechnology) pathways. The effects of ␤2M and anti-␤2M antibody on (1:1,000 dilution), phospho-ERK1/2 (Thr 185/Tyr 187) RCC cell growth and survival were also noted in Caki-1 and (BioSource, Camarillo, California) (1:1,000 dilution), caspase-3 ACHN cells of human RCC origin. (1:1,000 dilution), caspase-9 (1:500 dilution), PARP (1:1,000 dilution), phospho-Bad (Ser 136) (1:500 dilution), phospho-Bad MATERIALS AND METHODS (Ser 112) (1:1,000 dilution), Bcl-2 (1:1,000 dilution), phospho- Bcl-2 (Ser 70) (1:1,000 dilution), JNK (1:1,000 dilution) and Cell Culture phospho-JNK (Thr 183/Tyr 185) (Cell Signaling) (1:1,000 The human RCC cell lines SN12C, Caki-1 and ACHN cells, dilution), respectively, at 4C overnight. After washing with derived from clear cell carcinomas, were cultured in mini- Tween-tris buffered saline the membranes were incubated mum essential medium (Gibco BRL, Grand Island, New with corresponding secondary antibodies conjugated with York) supplemented with 10% heat inactivated fetal bovine horseradish peroxidase (Santa Cruz Biotechnology). The serum (Bio-Whittaker, Walkersville, Maryland) with 50 blots were stripped and reprobed with anti-␤-actin antibody ␮ IU/ml penicillin and 50 g/ml streptomycin (Gibco BRL) in (Sigma) (1:5,000 dilution). Immunoreactive bands were vi- 5% CO2 at 37C. sualized with enhanced chemiluminescence (Amersham Pharmacia Biotech, Little Chalfont, United Kingdom). Cell Viability Assay Cell viability was determined with a colorimetric MTS Flow Cytometric Analysis (Promega®) assay. Briefly, exponentially growing cells were For cell cycle analysis flow cytometric analysis of propidium seeded at a density of 1 ϫ 104 cells per well in 96-well plates. iodide stained nuclei was performed. Briefly, cells were After overnight culture the culture medium was changed to plated at a density of 5 ϫ 105 cells in a 60 mm dish over- fresh standard medium with various concentrations of re- night. The cells treated with anti-␤2M antibody were col- combinant ␤2M protein (Sigma®) (0 to 20 ␮g/ml) or anti- lected by trypsinization and fixed with 70% ethanol. Fixed ␤2M neutralizing polyclonal antibody (Santa Cruz Biotech- cells were incubated with 100 ␮g/ml RNase A (Sigma) for 30 nology, Santa Cruz, California) (0 to 20 ␮g/ml) for 96 hours, minutes and stained with 25 ␮g/ml propidium iodide or in the presence of 20 ␮g/ml recombinant ␤2M protein or (Chemicon, Temecula, California) for 30 minutes. The rela- 20 ␮g/ml anti-␤2M antibody for 0 to 120 hours. Isotype tive DNA content was determined by a FACScan™ flow specific IgG (Zymed, South San Francisco, California) (20 cytometer and the sub-G1 DNA population (apoptotic cells) ␮g/ml) served as a control. At the end of the treatment was calculated by CellQuest™ software. period 20 ␮l MTS reagent were added to each well containing 100 ␮l of fresh culture medium. After a 1-hour incubation period optical absorbance at 490 nm was measured. Cell Cytotoxicity Assay viability is expressed as a percent of the absorbance ob- To determine the involvement of PI3K/Akt, mitogen-acti- tained in treated cells relative to that in vehicle treated vated protein kinase and JNK pathways in cell growth and control cells. apoptosis cells were treated with LY294002, U0126 or SP600125 (Calbiochem, Darmstadt, Germany), respectively, Colony Forming Assay for 6 hours. Control cells were cultured in the presence of an Cells were cultured in a 2 layer Matrigel™ system (BD™ equivalent amount of DMSO as a vehicle. Biosciences) to prevent their attachment to the plastic surface. Cells (1 ϫ 103) were trypsinized to single cell suspen- Statistical Analysis sions, resuspended in Matrigel (150 ␮l, 3.7 mg/ml), added to Values are expressed as the mean Ϯ SE of 3 independent a preset Matrigel layer in 24-well plates and mixed with experiments. Statistical analysis was performed using Stu- control IgG (20 ␮g/ml), recombinant ␤2M protein (20 ␮g/ml) dent’s t test or 1-way ANOVA with p Ͻ0.05 considered or anti-␤2M antibody (20 ␮g/ml). The top Matrigel cell layers statistically significant. were covered with culture medium containing 10% fetal bovine serum. Colonies larger than 200 ␮m in 10 randomly RESULTS selected fields were scored 14 days after plating. Effects of Recombinant ␤2M and Immunoblot Analysis Anti-␤2M Antibody on the Growth of RCC Cells Protein was extracted from cell pellets with lysis buffer We first examined the effects of recombinant ␤2M and composed of 50 mM tris (pH 8.0), 150 mM NaCl, 0.02% anti-␤2M antibody on the growth of the 3 human RCC cell 294 ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER

FIG. 1. Effects of ␤2M and anti-␤2M antibody on growth of SN12C, Caki-1 and ACHN cells. Effects of ␤2M (A and B) and anti-␤2M antibody (C and D) on cell proliferation were determined by MTS assay. Cells (1 ϫ 104) were seeded and treated with various concentrations of ␤2M (A) or anti-␤2M antibody (C) for 96 hours, or treated with 20 ␮g/ml ␤2M (B) or anti-␤2M antibody (D) for indicated times, as described. Values represent mean Ϯ SE of 3 independent experiments. Asterisk indicates p Ͻ0.05 vs control SN12C, Caki-1 and ACHN cells.

lines SN12C, Caki-1 and ACHN by MTS assay. Recombi- Effects of ␤2M and Anti-␤2M nant ␤2M protein enhanced cell proliferation in a dose Antibody on the Activation of Akt, and time dependent manner (fig. 1, A and B). Conversely ERK and JNK Signaling in SN12C Cells anti-␤2M antibody showed potent growth inhibitory ef- To clarify the molecular mechanisms by which ␤2M stimulated fects on all RCC cell lines in a dose and time dependent the growth, survival and anti-␤2M antibody promoted cell manner (fig. 1, C and D). The isotype specific control IgG death of SN12C cells we examined the effects of ␤2M and failed to exert any growth inhibitory effect. We then used anti-␤2M antibody on the phosphorylation of Akt, ERK and SN12C cells for detailed molecular analysis to determine JNK. SN12C cells were serum starved overnight and then the signaling components altered by ␤2M and anti-␤2M treated with 20 ␮g/ml IgG, ␤2M or anti-␤2M antibody in se- antibody. We evaluated the effects of recombinant ␤2M rum-free media for 48 hours. In proliferating SN12C cells phos- and anti-␤2M antibody on SN12C cells grown as anchor- phorylated ERK and Akt were observed even in the absence of age independent Matrigel colonies. The number of colo- serum but JNK was only weakly phosphorylated. ␤2M treat- nies formed by ␤2M treated cells was significantly higher ment led to Akt phosphorylation at Ser 473, a site required for than the number of untreated and IgG treated control Akt activation, and to p42/p44 ERK phosphorylation at Thr cells (141 Ϯ 15 vs 67 Ϯ 4 and 61 Ϯ 4, respectively, p Ͻ0.01, 185 and Tyr 187, which are sites required for ERK1/2 activa- fig. 2, A). In contrast, anti-␤2M antibody significantly tion, but not to JNK1/2 phosphorylation (fig. 2, B). However, inhibited the growth of SN12C cells in Matrigel (11 Ϯ 1) conversely treatment with anti-␤2M antibody completely abol- compared to that of untreated or IgG treated controls ished phosphorylation of Akt and ERK, and strongly induced (p Ͻ0.01, fig. 2, A). These results collectively suggested that JNK1/2 phosphorylation (fig. 2, B). These results suggested ␤2M is responsible for stimulating the growth of SN12C that ␤2M positively regulates the activation of PI3K/Akt and cells on plastic dishes and as Matrigel colonies and anti-␤2M ERK pathways, whereas the blockade of ␤2M mediated signal- neutralizing antibody has potent growth inhibitory effects ing by anti-␤2M neutralizing antibody resulted in activation of on SN12C cells. the JNK pathway in SN12C cells. ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER 295

FIG. 2. Effects of ␤2M and anti-␤2M antibody on anchorage independent growth of SN12C human RCC cells with cell growth determined by colony forming assay (A). After 14 days of incubation visible colonies greater than more than 200 ␮m were photographed (left) and counted (right). Data on each experimental group are expressed as mean Ϯ SE of 3 independent experiments. a, control. b, IgG. c, ␤2M. d, anti-␤2M antibody. Asterisk indicates p Ͻ0.01 vs control SN12C cells. Effects of ␤2M and anti-␤2M antibody on phosphorylation of Akt, ERK1/2 and JNK1/2 in SN12C cells (B). Phosphorylation of Akt, ERK1/2 and JNK1/2 was determined by immunoblot analysis using phospho-Akt (Ser 473), phospho-ERK1/2 (Thr 185/Tyr 187) and phospho-JNK1/2 (Thr 183/Tyr 185) antibodies. Blots were stripped and reprobed with antibodies against total Akt, total ERK, total JNK and ␤-actin.

Effect of Anti-␤2M Antibody on cells treated with anti-␤2M antibody. Immunoblot analysis the Apoptotic Cell Death of SN12C Cells showed that treatment with anti-␤2M antibody for 48 hours To investigate whether the growth inhibitory effect by anti- induced the cleavage of caspase-9 and downstream execu- ␤2M antibody may be triggered by increased apoptosis in tioner of apoptosis, caspase-3, in a dose dependent manner SN12C cells we evaluated the apoptotic cells in the presence (fig. 3, C). The activation of effector caspase proteolytic func- or absence of anti-␤2M antibody by flow cytometry. Treat- tions is expected to result in the cleavage of the downstream ment with anti-␤2M antibody for 96 hours led to increased substrates, including the nuclear enzyme PARP engaged in apoptosis of SN12C cells in a dose dependent manner (fig. 3, A). DNA repair. We observed that treatment of SN12C cells Likewise, 20 ␮g/ml anti-␤2M antibody added in the absence of with anti-␤2M antibody resulted in PARP cleavage (fig. 3, exogenously recombinant ␤2M protein markedly induced apo- C). When we investigated the time course of activation of ptosis in a time dependent manner (fig. 3, B). The growth of caspase-3 by treatment of SN12C cells with 20 ␮g/ml anti- SN12C cells was unaffected by treatment with 20 ␮g/ml iso- ␤2M antibody, processing of caspase-3 was induced within type matched control IgG. These results are consistent with 12 hours of treatment with a peak occurring in 72 hours, the significant growth stimulation by ␤2M protein and inhibi- which correlated with the increased processing of caspase-9 tion by anti-␤2M antibody observed in SN12C cells. (fig. 3, D). Consistent with caspase activation we also ob- Since apoptosis can be triggered by death receptor medi- served increased PARP cleavage in a time dependent man- ated or mitochondria mediated cascade depending on the ner by anti-␤2M antibody (fig. 3, D). In this series of exper- type of caspase activation, we evaluated caspase-9 and iments we did not observe any activation of caspase-8 (data caspase-3 activation, and the cleavage of PARP in SN12C not shown). These results taken together provide supportive 296 ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER

FIG. 3. Anti-␤2M antibody induced apoptosis in SN12C cells, as detected and quantified by flow cytometry (A and B). Note percent of apoptotic cells with sub-G1 DNA content. SN12C cells were treated with anti-␤2M antibody at concentrations of 0.5, 1, 10 and 20 ␮g/ml for 96 hours (A)or20␮g/ml anti-␤2M antibody for indicated times (B). Values represent mean Ϯ SE of 3 independent experiments. Asterisk indicates p Ͻ0.05 vs control SN12C cells. Activation of caspase-9 and caspase-3, and PARP cleavage after several concentrations of anti-␤2M antibody treatment for 48 hours was determined by immunoblot analysis using caspase-9, caspase-3 and PARP antibodies (C). Blots were stripped and reprobed with antibody against ␤-actin. Serial changes in activation, processing of caspase-9 and caspase-3, and PARP cleavage induced by 20 ␮g/ml anti-␤2M antibody were determined by immunoblot analysis using caspase-9, caspase-3 and PARP antibodies (D). Phosphorylation of Bad and Bcl-2 induced by ␤2M and anti-␤2M antibody was determined by immunoblot analysis using phospho-Bad (Ser 136), phospho-Bad (Ser 112) and phospho-Bcl-2 (Ser 70) antibodies (E). Blots were stripped and reprobed with antibodies against total Bad, total Bcl-2 and ␤-actin. evidence that anti-␤2M antibody induced cell death involves results suggest that phosphorylation of Bad at the key primarily a mitochondria mediated pathway. amino acid residues, Ser 136 and Ser 112, is mediated by To elucidate further the molecular mechanisms underly- PI3K/Akt and/or ERK. Aside from Bad activation anti-␤2M ing anti-␤2M antibody mediated apoptosis of SN12C cells we antibody increased the levels of Bcl-2 phosphorylation but investigated the Bcl-2 family proteins that are known to be molecular events were not affected by exogenously added under regulation by PI3K/Akt and ERK signaling. We ob- recombinant ␤2M protein (fig. 3, E). served that levels of phosphorylated Bad at Ser 136 and Ser 112 but not total Bad protein were decreased by anti-␤2M Bad Phosphorylation antibody compared with levels in control (nontreated or IgG Depends on the Activation of treated) cells, whereas the levels of phosphorylated Bad on PI3K/Akt and ERK Signaling in SN12C Cells Ser 136 and Ser 112 residues were increased by the treat- To determine if inhibition of selected survival pathways is ment of SN12C cells with recombinant ␤2M (fig. 3, E). These sufficient to induce apoptosis, we used pathway specific in- ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER 297

FIG. 4. Effects of specific kinase inhibitors on select signaling pathways and apoptosis in SN12C cells. Cells were pretreated with 25 ␮M LY294002 and 20 ␮M U0126 separately or in combination for 6 hours and cultured for 24 hours in presence of 20 ␮g/ml ␤2M. Control cells were grown in presence of DMSO in serum-free medium. Note percent of apoptotic cells with sub-G1 DNA content. Values represent mean Ϯ SE of 3 independent experiments. Asterisk indicates p Ͻ0.05 vs control SN12C cells (A). Immunoblot analysis was performed using antibodies that specifically recognize total and phosphorylated Akt, ERK1/2, JNK1/2 and Bad (Ser 136/Ser 112) (B). Blots were stripped and reprobed with antibody against ␤-actin. SN12C cells were pretreated with SP600125 (10 ␮M) for 6 hours and cultured for 24 hours with or without anti-␤2M antibody (20 ␮g/ml). Note percent of apoptotic cells with sub-G1 DNA content is indicated. Values represent mean Ϯ SE of 3 independent experiments. Asterisk indicates p Ͻ0.05 vs control SN12C cells (C). Immunoblot analysis was performed using antibodies that specifically recognize total and phosphorylated Akt, ERK1/2, JNK1/2, Bad (Ser 136/Ser 112) and Bcl-2 (Ser 70) (D). Blots were stripped and reprobed with antibody against ␤-actin. hibitors of Akt, ERK and JNK signaling as tools to address A and B). These results suggested that ␤2M enhances the this question. The effects of LY294002 (PI3K inhibitor), phosphorylation of Bad on Ser 136 and Ser 112 via Akt and U0126 (mitogen-activated protein kinase inhibitor) and ERK pathways, respectively. When cells stimulated with SP600125 (JNK inhibitor) on SN12C cell apoptosis were ␤2M were incubated with SP600125, JNK phosphorylation examined by flow cytometry, which assessed a sub-G1 pop- was attenuated, whereas no alteration in Bad phosphoryla- ulation of apoptotic cells. In these experiments serum tion (Ser 136/Ser 112) was observed (fig. 4, B). This result starved SN12C cells were treated with LY294002 (25 ␮M) or indicate that JNK is an independent signaling component U0126 (20 ␮M) alone, or together for 6 hours and then with signaling not converging with PI3K/Akt and ERK, cultured in the presence of recombinant ␤2M (20 ␮g/ml) for which affect the phosphorylation of Bad in ␤2M stimulated 24 hours. LY294002 or U0126 alone enhanced the percent of cells. apoptotic sub-G1 population in the presence of ␤2M com- We next examined the further involvement of JNK phos- pared to that in control (DMSO treated) cells (fig. 4, A). The phorylation in anti-␤2M antibody induced apoptosis. In combined use of LY294002 and U0126 promoted cell death and these experiments serum starved SN12C cells were pre- their effects were additive (fig. 4, A). In contrast, when cells treated with SP600125 (10 ␮M) and cultured for 24 hours treated with ␤2M were incubated with SP600125, we observed with or without anti-␤2M antibody (20 ␮g/ml). Figure 4, C no change in the percent of apoptotic cells (fig. 4, A). shows that anti-␤2M antibody induced apoptosis was not To further evaluate whether PI3K/Akt, ERK and JNK blocked by SP600125. To determine the possible convergent signaling pathways affect Bad phosphorylation in ␤2M stim- signaling between JNK activation, and Bcl-2 and Bad phos- ulated cells we performed immunoblot analysis using these phorylation via respective PI3K/Akt and ERK activation in pathway specific inhibitors. LY294002 decreased ␤2M stim- SN12C cells we examined the effect of SP600125 on Bcl-2 ulated phosphorylation of Bad (Ser 136) and Akt (Ser 473) and Bad phosphorylation in cells treated with anti-␤2M but did not affect the phosphorylation of Bad (Ser 112) (fig. antibody. Figure 4, D shows that treatment with SP600125 4, B). Treatment with U0126 significantly attenuated ␤2M decreased anti-␤2M antibody stimulated phosphorylation of stimulated phosphorylation of Bad (Ser 112) and ERK1/2 Bcl-2 and JNK. This result suggests that anti-␤2M antibody but it did not affect the phosphorylation of Bad (Ser 136) (fig. induced phosphorylation of Bcl-2 occurs through JNK acti- 4, B). When the 2 inhibitors were added simultaneously, we vation. When the cells were treated with SP600125, which found that the amount of Bad phosphorylated on Ser 136 completely inhibited JNK phosphorylation, no alteration in and Ser 112 decreased in SN12C cells compared to that in phosphorylated Bad (Ser 136/Ser 112) was observed (fig. 4, controls (fig. 4, B). The level of phosphorylated Bad (Ser D). These results support the view that the JNK pathway is 136/Ser 112) was associated with apoptosis inhibition (fig. 4, not involved in Bad activation in SN12C cells. Taken to- 298 ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER gether these results suggest that Bcl-2 phosphorylation is decreased prostate cancer cell growth in vitro and tumor closely linked to JNK activation, whereas Bad phosphoryla- growth in vivo.1 The activation of PI3K/Akt and ERK sig- tion by PI3K/Akt and ERK is independent of JNK activation. naling pathways is a common response of cells to growth The changes in the phosphorylation status of Bad and Bcl-2 factor stimulation and it is essential for cell survival. We are central to apoptotic cell death in SN12C cells. observed that ␤2M up-regulates these 2 cell signaling pathways critical for SN12C cell survival and proliferation (fig. 2, ␤ DISCUSSION B). Consistent with these observations, interrupting 2M signaling with anti-␤2M antibody inhibited the growth of all Because of the high levels of ␤2M detected in blood and RCC cell lines tested (fig. 1, C and D). In this study we noted tissue specimens, and its association with cancer progres- that the growth inhibitory effect of anti-␤2M antibody on sion and poor prognosis in patients with RCC,6,7 the goals of SN12C cells occurred through a decrease in phosphorylated this study were to 1) define the possible direct biological Akt and ERK, leading to the induction of apoptosis (figures effects of ␤2M and anti-␤2M neutralizing antibody in human 2, B and 3, A and B). Accompanying this apoptotic induction, RCC cells, 2) characterize the downstream signaling path- we observed that anti-␤2M antibody induced caspase-9 ac- ways of ␤2M and anti-␤2M antibody in human RCC cells, tivation (fig. 3, C and D), which is the hallmark of mitochon- and 3) assess the status of phosphorylation of Bad and Bcl-2 dria dependent events. In contrast to caspase-9 activation, in RCC cell growth and death. This approach allowed us to the activation of caspase-8, which is identified as a death advance our understanding of the possible importance of receptor mediated pathway, was not observed (data not ␤2M in the regulation of cancer progression beyond the shown). Taken together these results suggest that anti-␤2M commonly described immunological association. antibody inhibits SN12C cell growth through the induction In the current study we made certain observations. 1) of apoptosis mediated by mitochondria rather than death ␤2M promoted cell proliferation in vitro, whereas anti-␤2M receptor mediated signaling. neutralizing antibody blocked the growth of human RCC ␤2M mediated pro-survival signaling and anti-␤2M anti- cells. 2) ␤2M activated pro-survival signaling pathways, in- body induced pro-apoptotic signaling converged on the pro- cluding the activation of PI3K/Akt and ERK, which caused apoptotic Bcl-2 family protein Bad, which is a common tar- downstream Bad phosphorylation. 3) Anti-␤2M antibody get of Akt and ERK.12,13 We noted that inhibition of survival promoted apoptosis through the inhibition of Akt and ERK kinase cascades targeting Bad, including the inhibition of phosphorylation but the activation of JNK phosphorylation. PI3K/Akt and ERK, by anti-␤2M antibody resulted in apo- 4) Whereas convergent pro-apoptotic signaling mediated by ptotic cell death, leading to disruption of the mitochondrial PI3K/Akt and ERK pathways induced by anti-␤2M antibody membrane, which could cause the release of cytochrome c in through the inhibition of Bad phosphorylation was observed, support of apoptotic cell death signaling (figs. 2, B and 3). Bcl-2 phosphorylation was induced through activation of the Anti-␤2M antibody was found to attenuate the phosphory- JNK signaling pathway. To our knowledge this is the first lation of Bad (Ser 136/Ser 112) and it was associated with report to demonstrate the possible direct pro-survival roles decreased cell survival as a consequence of the disruption of of ␤2M and the pro-apoptotic roles of anti-␤2M antibody in Akt and ERK signaling pathways (figs. 1, C and D,2,B and human RCC. In this study we also dissected the survival and 3, E). Conversely as expected, ␤2M enhanced the phosphor- apoptotic signals of RCC cells with their convergence at the ylation of Bad (Ser 136/Ser 112) via the activation of Akt and level of phosphorylation of Bad and Bcl-2. ERK, leading to increased survival of SN12C cells (figs. 1, A ␤2M, a 12 kDa nonglycosylated polypeptide composed of and B,2,B and 3, E). Bad phosphorylation in response to 100 amino acids, is one of the components presenting and survival signaling has been shown to occur at amino acid stabilizing MHC class I ␣-chain on the cell surface of all residues of Ser 112 and Ser 136.12,14 While Akt has been nucleated cells. MHC molecule complexes with ␤2M to reg- observed to promote cell survival by its ability to phosphor- ulate tumor immunity as well as cellular and humoral im- ylate Bad at Ser 136, ERK promotes cell survival through mune responses.2 However, the complex roles of ␤2M in the phosphorylation of Bad at Ser 112.12,14 We found that cancer remain largely unknown. It has been reported that LY294002 treatment caused a decrease in the phosphoryla- increased synthesis and release of ␤2M, as indicated by an tion of Bad (Ser 136) with a concomitant reduction in the increased serum or urine ␤2M concentration, occurs in sev- phosphorylation of Akt (Ser 473) (fig. 4, B). These results eral malignant diseases, including prostate cancer, lung support the view that the PI3K/Akt pathway is involved in cancer, RCC, myeloma and lymphocytic malignancies as Bad phosphorylation at Ser 136.12 However, Bad phosphor- well as autoimmune and infectious diseases.6,8–11 In these ylation at Ser 112 in SN12C cells was completely abrogated malignant and inflammatory conditions the serum ␤2M by U0126 with an expected decrease in ERK1/2 phosphory- level is an independent prognostic factor. lation (fig. 4, B). These results support the interpretation We hypothesized that ␤2M may have a key role in the that Bad phosphorylation on Ser 112 depends on ERK acti- regulation of cancer cell growth and survival. To test this vation in SN12C cells.14 Thus, the down-regulation of PI3K/ hypothesis we examined the effect of recombinant ␤2M pro- Akt and ERK signaling pathways by anti-␤2M antibody tein and its neutralizing antibody on the growth and down- might result in the observed alterations in Bad phosphory- stream mediated cell signaling pathways in RCC cells. Fig- lation at respective Ser 136 and Ser 112 regulatory residues, ure 1 shows that recombinant ␤2M protein activated but which in turn could trigger apoptotic cell death. anti-␤2M antibody inhibited human RCC growth in vitro. JNK is preferentially and markedly activated by various These results are consistent with our recent observations in environmental stresses mediated by cytokines and growth human prostate cancer cells, in which treatment with re- factor signaling. In addition to c-jun mediated transcription combinant ␤2M protein enhanced but down-regulation of mechanisms, JNK promotes apoptotic cell death by the di- endogenous ␤2M protein using sequence specific ␤2M siRNA rect regulation of Bcl-2 family proteins, such as Bcl-2, Bim ␤2-MICROGLOBULIN MEDIATED SIGNALING AND HUMAN RENAL CELL CANCER 299

FIG. 5. Proposed molecular mechanisms of ␤2M mediated signaling pathways in SN12C cells. ␤2M can phosphorylate Bad at Ser 136 and Ser 112 via PI3K/Akt and ERK pathways, respectively, resulting in cancer cell survival (A). Anti-␤2M antibody can block ␤2M mediated signaling pathways and, thus, Bcl-2 is phosphorylated at Ser 70 by SAPK/JNK activation, resulting in apoptosis (B).

and Bad.15–17 Moreover, studies have shown that dephos- ACKNOWLEDGMENTS phorylation of Bad at Ser 136 is accompanied by an increase in JNK phosphorylation and JNK activity, and it promotes Dr. John A. Petros provided RCC cell lines and Gary Mawyer assisted with the article. the association of Bad with Bcl-XL or Bcl-2 during apoptosis.18 That is, Bad is a converging signaling molecule between survival PI3K/Akt, ERK and death JNK pathways. We found that anti-␤2M antibody promotes the apoptotic Abbreviations and Acronyms death of SN12C cells via dephosphorylation of Bad (Ser ␤2M ϭ ␤2-microglobulin 136/Ser 112) but with JNK activation (figs. 2, B and 3). Since Bad ϭ Bcl-xL/Bcl-2-associated death promoter phosphorylation of Bad (Ser 136/Ser 112) was not affected by Bcl-2 ϭ B-cell lymphoma 2 SP600125 (fig. 4, D), this result suggests that Bad activation DMSO ϭ dimethyl sulfoxide ϭ is independent of the JNK mediated apoptotic cell death ERK extracellular signal-regulated kinase ϭ signaling pathway in SN12C cells. It has been reported that JNK c-jun N-terminal kinase MHC ϭ major histocompatibility complex JNK activation leads to inactivation of the survival func- ϭ 19 MTS 3-(4, 5-dimethylthiazol-2-yl)-5- tions of Bcl-2 through phosphorylation at Ser 70. In the (3-carboxymethoxyphenyl)-2- current study Bcl-2 phosphorylation at Ser 70 residue with (4-sulfophenyl)-2H-tetrazolium activation of JNK was found to be increased by anti-␤2M PARP ϭ poly(adenosine diphosphate-ribose) antibody (figs. 2, B,3,E and 4, D), suggesting that JNK polymerase positively regulates apoptosis induction through Bcl-2 phos- PI3K ϭ phosphatidylinositol 3-kinase ϭ phorylation specifically at Ser 70, which is a result in agree- RCC renal cell carcinoma ment with previous reports.19 REFERENCES

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Kazumori Kawakami, Hideki Enokida,* Tokushi Tachiwada, Kenryu Nishiyama, Naohiko Seki and Masayuki Nakagawa From the Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University (KK, HE, TT, KN, MN), Kagoshima and Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba (KK, NS), Japan

Purpose: SKP2 and CKS1 promote aggressive tumor behavior via the regulation of p27 degradation. Our previous DNA microarray analysis of human urothelial carcinoma and normal urothelial epithelium showed that in urothelial carcinoma the 2 most highly up-regulated genes among SKP2-p27 interaction related genes are SKP2 (4.7-fold) and CKS1 (2.2-fold). We hypothesized that SKP2 and CKS1 gene expression is associated with urothelial carcinoma invasiveness and prognosis. Materials and Methods: A total of 84 urothelial carcinoma specimens from patients with bladder (71) and upper urinary tract (13) cancer were examined by real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. Results: Real-time reverse transcriptase-polymerase chain reaction showed that the average mRNA expression level of SKP2 and CKS1 significantly correlated with tumor stage, that is superficial vs invasive urothelial carcinoma (SKP2 and CKS1, p Ͻ0.001 and 0.006) and grade (p Ͻ0.001 and 0.009, respectively). Of the superficial urothelial carcinomas examined the SKP2 and CKS1 expression level was significantly higher in pT1 than in pTa samples (p ϭ 0.005 and 0.017, respectively). Immunohistochemical expression patterns of SKP2 and CKS1 also significantly correlated with tumor stage (p Ͻ0.001 and 0.048) and grade (p ϭ 0.003 and 0.025, respectively). In contrast, p27 expression inversely correlated with tumor stage and grade (p Ͻ0.001 and 0.011, respectively). Logistic regression analysis revealed that while SKP2 mRNA expression was a significant dependent predictor of p27 expression (p ϭ 0.021), there was no correlation between CKS1 mRNA expression and p27 (p ϭ 0.748). Kaplan-Meier curves and log rank tests revealed that the high mRNA expression levels of SKP2 and CKS1 had a significant adverse effect on prognosis (p ϭ 0.043 and 0.003, respectively). Conclusions: Our results suggest that SKP2 has a major role in the regulation of p27 degradation and CKS1 has a supporting role for SKP2 function in human urothelial carcinoma. Key Words: bladder, urinary bladder neoplasms, microarray analysis, urothelium, gene expression

rothelial carcinoma, which is among the 5 most com- differently and to our knowledge it is currently not possible mon malignancies worldwide, is the second most to identify patients who will experience tumor recurrence or U common tumor of the genitourinary tract and the disease progression. Therefore, the ability to predict at the second most common cause of death in patients with urinary first biopsy whether a UC shift to progression is probable tract malignancies.1 Based on its histopathology and clinical would facilitate the selection of appropriate treatment mo- behavior it can be classified as superficial or invasive. Al- dalities and improve the prognosis of patients with this though 70% to 80% of these tumors are superficial (no mus- cancer. cle invasion defined as less than T2), approximately 70% Some investigators suggested that the important role of recur. Any recurrence of originally superficial bladder can- CKS1 lies in facilitating the ubiquitin mediated proteolysis cer progresses and 10% to 15% proceed to muscle invasion of p27 through interaction with SKP2.3–5 Subsequent stud- and metastasis. Namely any progressive tumors originate ies demonstrated that the expression level of SKP2 and from pT1 cases. Moreover, 20% of tumors with muscle inva- CKS1 is up-regulated and p27 expression is down-regulated sion at diagnosis tend to progress rapidly and the prognosis 2 in various human malignancies, and they suggested that is unfavorable. Morphologically similar tumors can behave CKS1 and SKP2 may have an important role in promoting aggressive tumor behavior via the regulation of p27 degradation.6–12 However, these studies did not specifically target Submitted for publication August 21, 2006. human UC. Microarray analysis of UC samples has detected Study received Kagoshima University Bioethics Committee ap- new cancer related genes.13 We reported gene expression proval. Supported by a Japan Society for the Promotion of Science grant. profiling by DNA microarray analysis for 14 UC and 4 NUE * Correspondence and requests for reprints: Department of Urol- samples.14 Consistent with previous studies we found that ogy, Graduate School of Medical and Dental Sciences, Kagoshima several genes, including SKP2 and CKS1, were up-regulated University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan (telephone: ϩ81-99-275-5395; FAX: ϩ81-265-9727; e-mail: enokida@ms. in UC compared to NUE (SKP2 and CKS1 average 4.7 and kagoshima-u.ac.jp). 2.2-fold, respectively). We hypothesized that, as in other

0022-5347/07/1781-0301/0 301 Vol. 178, 301-307, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.002 302 INCREASED GENE EXPRESSION AND HUMAN UROTHELIAL CANCER PROGRESSION

neoplasms, SKP2 and CKS1 gene expression is associated pared. After combining the primer RNA mixture 0.25 U with the invasiveness and prognosis of human UC. avian myeloblastosis virus RT (Promega) and 0.5 U ribonu- We subjected 84 UC samples to real-time RT-PCR assay clease inhibitor the RT reaction was done at 45C for 45 and immunohistochemical staining, and analyzed the rela- minutes. The cDNA was then incubated at 95C for 5 minutes tionship between clinicopathological parameters and the ex- to inactivate RT transcriptase. TaqMan® probes, and prim- pression level of SKP2, CKS1 and p27. In addition, we as- ers for SKP2, CKS1 and GAPDH were assay on demand sessed cause specific survival against the mRNA expression gene expression products (Applied Biosystems™). We syn- levels of SKP2 or CKS1 in our UC series. thesized first strand cDNA with 1 ␮g total RNA using random primers and TaqMan reverse transcription reagents MATERIALS AND METHODS (Applied Biosystems). Gene specific PCR products were measured continuously by an ABI™ PRISM™ 7900 sequence Tissue Samples detection system. The initial PCR step was 2 minutes at 50C Tissue samples were obtained from 84 UC patients, includ- for AmpErase® uracil-N-glycosylase activation, followed by ing 50 with superficial UC (pTis in 1, pTa in 13 and pT1 in a 10-minute hold at 95C. The 45 cycles consisted of a 15- 36) and 34 with invasive UC (pT2 in 18, pT3 in 14 and pT4 second denaturation step at 95C, followed by 1-minute in 2), who had undergone nephroureterectomy, cystectomy annealing/extension at 60C. All reactions were performed in or transurethral resection of bladder tumors. A total of 13 duplicate and a negative control lacking cDNA was included. patients had upper urinary tract carcinoma. All were The relative expression of SKP2 and CKS1 mRNA was nor- treated at Kagoshima University Hospital and 3 affiliated malized to the amount of GAPDH in the same cDNA using hospitals between 2001 and 2005. Table 1 lists patient back- the standard curve method provided by the manufacturer. grounds and clinicopathological characteristics. Samples were staged according to the American Joint Committee on Cancer- UICC TNM classification and histologically graded.15 The con- Immunohistochemistry trols were 5 NUE samples from patients with noncancerous Immunohistochemical staining for CKS1, SKP2 and p27 diseases. Our study was approved by the Bioethics Commit- was performed in formalin fixed, paraffin embedded tissue tee of Kagoshima University. Written, prior informed con- sections from matched 47 UCs, including 9 pTa, 17 pT1, 13 sent was obtained from all patients to use their samples, and pT2, 7 pT3 and 2 pT4 samples, which were available for clinical and pathological data. study. We used the avidin-biotin-peroxidase method with 1:100 diluted polyclonal SKP2 antibody (sc-7164), 1:50 diluted polyclonal CKS1 antibody (sc-6238, Santa Cruz Bio- Sample Preparation and Total RNA Extraction technology, Santa Cruz, California) or 1:40 diluted mono- Tissues were freshly harvested, immediately frozen in liquid clonal p27 antibody (Lab Vision, Fremont, California). nitrogen and stored at Ϫ80C until processing. They were Negative controls were slide sections positive for each stain. dissolved in TRIzol® reagent for total RNA extraction ac- They were treated with 10% nonimmune rabbit or mouse cording to the manufacturer protocol. RNA density was mea- serum instead of primary antibody. Positive controls were sured in an Ultrospec™ 3100 Pro instrument and RNA prepared with the corresponding recombinant protein for all quality was assessed in an Agilent™ 2100 bioanalyzer. 3 proteins. We examined 1,000 carcinoma cells in at least 5 high power fields and scored tumor cells positive for SKP2 cDNA Preparation and and CKS1 staining. When no nuclear positive tumor cell Quantitative Real-Time RT-PCR stain could be identified or up to 5% of the cells were focally ␮ ␮ RNA (1 g) was added to 0.5 g oligodeoxythymidilic acid distributed, nuclear positive tumor cells, the sample was ␮ primer (Promega™) and a final volume of 25 l was pre- considered stain negative. When 5% to 25% and more than 25% of the tumor cells showed positive nuclear staining, the sample was categorized as partial positive and diffuse posi- 6 TABLE 1. Patient characteristics tive, respectively. To determine the degree of p27 staining a score of high staining—greater than 50% of cells or low stain- Factors Superficial Ca Invasive Ca p Value ing—50% or less was assigned, as described previously.7 All No. pts 50 34 immunohistochemical scores were calculated by the average Median age (range) 70.9 (47–100) 74.4 (56–93) 0.129 No. sex (%): 0.410 of duplicated studies. All samples were scored indepen- M 36 (72) 21 (62) dently by 2 of us (KK and EH) who were blinded to patient F 14 (28) 13 (38) status. No. tumor grade (%): Ͻ0.001 G1 10 (20) 0 (0) G2 30 (60) 10 (29) G3 10 (20) 24 (71) Statistical Analysis No. tumor region (%): 0.004 The relationship between pathological findings and numer- Upper urinary tract 3 (6) 10 (29) Bladder 47 (94) 24 (71) ical values on real-time RT-PCR assay was analyzed by the No. operation method (%): 0.032 Mann-Whitney U or Kruskal-Wallis test. To examine the Nephroureterectomy 3 (6) 10 (29) correlation among the expression of the 3 genes we applied Cystectomy 7 (14) 8 (24) Transurethral bladder 40 (80) 16 (47) the chi-square test, Spearman’s correlation coefficient and tumor resection logistic regression analysis. Kaplan-Meier survival curves of No. recurrence (%): 0.996 patients with bladder cancer classified according to mRNA Yes 18 (36) 16 (47) No 32 (64) 18 (53) expression levels of SKP2 and CKS1 were prepared and Median mos followup 16.1 (2–50) 17.4 (2–38) 0.449 compared using the log rank test. The analysis software (range) used was Expert StatView™, version 4 with p Ͻ0.05 consid- INCREASED GENE EXPRESSION AND HUMAN UROTHELIAL CANCER PROGRESSION 303 ered statistically significant. Cutoff values of SKP2 and 0.18, respectively, p ϭ 0.009, fig. 2, C). Interestingly the CKS1 expression levels with optimal sensitivity and speci- Spearman correlation coefficient obtained with the rank test ficity for distinguishing superficial from invasive tumors revealed a significant positive correlation between the were determined by ROC curve analysis using MedCalc mRNA expression of SKP2 and CKS1 in the 84 UC samples (MedCalc Software, Mariakerke, Belgium). (r ϭ 0.566, p Ͻ0.001, fig. 3).

RESULTS Immunohistochemistry SKP2-p27 Interaction Related Gene In most UC samples cells positive for SKP2 and CKS1 Expression in UC Compared to NUE showed no or low p27 expression and vice versa (fig. 4). Based on our DNA microarray analysis results in 14 UC and Significantly more superficial than invasive UCs showed 4 NUE samples14 we reevaluated several SKP2-p27 inter- high p27 staining (15 of 25 or 60.0% vs 1 of 22 or 4.5%, Ͻ action related genes reported by others (fig. 1, top).3–5 The 2 p 0.001). In contrast, the frequency of positive (partial and most highly up-regulated genes were SKP2 and CKS1. Ex- diffuse positive) staining for SKP2 and CKS1 was signifi- pression levels in UC samples were 4.7 and 2.2-fold higher, cantly lower in superficial vs invasive UC (SKP2, 13 of 25 or Ͻ respectively, than in NUE samples (fig. 1, bottom). 52.0% vs 21 of 22 or 95.5%, p 0.001, and CKS1, 22 of 25 or 88.0% vs 21 of 22 or 95.5%, p ϭ 0.048, fig. 5, A). Moreover, the frequency of high p27 staining inversely correlated with Correlation of SKP2 or CKS1 mRNA tumor grade (G1 to G3, 4 of 6 or 66.7%, 9 of 18 or 50.0% and Expression Levels and Pathological Findings 3 of 23 or 13.0%, respectively, p ϭ 0.011, fig. 5, B). The To validate the results of our microarray analysis we used frequency of positive staining for SKP2 and CKS1 correlated quantitative real-time RT-PCR assay to determine the ex- positively with tumor grade (G1 to G3 SKP2, 2 of 6 or 33.3%, pression levels of SKP2 and CKS1 mRNA in 84 UC and 5 10 of 18 or 55.6% and 21 of 23 or 91.3%, p ϭ 0.003 and CKS1, NUE samples. We found a significant correlation between 4 of 6 or 66.7%, 15 of 18 or 83.3% and 23 of 23 or 100%, the average Ϯ SD mRNA expression level of SKP2 and respectively, p ϭ 0.025, fig. 5, B). CKS1, and pathological cancer stage (superficial vs invasive SKP2, 7.18 Ϯ 1.87 vs 19.4 Ϯ 3.71, p Ͻ0.001, and CKS1, 0.92 Ϯ 0.12 vs 1.62 Ϯ 0.19, p ϭ 0.006, fig. 2, A). ROC curve analysis Correlation of Immunohistochemical demonstrated that SKP2 mRNA expression had 72.7% sen- Score and mRNA expression of SKP2 sitivity and 70.0% specificity for distinguishing superficial and CKS1 on Quantitative Real-Time RT-PCR from invasive UC with a cutoff value of 4.33. CKS1 mRNA The mRNA expression level of SKP2 and CKS1 increased expression had 54.5% sensitivity and 84.8% specificity with with the immunohistochemical score (negative, partial pos- a cutoff value of 1.46. The expression level of SKP2 and itive and diffuse positive SKP2 3.87 Ϯ 3.07, 4.9 Ϯ 1.79 and CKS1 mRNA in the NUE control was 0.72 Ϯ 0.29 and 0.63 Ϯ 17.82 Ϯ 4.33, p Ͻ0.001, and CKS1, 0.38 Ϯ 0.10, 0.66 Ϯ 0.10 0.18, respectively, and there was no significant difference and 1.97 Ϯ 0.21, respectively, p Ͻ0.001, fig. 6). These results between controls and carcinoma samples. In the superficial suggest that SKP2 and CKS1 mRNA expression is directly UCs examined the expression level of SKP2 was signifi- related to protein synthesis in the absence of post-transla- cantly higher in pT1 than in pTa samples (9.38 Ϯ 2.50 vs tional modification. 1.62 Ϯ 0.55, p ϭ 0.005, fig. 2, B). The expression level of CKS1 was also higher in pT1 than in pTa samples (1.04 Ϯ Correlation of p27 Expression, 0.15 vs 0.491 Ϯ 0.10, p ϭ 0.017, fig. 2, B). The expression and SKP2 or CKS1 mRNA Expression level of SKP2 and CKS1 increased with tumor grade (G1 to Multivariate logistic regression analysis after age and G3 SKP2, 2.14 Ϯ 0.92, 9.99 Ϯ 2.53 and 15.59 Ϯ 3.48, gender adjustments revealed that SKP2 mRNA expres- p Ͻ0.001, and CKS1, 0.77 Ϯ 0.24, 0.98 Ϯ 0.15 and 1.52 Ϯ sion is a significant dependent predictor of p27 expression (p ϭ 0.021). However, there was no correlation between the expression of CKS1 mRNA and p27 expression (p ϭ 0.748, table 2).

Correlation of SKP2 and CKS1 mRNA Expression Levels, and Prognosis A total of 73 patients were available for study and 11 were lost to followup. Followup was 2 to 50 months (average 16.6). The mRNA expression level of SKP2 was classified as high in 32 patients and low in 41. The mRNA expression level of CKS1 was also classified as high in 23 patients and low in 50 when ROC curve analysis cutoff values were used. We found that high expression levels of SKP2 had a significant adverse effect on prognosis (p ϭ 0.043, fig. 7, A). Similarly patients with high CKS1 expression levels had a significantly poorer prognosis than patients with low expression FIG. 1. SKP2-p27 interaction related gene expression in UC vs levels (p ϭ 0.003, fig. 7, A). However, multivariate survival NUE. Our previous DNA microarray analysis showed that several SKP2-p27 interaction related genes were up-regulated or down- analysis demonstrated that these 2 biomarkers were not regulated in UC vs NUE samples. CDK, cyclin-dependent kinase. predictors of survival independent of pathological param- 304 INCREASED GENE EXPRESSION AND HUMAN UROTHELIAL CANCER PROGRESSION

FIG.2.SKP2 or CKS1 mRNA expression vs pathological ﬁndings on real-time RT-PCR. SKP2 and CKS1 expression increased with pathological cancer stage (A and B) and tumor grade (C). All reactions were performed in duplicate.

eters. Only 1 of 7 patients who died of UC had superficial DISCUSSION UC with CKS1 expression classified as high. The other 6 patients had invasive UC. Furthermore, none of the pa- We previously reported DNA microarray analysis results tients with low CKS1 and low SKP2 expression died of indicating that several genes, including SKP2 and CKS1, causes attributable to UC during followup (p ϭ 0.030, fig. are up-regulated in UC compared to those in NUE sam- 7, B). There was no significant correlation between bio- ples.14 Our current study of 84 UC samples revealed that the marker expression and superficial bladder cancer recur- expression of SKP2 and CKS1 was higher in invasive than in rence. superficial UC. Others reported that CKS1 expression, INCREASED GENE EXPRESSION AND HUMAN UROTHELIAL CANCER PROGRESSION 305

tumor stage or grade. Furthermore, p27 expression was significantly down-regulated in tumors of a higher stage or grade. The down-regulation of p27 and its inverse correlation with poor prognosis in patients with invasive UC was attributed to the up-regulation of SKP2 and CKS1.16 To our knowledge we provide the first documentation that SKP2 and CKS1 expression is associated with human UC stage and grade. CKS1 was identified as an essential cofactor for efficient SKP2 dependent p27 ubiquitination.3–5 In vitro the critical role of CKS1 in the targeting of p27 for efficient degradation by SKP2 was demonstrated by the lack of p27 ubiquitination in its absence.3 In vivo experiments in CKS1 knockout mice revealed the slow proliferation and accumulation of p27.4 However, to our knowledge there are no previous reports of the role of CKS1 and SKP2 in human cancer. We found that,

FIG. 3. There was significant positive correlation between mRNA although the mRNA expression of SKP2 and CKS1 was expression patterns of SKP2 and CKS1 (rank test Spearman’s cor- up-regulated in invasive vs superficial UC, SKP2 was the relation coefficient r ϭ 0.566, p Ͻ0.001). only significant dependent predictor that inversely regulated p27 expression. In addition, tumor stage and grade which is essential for the efficient SKP2 dependent degra- more closely correlated with SKP2 than with CKS1 expres- dation of p27, is increased in aggressive cancers, strongly sion. Our findings imply strongly that SKP2 has a major role correlated with SKP2 expression and inversely correlated in the regulation of p27 degradation and CKS1 has a sup- with p27 levels.9–12 In progressive-type gastric,7 colorec- porting role for SKP2 in human UC. 18 tal,8,9 oral squamous cell10 and nonsmall cell lung cancer11 After the consensus of the 2004 WHO classification it the expression levels of SKP2 and CKS1 were up-regulated, seems to be the current consensus that major molecular while p27 expression was down-regulated. Similarly immu- differences exist between noninvasive papillary tumor (pTa) nohistochemical studies showed that p27 expression was and superficially invasive carcinoma (pT1), which used to be 19 down-regulated in bladder UC.16 classified as superficial tumor. We also found a significant Langner et al, who subjected 53 upper urinary tract UCs difference in SKP2 and CKS1 expression between pTa and to immunohistochemical study, found a positive correlation pT1 samples, supporting the consensus. between SKP2 expression and tumor stage or grade.17 How- There was a significant positive correlation between ever, they did not examine CKS1 expression and their sam- SKP2 and CKS1 mRNA expression, suggesting a common ples did not include bladder UC. Consistent with previous regulating mechanism for SKP2 and CKS1 expression. reports, our study of 84 human UCs, including 71 bladder Studies are under way at our laboratory to test this hypoth- UCs, demonstrated a significant positive correlation be- esis. Decreased p27 expression may be attributable to post- tween the mRNA expression level of SKP2 and CKS1, and transcriptional alterations rather than to decreased mRNA

FIG. 4. Invasive human urothelial carcinoma showed strong diffuse nuclear staining for SKP2 and CKS1, while it was negative for p27 staining. In contrast, low SKP2 and CKS1, and high p27 staining was observed in superﬁcial carcinoma. Reduced from ϫ200. 306 INCREASED GENE EXPRESSION AND HUMAN UROTHELIAL CANCER PROGRESSION

FIG. 5. Immunohistochemical vs pathological findings. Frequency of high staining for p27 decreased with pathological cancer stage and grade (A and B). In contrast, frequency of positive staining for SKP2 and CKS1 increased with pathological cancer stage and grade (C and D). expression.11,20 Inui et al, who compared normal tissues and with a poor outcome. Currently to our knowledge there are tissues from human nonsmall cell lung carcinomas, reported no other reports demonstrating a significant correlation be- that p27 mRNA expression levels were not different.11 The tween SKP2 and CKS1 expression, and prognosis in human results of our microarray analysis are consistent with their UC. Interestingly only 1 of the 7 patients who died of UC in findings. We found no difference between UC and normal our series had superficial UC with CKS1 over expression. bladder tissues with respect to the average mRNA expres- This suggests that patients with over expressed SKP2 or sion level of p27.14 In this study there was no significant CKS1 may have a poor prognosis, although their pathologi- difference in the expression level of SKP2 and CKS1 mRNA cal diagnosis is superficial UC. In this study we could not between controls and carcinoma samples, possibly because determine whether these biomarkers were superior to the number of our control samples (5) was too small. pathological parameters for predicting the prognosis of hu- Others reported that SKP2 and CKS1 over expression man UC. With respect to the recurrence of superficial BT was associated with poor survival in patients with gastric,7 there was no significant correlation between SKP2 or CKS1 colorectal9 and oral squamous cell carcinoma,10 and p27 expression and recurrence. We speculate that superficial expression inversely correlated with a poor prognosis. Con- tumor recurrence might not always be affected by biomarker sistent with their results, our study demonstrated that expression when the tumor is completely resected at a trans- SKP2 and CKS1 over expression significantly correlated urethral prostate resection procedure. Longer followup in a larger number of samples is needed to elucidate the usefulness of these biomarkers for predicting the aggressiveness and prognosis of human UC.

CONCLUSIONS To our knowledge we report the ﬁrst demonstration that SKP2 and CKS1 expression correlates with tumor stage, grade and prognosis in human UC. Our results suggest that

TABLE 2. Multivariate logistic regression analysis of P27 expression in patients with UC, adjusted by age and gender SKP2 mRNA CKS1 mRNA

Coefﬁcient 0.486 0.193 SE 0.211 0.602 Chi-square test 5.304 0.103 FIG. 6. Immunohistochemical score vs mRNA expression of SKP2 and CKS1 on quantitative real-time RT-PCR. SKP2 and CKS1 p Value 0.021 0.748 HR 0.615 0.824 mRNA expression showed stepwise increase with increasing immu- 95% CI 0.407–0.930 0.253–2.683 nohistochemical score. INCREASED GENE EXPRESSION AND HUMAN UROTHELIAL CANCER PROGRESSION 307

4. Spruck C, Strohmaier H, Watson M, Smith AP, Ryan A, Krek TW et al: A CDK-independent function of mammalian Cks1: Targeting of SCF (Skp2) to the CDK inhibitor p27Kip1. Mol Cell 2001; 7: 639. 5. Bartek J and Lukas J: p27 destruction: Cks1 pulls the trigger. Nat Cell Biol 2001; 3: E95. 6. Shigemasa K, Gu L, O’Brien TJ and Ohama K: Skp2 overexpression is a prognostic factor in patients with ovarian adenocarcinoma. Clin Cancer Res 2003; 9: 1756. 7. Masuda TA, Inoue H, Nishida K, Sonoda H, Yoshikawa Y, Kakeji Y et al: Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma. Clin Cancer Res 2003; 9: 5693. 8. Hershko D, Bornstein G, Ben-Izhak O, Carrano A, Pagano M, Krausz MM et al: Inverse relation between levels of p27 (Kip1) and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas. Cancer 2001; 91: 1745. 9. Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I and Hershko DD: The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer FIG. 7. Kaplan-Meier cause specific survival curves of patients with 2005; 103: 1336. UC after treatment, grouped according to high or low SKP2 or CKS1 10. Kitajima S, Kudo Y, Ogawa I, Bashir T, Kitagawa M, Miyauchi mRNA expression, as determined by ROC curve analysis cutoff value (A). SKP2 and CSK1 expression pattern vs patient prognosis M et al: Role of Cks1 overexpression in oral squamous cell (B). During followup no cancer deaths occurred in patient with low carcinomas: cooperation with Skp2 in promoting p27 deg- CKS1 and low SKP2 expression. NED, no disease evidence. radation. Am J Pathol 2004; 165: 2147. 11. Inui N, Kitagawa K, Miwa S, Hattori T, Chida K, Nakamura H et al: High expression of Cks1 in human non-small cell lung SKP2 has a major role in the regulation of p27 degrada- carcinomas. Biochem Biophys Res Commun 2003; 303: 978. tion and CKS1 has a supporting role for SKP2 function in 12. Shapira M, Ben-Izhak O, Bishara B, Futerman B, Minkov I, human UC. Krausz MM et al: Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma. Cancer 2004; 100: 1615. ACKNOWLEDGMENTS 13. Sanchez-Carbayo M, Socci ND, Lozano JJ, Li W, Charytonowicz M. Miyazaki provided laboratory assistance. E, Belbin TJ et al: Gene discovery in bladder cancer progression using cDNA microarrays. Am J Pathol 2003; 163: 505. 14. Kawakami K, Enokida H, Tachiwada T, Gotanda T, Tsuneyoshi K, Arai M et al: Identification of differentially expressed Abbreviations and Acronyms genes in human bladder cancer through genome-wide gene CKS1 ϭ cyclin-dependent kinase subunit 1 expression profiling. Oncol Rep 2006; 16: 521. GAPDH ϭ glyceraldehyde-3-phosphate 15. Sobin LH and Wittekind C: TNM Classification of Malignant dehydrogenase Tumours, 6th ed. International Union Against Cancer NUE ϭ normal urothelial epithelium (UICC). New York: Wiley-Liss Publications 2002. PCR ϭ polymerase chain reaction 16. Sgambato A, Migaldi M, Faraglia B, Garagnani L, Romano G, RT ϭ reverse transcriptase De Gaetani C et al: Loss of P27Kip1 expression correlates SKP2 ϭ S-phase kinase-associated protein 2 with tumor grade and with reduced disease-free survival in UC ϭ urothelial carcinoma primary superficial bladder cancers. Cancer Res 1999; 59: 3245. 17. Langner C, von Wasielewski R, Ratschek M, Rehak P and REFERENCES Zigeuner R: Expression of p27 and its ubiquitin ligase subunit Skp2 in upper urinary tract transitional cell carci- 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al: noma. Urology 2004; 64: 611. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106. 18. Eble JN, Sauter G, Epstein JI and Sesterhenn IAE: Pathology 2. Holmang S, Hedelin, H. Anderstrom C and Johansson SL: The and genetics of tumours of the urinary system and male relationship among multiple recurrences, progression and genital organs. In: World Health Organization Classifica- prognosis of patients with stages Ta and T1 transitional cell tion of Tumours. Lyon: IARC Press 2004; p 93. cancer of the bladder followed for at least 20 years. J Urol 19. Nieder AM and Soloway MS: Eliminate the term “superficial” 1995; 153: 1823. bladder cancer. J Urol 2006; 175: 417. 3. Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M 20. Nakayama KI, Hatakeyama S and Nakayama K: Regulation et al: The cell-cycle regulatory protein Cks1 is required for of the cell cycle at the G1-S transition by proteolysis of SCF(Skp2)-mediated ubiquitinylation of p27. Nat Cell Biol cyclin E and p27Kip1. Biochem Biophys Res Commun 2001; 3: 321. 2001; 282: 853. Interstitial Photodynamic Therapy of the Canine Prostate Using Intra-Arterial Administration of Photosensitizer and Computerized Pulsed Light Delivery

Zhengwen Xiao, Dwayne Dickey, Richard J. Owen, John Tulip and Ronald Moore*,† From the Departments of Oncology (ZX, RM), Electric and Computer Engineering (DD, JT), Diagnostic Imaging (RJO) and Surgery (RM), University of Alberta, Edmonton, Alberta, Canada

Purpose: We determined the feasibility of complete treatment of the canine prostate and long-term effectiveness of interstitial photodynamic therapy using the intra-arterial photosensitizer QLT0074 (benzoporphyrin derivative 1,3-diene C,D-diethylene glycol ester A ring) (QLT, Vancouver, British Columbia, Canada) administration and pulsed light delivery. Materials and Methods: The prostate gland of 11 dogs were infused with QLT0074 via the prostatovesical arteries (2 mg drug per artery bilaterally) under fluoroscopic guidance. Immediately following infusion the prostate was surgically exposed and 7 optical fibers with 1.5 cm cylindrical diffusers in after loading sheaths were inserted into the prostate through a template. Light was delivered sequentially to the optic fibers via a computer driven switch system. One dog was sacrificed 6 days after photodynamic therapy to assess acute tissue effects. The other 10 dogs were monitored for clinical tolerance and urinary function, and sacrificed at between 3 and 11 months. Prostate specimens were examined microscopically to evaluate long-term tissue reactions. Results: Comprehensive destruction of the prostate was noted in the acute dog. Except for urinary retention and mild hematuria no other perioperative complications were observed in the chronic dogs. Urodynamic examination did not reveal deleterious bladder and urethral function. Average prostate volume decreased 71% at 3 months and 56% after 6 months (p ϭ 0.007 and 0.014, respectively). Microscopic evaluation revealed prostate glandular epithelial atrophy, stromal fibrosis and mononuclear cell infiltration. Conclusions: Interstitial photodynamic therapy using intra-arterial QLT0074 and pulsed light delivery is safe and feasible for comprehensive destruction of the canine prostate. Clinical trials are required to confirm it for managing prostate diseases. Key Words: prostate, drug delivery systems, photochemotherapy, dogs, QLT0074

rostate cancer is the most common malignancy in men oxygen, limiting further phototoxicity. However, this PDT in the United States.1 Current therapeutic modalities induced hypoxic phase is reversible in its early stage by P for localized prostate cancer are associated with sig- fractionated illumination.5 Recently a novel pulsed light nificant morbidity, such as sexual and urinary dysfunction.2 delivery system was used to treat rat prostate tumors, which PDT is a minimally invasive treatment that may be used in showed that pulsed light delivery was more effective than benign and malignant prostate diseases. PDT is a dual se- continuous illumination in interstitial PDT of prostate tu- lective experimental treatment modality using light of a mors.6 We determined 1) if comprehensive treatment of the specific wavelength to locally activate a photosensitizer ac- entire prostate could be achieved by interstitial PDT with cumulated in the target tissue, leading to photochemical intra-arterial (prostatovesical artery) drug delivery and destruction of the target tissue, even radiation and drug switched (pulsed) interstitial light delivery, 2) long-term resistant cells.3,4 However, a major obstacle to clinical PDT clinical tolerance and PDT effectiveness, and 3) treatment of the prostate is damage to adjacent structures, especially related toxicity and side effects to adjacent tissues. the rectum.3 To avoid adjacent normal tissue damage the photosensitizer and light must be delivered selectively to MATERIALS AND METHODS treat the target tissue/organ. To date continuous illumination has been applied in PDT, which easily depletes tissue Photosensitizer Lipid formulated QLT0074 was reconstituted with sterile water to 2 mg drug per ml immediately before use. QLT0074 Submitted for publication October 19, 2006. is a member of the same chemical class as the approved Study received University Animal Care Committee approval. 7 Supported by the National Cancer Institute of Canada (NCIC), clinical photosensitizer verteporfin. Alberta Cancer Board, Alberta Heritage Foundation for Medical Research and QuestPharmatech. * Correspondence: Departments of Surgery and Oncology, Univer- Animals, Angiography and Drug Delivery sity of Alberta, 2D2 Walter Mackenzie Health Sciences Centre, Male mongrel dogs and purposely bred beagles were used 8440-112 St., Edmonton, Alberta, Canada T6G 2B7 (telephone: 780- under a protocol approved by the University Animal Care 407-6330; FAX: 780-407-6331; e-mail: [email protected]). † Financial interest and/or other relationship with QuestPharma- Committee. All dogs were maintained according to guide- tech. lines of the Canadian Council on Animal Care. Surgical

0022-5347/07/1781-0308/0 308 Vol. 178, 308-313, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.008 INTERSTITIAL PHOTODYNAMIC THERAPY OF CANINE PROSTATE 309 procedures were performed using standard surgical tech- for signs of discomfort and complications. In particular fluid nique. intake, urination and defecation were carefully monitored. A total of 11 dogs older than 2 years with a mature Prophylactic antibiotics (cefazoline 50 mg/kg intramuscu- prostate were used in this study. Fasting dogs were anes- larly) and analgesic (buprenorphine 0.05 mg/kg subcutane- thetized with acepromazine (0.1 mg/kg intravenously) and ously) were given as indicated. Catheterization was per- maintained with 2% isoflurane inhalation in oxygen via an formed when residual urine was evident. endotracheal tube. All dogs were monitored by pulse oxim- etry. The animals were positioned supine on a radiolucent Urodynamic Studies surgical table. The lower abdomen and groin hair was To examine for functional changes of the bladder and ure- shaved and the skin was prepared with povidone-iodine. The thral sphincter CMG and UPP were performed before PDT right common femoral artery was percutaneously cannu- and then 3 to 11 months after PDT using a clinical urody- lated using a standard Seldinger technique. A 5Fr vascular namic system (Laborie Medical Technologies, Brossard, sheath was placed and a 5Fr Rim catheter (Cook Canada, Quebec, Canada). For CMG a 6Fr dual lumen catheter (Life- Stouffville, Ontario, Canada) was used to selectively cannu- Tech, Stafford, Texas) was inserted into the bladder of an late 1 internal iliac artery. A 3Fr Rapid Transit™ microcath- anesthetized dog and the bladder was emptied by drainage eter and 0.018-inch Transend® Platinum guidewire were with a syringe. The filling port of the catheter was connected then used to cannulate the ipsilateral prostatovesical artery, to a computerized pump, which filled the bladder at 20 ml which is a visceral branch of the internal iliac artery. The per minute with 0.9% normal saline containing 10% contrast procedure was done under fluoroscopic guidance. After the medium. CMG was recorded by a computer with UDS Client prostatovesical artery was cannulated with the 3Fr micro- 1 software (Laborie Medical Technologies, Mississauga, On- catheter 1 ml photosensitizer (liposomal QLT0074, 2 mg) tario, Canada). Maximal bladder volume was logged when was injected. Subsequently the contralateral internal iliac leakage around the catheter was first noted (leak point). artery and prostatovesical artery were cannulated using a Bladder pressure was determined by subtracting abdominal similar technique and another 1 ml QLT0074 was infused. pressure measured simultaneously by a rectal tube. Follow- After drug infusion the catheter and sheath were removed ing CMG the bladder was emptied again. UPP was then and the right femoral artery was compressed for 10 minutes tested by a pull-out technique while monitoring the pressure to prevent bleeding. profile, which was recorded by a computer. All measurements were repeated 3 times. Vesicoureteral reflux was monitored by fluoroscopy. Interstitial PDT With Pulsed Light Delivery Immediately after intra-arterial infusion of liposomal QLT0074 a lower abdomen incision was made to expose the Pathological Study prostate anterior surface. The prostatic dimensions were All dogs were sacrificed the day of urodynamic studies 3 to measured and volume (v) was calculated using the formula, 11 months after PDT as planned except the initial mongrel v ϭ ␲/6 ϫ transverse diameter ϫ anteroposterior ϫ cepha- dog, which was sacrificed 6 days after PDT and underwent locaudal diameter. Laser light was delivered through 7 optic necropsy. At necropsy the prostate was dissected carefully fibers with 1.5 cm cylindrical light diffusing tips (Medlight®) from the rectum and surrounding connective tissue while placed in 7 after loading needle sheaths. The after loading recording any evidence of adhesion or gross injury to these needles were inserted in a hexagonal pattern through a tissues. The bladder, prostate and membranous urethra template placed on the anterior surface of the prostate and were removed en bloc. Prostate size was measured and the passed in an anteroposterior direction until the tip could be volume was calculated and compared with baseline volume felt on the posterior surface. The needle metal trocars were before PDT. The rectum was excised and cut into anterior removed and the optic fibers were inserted into the sheaths. and posterior parts. All tissues were fixed in 10% neutral The fibers were spaced 8 to 10 mm apart depending on buffered formalin. The prostates were serially divided trans- prostate size and 5 mm or greater away from the capsule versely in thin blocks. All tissues were embedded in paraffin, edge. Two diode lasers (Optical Fiber Systems, Chelmsford, sectioned as whole mounts and stained with hematoxylin Massachusetts) were used to generate red light of 690 nm and eosin for histological examination by light microscopy. wavelength. Light delivery was controlled by a computer driven switch (Model LT3000) with multiple light outputs Statistical Analysis (LIGHTech Fiberoptics, San Leandro, California). Light The 2-tailed Student t test (Prism®) was applied to compare launched from 2 diode lasers was first transmitted to the prostate volume changes before and after PDT with p Ͻ0.05 switch by fiberoptic cables and then delivered to the 7 cylin- considered significant. drical diffusing fibers in cyclic fashion. Two at a time the 7 fibers were sequentially illuminated for 100 seconds each. RESULTS Pulsed light delivery was used to allow an iterative light dosing and real-time feedback, as in previous studies.6 The Clinical Tolerance and Toxicity total accumulative light dose delivered to the prostate was Animals tolerated well the angiographic procedure (selective 900 J with a maximal fiber output of 150 mW or less (fluence drug delivery) and interstitial PDT of the prostate. After rate 100 mW/cm or less). recovering from the surgical procedures all dogs could spon- After PDT the incision was closed by absorbable polygly- taneously void and defecate in the first few days. However, colic sutures and a cone-shaped collar was applied to prevent half of the dogs were in urinary retention, which started 5 to the dogs from licking the incision. Animals were housed in 7 days after PDT, presumably due to prostate swelling, and warm cages with subdued lighting and observed carefully they required intermittent catheterization. The initial dog (a 310 INTERSTITIAL PHOTODYNAMIC THERAPY OF CANINE PROSTATE mongrel) was sacrificed 6 days after PDT to examine the acute tissue effect of PDT. At necropsy the whole prostate appeared necrotic and dark brown with marked swelling. There was hemorrhage noted outside of the left posterior capsule of the prostate. This bleeding outside of the prostate was thought to be secondary to a needle puncture injury as opposed to a PDT effect. Microscopic findings are detailed. In chronic dogs no hemorrhagic necrosis was noted outside of the prostate and all surrounding structures appeared healthy.

Urodynamic Testing There was a large range in bladder volume before PDT among the beagle dogs (60 to 300 ml, mean 180). After PDT irritating bladder symptoms, ie frequency and dribbling, and urinary retention were the common complications observed. These complications recovered within 4 weeks. All animals eventually voided with a strong stream at normal FIG. 2. UPP of dog before and after PDT. a, typical pressure profile intervals. Normal bladder compliance and volume were not from bladder (1), prostatic urethra (2), membranous urethra (3) and debilitated after PDT (fig. 1). Urethral sphincter function penile urethra (4) before PDT. b, similar profile 6 months after PDT. remained normal (fig. 2). No vesicoureteral reflux was observed. demonstrate the observed pathological patterns of the pros- Pathology Findings tate after PDT with time. Figure 4, a shows that shortly Three to 11 months after interstitial PDT of the prostate after PDT the whole prostate appeared evidently swollen fibrous scar tissue adhesion to the ventral surface of the with subcapsular hemorrhage and comprehensive damage prostate was the only gross pathological finding outside of (fig. 3). The prostate urethra appeared partly damaged with the prostate. This change may have resulted from surgical a patent lumen (circled area, fig. 4, a). The juxtaposed rectal exposure. Compared with that before PDT prostate volumes wall did not show any damage (fig. 4, d). Three months after were significantly reduced after PDT by 71% at 3 to 4 PDT the prostate parenchyma and stroma had shrunken months, while a 56% reduction was noted at 6 to 11 months dramatically, such that the prostatic urethra appeared widely (see table). Volume changes were in accordance with pros- open (fig. 4, b). The urothelium was completely regenerated at tate histological changes. Six days after PDT the prostate of this time (fig. 4, e). Six months after PDT histological prostate the mongrel dog showed comprehensive destruction, includ- changes were similar to those at 3 months except for more ing hemorrhagic and coagulative necrosis, glandular cell glandular tissue regeneration (fig. 4, c). Microscopically the degeneration with sloughing, stromal edema and vascular predominant histological findings after PDT were glandular stasis (fig. 3). Figure 4 shows whole mount, typical trans- atrophy and cystic formation, stromal fibrosis and mononu- verse sections of 3 prostates 6 days, 3 months and 6 months clear cell infiltration (fig. 5, a to c). However, the proportion of after interstitial PDT. These whole mount sections clearly glandular tissue increased with time.

DISCUSSION The increasing prevalence of prostate speciﬁc antigen based screening for prostate cancer has facilitated early diagnosis and treatment of this tumor, resulting in age and stage migration of this disease. Patients in this group have high motivation to preserve sexual function and avoid later complications. Therefore, brachytherapy and cryotherapy have been increasingly used as a primary treatment for localized prostate can-

Prostate volume before, and 3 to 11 months after interstitial PDT of canine prostate Pre-PDT 3–4 Mos Pre-PDT 6–11 Mos

Prostate size (cm3) 17.95 4.77 11.04 2.8 9.42 3.35 7.85 5.65 10.99 2.64 9.42 6.96 6.54 2.86 10.59 3.77 10.99 2.8 10.91 2.65 Ϯ Ϯ Ϯ Ϯ Ϯ FIG. 1. CMG in dog before and after PDT of prostate. a, before PDT Mean SD 11.18 4.2 3.28 0.87 9.97 1.34 4.36 1.88 prostate size bladder pressure gradually increased with continuous ﬁlling of sa- 3 line. First urgency (leaking around catheter) was noted when blad- (cm ) % Vol change Ϫ71 Ϫ56 der volume reached 178 ml at pressure of 40 cm H2O. b, similar p Value 0.0147 0.0147 result 3 months after PDT. INTERSTITIAL PHOTODYNAMIC THERAPY OF CANINE PROSTATE 311

FIG. 3. Histological section of dog prostate 6 days after PDT shows FIG. 5. Histological sections of canine prostates. a, 3 months after hemorrhagic necrosis (h), and comprehensive damage to glandular PDT glandular atrophy with cystic change (cy), stromal fibrosis (f) tissue (g) and stroma. H & E. Bar represents 400 ␮m. and inflammatory cell infiltration (arrows) were predominant findings. Viable glandular tissue (g) was scattered in atrophic tissues. b, 6 months after PDT there were changes similar to those at 3 months cers.8,9 However, all available standard treatments have a except for larger proportion of glandular tissues. c, 11 months after 10 PDT there were changes similar to those at 3 months except for significant adverse impact on patient quality of life. larger proportion of glandular tissues. d, normal control canine Photodynamic therapy, which is a dual selective and min- prostate section. H & E. Bar indicates 400 ␮m. imally invasive local therapy, has been investigated preclini- cally and clinically as an alternative therapy for prostate 3,4 cancer. Traditionally photosensitizers are administered the current study we directly delivered QLT0074, an ana- intravenously, which produces a low prostate-to-rectum logue of Food and Drug Administration approved vertepor- drug ratio. This may be attributable to rectal wall damage fin, to the prostate via prostatovesical arteries. This new 3,4 from PDT of the prostate, as reported in the literature. In drug delivery strategy increased targeting selectivity by decreasing drug accumulation in tissues surrounding the prostate and it also increased drug availability by avoiding first pass loss of the photosensitizer during circulation.11 Fur- thermore, light illumination can be performed immediately following drug administration. Another important issue in PDT is the light delivery strategy. Since prostate cancer is usually multifocal, the entire prostate must be effectively treated with multiple fibers implanted in the tissue for accurate and uniform light dosimetry. Prostate tissue optics, such as light attenuation and scattering coefficients, have been established for dogs and humans.12–14 However, in-depth preclinical studies are required for more accurate light and drug delivery, and real-time dosimetry for monitoring alterations of light fluence during PDT. Such studies would provide the ability to detect photosensitizer concentration and predict end points such as fluence changes with deoxygenated hemoglobin. These studies can be done using our computerized switch system and they are under way.15 In addition, PDT rapidly deprives tissues of oxygen.5 Oxygen preserving strategies, FIG. 4. Pathological findings in canine prostates followed to 6 such as pulsed light delivery, may overcome this self-limi- months as well as rectum and prostatic urethra. a, in whole mount tation via tissue re-oxygenation during PDT.5,6 We also section through seminal colliculus (asterisk) of dog prostate 6 days after PDT entire prostate, including urethra (circled area) and cap- adapted techniques from brachytherapy to place 7 parallel sule, show damage (fig. 3). Prostate volume increased due to tissue fibers through a template in an intent to deliver effective edema. b, whole mount section of canine prostate 3 months after light dose to the entire prostate. Longer wavelength red PDT shows that prostate volume decreased with urethral dilation (circled area). Viable glandular epithelium (g) was scattered in light (690 nm) has greater tissue penetration, which is a atrophic tissues. c, whole mount section of dog prostate 6 months desirable property for treating the large prostate volume. after PDT reveals more glandular tissue than at 3 months. We chose an open transabdominal approach in the dog d, section of anterior rectal wall demonstrates normal structures at model rather than the transperineal method in patients day 6 after PDT. e, prostatic urethra (u) epithelium was completely regenerated 3 months after PDT. H & E. Bars represent 1.0 (a to c) because of limited perineal access to the canine prostate. and 400 (d and e) ␮m. Our results in the canine model demonstrate that intersti- 312 INTERSTITIAL PHOTODYNAMIC THERAPY OF CANINE PROSTATE tial PDT with these new light and drug delivery strategies is rectal toxicity and bladder toxicity seen with brachytherapy effective and safe, and it may be used as an alternative and external beam radiotherapy.19 Clinical studies for opti- treatment for prostate diseases. mizing selective strategies with PDT are now needed. The acute PDT damage to the prostate seems comprehensive, although some glandular epithelial cells appeared viable in areas between fibers (figs. 3 and 4, a). In initial clinical CONCLUSIONS trials of prostate cancers treated with PDT early computer- Interstitial PDT of the canine prostate using intra-artery ized tomography and magnetic resonance imaging of the 3 drug delivery and pulsed light delivery is safe and effective. prostate also documented comprehensive tissue damage. The acute histological change is comprehensive hemorrhagic Three months after PDT the majority of prostate glands and coagulative necrosis of the prostate. The long-term bio- appeared atrophic with stromal fibrosis and mononuclear logical effect is characterized by glandular atrophy and stro- cell infiltration, although regeneration of viable glandular mal fibrosis with prostate shrinkage. Urodynamic study did epithelium commenced (fig. 5, a). This regeneration may be not detect any debilitated bladder and urethral function. exaggerated by the volume reduction of the prostate. The These results suggest that clinical trials of PDT for benign prostate volume decreases significantly with complete ure- prostatic hyperplasia and probably for prostate cancer thral epithelial regeneration (see table and fig. 4). Six to 11 should be done to determine if multiple treatments can months after PDT glandular atrophy and inflammatory cell destroy all glandular cells. infiltration are still evident. However, glandular tissue re- growth appears more evident as prostate volume starts to increase (figs. 4 and 5). Similar findings were reported in ACKNOWLEDGMENTS studies of intravenous photosensitizer administration.4,16 Selman et al previously reported that after SnET2 mediated QLT0074 was provided by QLT, Inc., Vancouver. PDT more viable glandular tissue was observed in animals sacrificed 3 months compared to 48 hours or 3 weeks after treatment.4 These data suggest that, although interstitial Abbreviations and Acronyms PDT may represent a satisfactory new treatment modality CMG ϭ cystometrography for benign prostatic hyperplasia, as a cancer therapy multi- PDT ϭ photodynamic therapy ple treatment sessions may be needed to treat persistent QLT0074 ϭ benzoporphyrin derivative 1,3-diene glandular tissue (carcinoma or adenoma). Furthermore, re- C,D-diethylene glycol ester A ring sults obtained in a canine model of normal prostate tissue do UPP ϭ urethral pressure profile not necessarily predict efficacy for human prostate cancer. Unfortunately no good large animal prostate cancer model exists for PDT studies. However, prostate cancer should be REFERENCES at least as sensitive, if not more so, as normal prostate epithelium to PDT based on preclinical studies in rodent 1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A tumor models.17 et al: Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10. Although the toxicity of interstitial PDT of the canine 2. Potosky AL, Davis WW, Hoffman RM, Stanford JL, Stephenson RA, Penson DF et al: Five-year outcomes after prostatectomy prostate using these new drug and light delivery techniques or radiotherapy for prostate cancer: the prostate cancer out- was primarily assessed by clinical signs and symptoms, and comes study. J Natl Cancer Inst 2004; 96: 1358. urodynamic testing, there was no histological evidence of 3. Nathan TR, Whitelaw BE, Chang SC, Lees WR, Ripley PM, injury to the bladder, urethra or rectum. The most common Payne H et al: Photodynamic therapy for prostate cancer acute side effects were voiding difficulties, including fre- recurrence after radiotherapy: a phase I study. J Urol 2002; quency, retention and minor hematuria. These symptoms 168: 1427. lasted for 5 to 10 days and they appeared to be related to 4. Selman SH, Albrecht D, Keck RW, Brennan P and Kondo S: prostate edema and limited urethral damage of the prostatic Studies of tin ethyl etiopurpurin photodynamic therapy of portion. Half of the dogs (5 of 10) needed daily catheteriza- the canine prostate. J Urol 2001; 165: 1795. tion to empty the bladder for 5 to 10 days after PDT. Similar 5. Tromberg BJ, Orenstein A, Kimel S, Barker SJ, Hyatt J, Nelson JS et al: In vivo tumor oxygen tension measure- problems were previously reported by others.4,16 No severe ments for the evaluation of the efficiency of photodynamic complications were noted, such as rectal toxicity/fistulas and therapy. Photochem Photobiol 1990; 52: 375. retroperitoneal infection, which have been reported in studies 6. Xiao Z, Halls S, Dickey D, Partridge K, Tulip J and Moore RB: 16 using traditional PDT. Long-term followup of the dogs Pulsed light delivery is more effective than continuous light showed normal bladder compliance and urethral sphincter delivery in interstitial photodynamic therapy of the Dun- function, as evaluated clinically and by urodynamic testing. ning Prostate carcinomas. Presented at World Congress of The limited urethral epithelial injury appears to completely International Photodynamic Association, Munich, Ger- regenerate with dilated prostatic urethra by 3 months. many, June 22–25, 2005. Clinically the prostatovesical arteries should be readily 7. Sternberg E and Dolphin D: Pyrrolic photosensitizers. Curr catheterized using the techniques described in this study Med Chem 1996; 3: 239. 8. Cooperberg MR, Lubeck DP, Meng MV, Mehta SS and Carroll and previously,11 especially in younger patients. Previously PR: The changing face of low-risk prostate cancer: trends in intra-arterial chemotherapy for prostate and bladder cancer clinical presentation and primary management. J Clin On- was described by infusing drugs via the hypogastric ar- col 2004; 22: 2141. 18 tery. This drug delivery method provides a high therapeu- 9. Touma NJ, Izawa JI and Chin JL: Current status of local tic ratio between the target organ and surrounding struc- salvage therapies following radiation failure for prostate tures. Like cryotherapy, PDT does not carry the late risks of cancer. J Urol 2005; 173: 373. INTERSTITIAL PHOTODYNAMIC THERAPY OF CANINE PROSTATE 313

10. Wei JT, Dunn RL, Sandler HM, McLaughlin PW, Montie JE, 15. Dickey DJ, Partridge K, Moore RB and Tulip J: Light dosim- Litwin MS et al: Comprehensive comparison of health-related etry for multiple cylindrical diffusing sources for use in quality of life after contemporary therapies for localized pros- photodynamic therapy. Phys Med Biol 2004; 49: 3197. tate cancer. J Clin Oncol 2002; 20: 557. 16. Chang S, Buonaccorsi G, MacRobert A and Bown SG: Intersti- 11. Moore RB, Xiao Z, Owen R, Ashforth R, Dickey D and Tulip J: tial and transurethral photodynamic therapy of the canine Selective intra-arterial drug delivery for photodynamic prostate using meso-tetra (hydroxyphenyl) chlorin. Int J therapy of the canine prostate. Presented at annual meet- Cancer 1996; 67: 555. ing of Western Section, American Urological Association, 17. Xiao Z, Tamimi Y, Brown K, Tulip J and Moore R: Interstitial Maui, Hawaii, October 22–27, 2006. photodynamic therapy in subcutaneously implanted urologic tumors in rats after intravenous administration of 12. Chen Q and Hetzel FW: Laser dosimetry studies in the pros- 5-aminolevulinic acid. Urol Oncol 2002; 7: 125. tate. J Clin Laser Med Surg 1998; 16: 9. 18. Kuriyama M, Takeuchi T, Takahashi Y, Takeda A, Ishihara S, 13. Chen Q, Wilson BC, Shetty SD, Patterson MS, Cerny JC and Ozeki S et al: Intra-arterial chemotherapy using a reservoir Hetzel FW: Changes in in vivo optical properties and light for endocrine-refractory prostate cancer. Cancer Chemo- distribution in normal canine prostate during photody- ther Phamacol 1994; 35: S27. namic therapy. Radiat Res 1997; 147: 86. 19. Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak 14. Barajas O, Ballangrud AM, Miller GG, Moore RB and Tulip J: H, Mens JW et al: Acute and late complications after ra- Monte Carlo modeling of angular radiance in tissue phan- diotherapy for prostate cancer: results of a multicenter toms and human prostate: PDT light dosimetry. Phys Med randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Biol 1997; 42: 1675. Oncol Biol Phys 2005; 61: 1019. Enhanced Kidney Stone Fragmentation by Short Delay Tandem Conventional and Modiﬁed Lithotriptor Shock Waves: A Numerical Analysis

Leung-Mun Tham,* Heow Pueh Lee and Chun Lu From the Institute of High Performance Computing (LMT, HPL, CL) and Department of Mechanical Engineering, National University of Singapore (HPL), Singapore

Purpose: We evaluated the effectiveness of modified lithotriptor shock waves using computer models. Materials and Methods: Finite element models were used to simulate the propagation of lithotriptor shock waves in human renal calculi in vivo. Kidney stones were assumed to be spherical, homogeneous, isotropic and linearly elastic, and immersed in a continuum fluid. Single and tandem shock wave pulses modified to intensify the collapse of cavitation bubbles near the stone surface to increase fragmentation efficiency and suppress the expansion of intraluminal bubbles for decreased vascular injury were analyzed. The effectiveness of the modified shock waves was assessed by comparing the states of loading in the renal calculi induced by these shock waves to those produced by conventional shock waves. Results: Our numerical simulations revealed that modified shock waves produced marginally lower stresses in spherical renal calculi than those produced by conventional shock waves. Tandem pulses of conventional or modified shock waves produced peak stresses in the front and back halves of the renal calculi. However, the single shock wave pulses generated significant peak stresses in only the back halves of the renal calculi. Conclusions: Our numerical simulations suggest that for direct stress wave induced fragmentation modified shock waves should be as effective as conventional shock waves for fragmenting kidney stones. Also, with a small interval of 20 microseconds between the pulses tandem pulse lithotripsy using modified or conventional shock waves could be considerably more effective than single pulse lithotripsy for fragmenting kidney stones. Key Words: kidney; kidney calculi; lithotripsy; high-energy shock waves; models, theoretical

hock wave lithotripsy is the preferred approach for treat- cavitation induced inside blood vessels, especially the expan- ing most patients with symptomatic nephrolithiasis.1 sion of intraluminal bubbles.6 S This is undoubtedly due to the extraordinary success Novel and fundamental strategies were recently proposed of the original Dornier® HM-3 Lithotriptor. Despite its tre- to improve stone comminution while simultaneously de- mendous appeal there has been growing concern about the creasing tissue injury.1,6,7 An auxiliary shock wave can be poorer performance of the newer lithotriptors. Second and introduced to intensify the collapse of cavitation bubbles third generation lithotriptors do not break stones as easily near the stone surface that are produced by the primary and they appear to cause more patient discomfort and an shock wave for increased stone damage. Also, to reduce the increased rate of side effects, eg perinephric hematomas.1–5 propensity toward vascular injury the shock wave profile Lithotriptor design has been driven to date by empirical can be modified to suppress intraluminal bubble expansion. evidence rather than by a mechanistic understanding of Combined electrohydraulic and piezoelectric shock wave 6 6 stone comminution and tissue injury.6 It is now accepted generators, hybrid ellipsoidal reflectors, and single and 7 that the disintegration of renal calculi is the result of the double piezoelectric shock wave generators have been used synergistic interaction of shock wave induced dynamic frac- to produce these modified shock waves, which have been ture, which proceeds via the nucleation, growth and coales- tested on blood vessel and kidney stone phantoms in vitro cence of microcracks in the stone, and cavitation erosion, and in animal models in vivo. which occurs following the violent collapse of bubbles near In the absence of clinical data computer simulations can the stone surface.6–8 However, there is still no agreement on provide a rapid and inexpensive means of evaluating the the relative contributions of the 2 mechanisms.9,10 Mecha- effectiveness of modified shock waves. They can also supple- nisms proposed for lithotripsy induced tissue injury are ment the knowledge required for the design of safer and shear stresses due to the distortion of shock wave fronts and more effective lithotriptors and treatment strategies. Vari- ous numerical techniques, including the finite difference time domain scheme11 and the finite element method,12 have been used to simulate the propagation of conventional Submitted for publication September 18, 2006. shock waves to predict the evolution of stress fields in kidney * Correspondence: Institute of High Performance Computing, 1 Sci- stones. ence Park Rd., No. 01-01, The Capricorn, Singapore Science Park II, Singapore 117528 (telephone: (65) 6419-1576; FAX: (65) 6419-1280; We assessed the effectiveness of modified lithotriptor e-mail: [email protected]). shock waves. We used computer models to simulate the

0022-5347/07/1781-0314/0 314 Vol. 178, 314-319, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.009 ENHANCED KIDNEY STONE FRAGMENTATION BY SHORT DELAY SHOCK WAVES 315

Finite Element Model This problem was modeled using ABAQUS/Explicit, version 6.4 (Hibbitt, Karlsson and Sorensen, Pawtucket, Rhode Island), a commercial, explicit, dynamic finite element code. In our study only the region comprising the stone and tissue immediately surrounding it were modeled. Figure 1 shows the computational domain. The stone was assumed to be spherical (diameter 10 mm) and fully submerged in water. The latter is a reasonable approximation of the in vivo environment because the acoustical properties of kidney tissue are similar to those of water.12 We chose to model calcium oxalate kidney stones because this stone type accounts for about 75% of all kidney stones.14 Stones were regarded as homogeneous, isotropic and elastic, and water was considered the continuum fluid. Table 1 lists the physical and mechanical properties of the calcium oxalate kidney stone together with the corresponding properties of kidney tissue and water.12,15 The boundary of the computational domain was made nonreflecting to prevent reflected stress waves from reentering the model. We used axisymmetric solid and axisymmetric acoustic elements to model the kidney stone and water, respectively. The mesh size of our model was about 0.1 mm. FIG. 1. Computational domain comprising kidney tissue (water) and In this study we assessed conventional shock waves and spherical kidney stone. modified shock waves based on those proposed by Zhou et al.6 Figure 2, A shows a conventional shock wave with a pressure amplitude of 47 MPa, which is analytically described by ϭ Ϫ␣t ␻ ϩ ␲ 16 propagation of single and tandem pulse conventional and the equation, ps(t) 2PAe cos ( t /3) (equation 5), ␣ modified shock waves in kidney stones to predict the stress where PA is the pressure amplitude of the shock wave, is 5 -1 fields induced. Our simulations revealed that conventional the decay constant 9.1 ϫ 10 seconds and ␻ ϭ 2␲f is the shock waves produced marginally higher stresses in spher- radial frequency with f ϭ 83.3 kHz. Figure 2, B shows a ical kidney stones than modified shock waves. Tandem modified shock wave that was produced by superposing with pulses with short intervals between conventional or modi- an interval of 4 microseconds 2 conventional shock waves fied shock waves produced peak stresses in the front and with a pressure amplitude of 47 and 21 MPa, respectively. back halves of the kidney stones. However, single shock Figure 2, C and D show tandem pulse conventional and wave pulses generated significant peak stresses in only the modified shock waves, respectively. They were produced by back halves of the stones. Our simulations suggest that for coupling together pairs of conventional or modified shock direct stress wave induced fragmentation modified shock wave pulses. Zhou et al reported that for effective cavitation waves should be as effective as conventional shock waves. erosion of a cylindrical stone phantom tandem pulses should Also, with a small interval of 20 microseconds between the be separated by an interval of about 630 microseconds, so pulses tandem pulse lithotripsy using modified or conven- that the second or auxiliary shock wave can intensify the tional shock waves could be considerably more effective than collapse of the bubbles induced by the first or primary shock 6 single pulse lithotripsy for fragmenting kidney stones. wave. Loske et al similarly found that comminution was significantly enhanced for intervals of about 250 and 400 microseconds for spherical and rectangular stone phantoms, 17 MATERIALS AND METHODS respectively. However, in this study we chose to limit this interval to only 20 microseconds to maximize interactions Mathematical Model between the pulses and minimize computer simulation run By neglecting the effects of gravitational forces and body time. In our simulations the incident shock waves were movements and taking the kidney stone to be isotropic and linearly elastic11,13 the propagation of waves in a continuum ␦␴ ␦ ϭ ␳ ␦2 ␦ 2 is governed by Newton’s Second Law, ij/ xj ( ui/ t ) (equation 1), and the generalized constitutive equation for a TABLE 1. Water, kidney tissue and kidney stone acoustic and ␴ ϭ ␭⑀ ␦ ϩ ␮⑀ mechanical properties14,18 linearly isotropic material, ij kk ij 2 ij (equation 2), ⑀ ϭ ⑀ ϩ ⑀ ϩ ⑀ ϭ ␦ ␦ ϭ where kk 11 22 33 ui/ xi and i, j 1, 2, 3 Kidney (equation 3), and ␴ represents stress, ⑀ represents strain, t Water Tissue Ca Oxalate Stone represents time, x represents the spatial coordinate, u rep- Density (kg/m3) 1,000 1,050 1,820 resents displacement, ␳ represents material density, ␦ rep- Wave speed (m/sec) 1,500 1,580 2,338 resents the Kronecker Delta Function, and ␭ and ␮ repre- Acoustic impedance 1.5 1.65 2.82–5.93 ϫ 6 2 sent the Lamé constants. From the theory of elasticity the ( 10 kg/m sec) Modulus (GPa): constants can be written as ␭ ϭ ␯E/(1 ϩ ␯)(1 Ϫ 2␯) and ␮ ϭ Bulk 2.25 — — E/2(1 ϩ ␯) (equation 4), where E and ␯ represent Young’s Young’s — — 9.05 modulus and Poisson’s ratio, respectively. Poisson’s ratio — — 0.3 316 ENHANCED KIDNEY STONE FRAGMENTATION BY SHORT DELAY SHOCK WAVES

FIG. 2. Lithotriptor shock wave models. A, single pulse conventional. B, single pulse modiﬁed. C, tandem pulse conventional. D, tandem pulse modiﬁed.

considered plane and they were applied to the point where by the 2 shock wave types appeared to be similar. Stresses the model axis of symmetry intersected the computational increased with increasing distance from the front surface of the domain surface. An artificial bulk viscosity was also speci- stone to reach a peak close to the back surface of the stone. fied in our model. We used the scattered wave formulation Stresses generated by the conventional shock wave were also option in ABAQUS/Explicit and ran the analyses using dou- marginally higher than those generated by the modified shock ble precision and automatic time incrementation. Our finite wave. Table 2 lists the salient features of the stress distri- element model was validated by comparing the stresses butions. We determined the maximum stress by calculating induced by a conventional shock wave in a photoelastic stone the stress at each point along the axis of symmetry of the phantom, as reported by Xi and Zhong,18 with those pre- stone during the course of the simulation and taking the dicted by the model. The evolution of maximum shear largest stress. Stresses were calculated along the symmetry stresses in the stone phantom was accurately captured by axis because microcracks were experimentally observed to our model. form near the longitudinal axes of cylindrical stone phantoms.18 RESULTS

Single Pulse Shock Wave Lithotripsy Tandem Pulse Shock Wave Lithotripsy Figure 3 shows the predicted maximum normal stress dis- Figure 4 shows predicted maximum normal stress distribu- tributions produced by the single conventional and modified tions produced by tandem conventional and modified shock shock waves (fig. 2, A and B). Stress distributions generated waves (fig. 2, C and D). As before, the stress distributions

␴ FIG. 3. Maximum normal stress ( 22) distribution along spherical kidney stone axis of symmetry. A, impacted by single pulse conventional shock wave (fig 2, A). B, impacted by single pulse modified shock wave (fig. 2, B). ENHANCED KIDNEY STONE FRAGMENTATION BY SHORT DELAY SHOCK WAVES 317

wave over the stone generates surface waves that propagate TABLE 2. Predicted maximum normal stresses and locations produced by various incident shock waves in in a thin layer at the stone surface. Large mechanical spherical kidney stone model stresses are produced inside the stone when these different stress waves interact constructively. This fragmentation Stone Front Half Stone Back Half mechanism can be contrasted to the squeezing mechanism ␴ ␴ Shock Waves Max 22 Distance* Max 22 Distance* Types (MPa) (mm) (MPa) (mm) postulated by Eisenmenger, in which the pressure wave in the surrounding fluid exerts a compressive hoop stress on Single pulse: 20 Conventional — — 106.6 8.3 the stone. Locations where stresses are amplified are Modified — — 99.4 8.5 likely to be prime sites where cracks that lead to fracture are Dual pulse: initiated.12 Conventional 92.8 0.4 112.4 8.4 Modified 85.9 0.3 113.7 8.2 Figure 5 shows contour plots of the predicted normal stress, ␴ , in spherical stones for the different incident * Measured from the front surface of the stone. 22 shock waves at the times when maximum normal stresses occurred in the front and back halves of the stones. Peak normal stresses developed in the back halves of the stones produced by the 2 shock wave types appeared to be similar. along the axes of symmetry for all shock wave types (fig. 5). Overall the magnitude of the stresses generated by conven- However, they were produced in the front halves of the tional shock waves was higher than that generated by mod- stones along the symmetry axes for only the tandem shock ified shock waves. While the stress distribution at the back wave pulses (fig. 5, C, i and D, i). half of the stone appeared to mirror that produced by the corresponding single shock wave pulse (figs. 4, A vs 3, A and From a comparison of the estimated longitudinal (2,587 m per second), transverse (1,383 m per second) and surface 4, B vs 3, B), an additional stress peak was generated by the 13 tandem shock wave pulses close to the front surface of the (1,281 m per second) wave speeds for the stone material we stone. As expected, tandem shock wave pulses produced can infer that the maximum normal stresses produced in the higher stress levels than the corresponding single shock back halves of the stones were most likely caused by inter- wave pulses. Table 2 lists predicted maximum normal actions among refracted and reflected transverse stress stresses and their locations for the various incident shock waves, and surface waves. The critical role of transverse wave types. stress waves in stone fragmentation by conventional lithotriptor shock waves was previously reported by Cleveland and Sapozhnikov.11 On the other hand, the maximum nor- DISCUSSION mal stresses produced at the front of the stones probably Kidney stones are fragmented during shock wave lithotripsy arose as a result of the interactions among the refracted as a result of dynamic fracture of the stone material due to stress waves of the second pulse and the surface waves of the the mechanical stresses produced in part by incident litho- first pulse. We should note that the maximum normal triptor shock waves.10,19 If these mechanical stresses are stresses were produced only after the impact of the second sufficiently large, they can nucleate microcracks in the stone shock wave pulse during tandem pulse lithotripsy. The lower and cause new and existing microcracks to grow and coa- maximum normal stresses produced at the front of the stones lesce, eventually leading to stone fragmentation. When an was explained by greater attenuation of the surface waves due incident lithotriptor shock wave encounters the solid bound- to their long wave propagation distances. Depending on the ary of a spherical stone, various stress waves are produced failure strength of the stone material the presence of peak that propagate in the stone.11,18 Longitudinal and trans- stresses in each half of the stone could conceivably lead to the verse stress waves are produced by refraction at the stone formation of multiple fracture planes and result in more boundary. Reflected stress waves are produced when these effective fragmentation of kidney stones. refracted stress waves come into contact with the lateral and The constructive interactions between the stress waves of posterior surfaces of the stone. Passage of the incident shock the first and second shock wave pulses that produced the

␴ FIG. 4. Maximum normal stress ( 22) distribution along spherical kidney stone axis of symmetry. A, impacted by tandem pulse conventional shock wave (fig. 2, C). B, impacted by tandem pulse modified shock wave (fig. 2, D). 318 ENHANCED KIDNEY STONE FRAGMENTATION BY SHORT DELAY SHOCK WAVES

pulse has a second smaller pressure peak and a decreased tensile component. A reflected stress wave, having undergone phase inversion due to the decrease in the acoustic impedance from the stone to the surrounding tissue or fluid, subsequently interacts with the trailing portion of the incident shock wave pulse.10 Therefore, for the modified shock wave pulse the smaller tensile component of the same phase as the reflected wave and the second pressure peak of the opposite phase would be expected to result in the generation of lower normal stress levels. In this study we considered kidney stones to be spherical, homogeneous, isotropic and linearly elastic. The modeling of stones with more complex shapes and internal structures is relatively straightforward but it comes at a higher computational cost.11 For example, stone heterogeneity requires assigning different material properties to different parts of the stones. The incorporation of more sophisticated material models is currently limited only by the lack of appropriate material data. However, the simple linear elastic assumption is not unreasonable, given that most kidney stones are brittle by nature. We should note that the numerical simulations are valid only when the stones are surrounded by a liquid medium. Kidney stones that are trapped in the ureter, where little or no urine surrounds the stones, are known to be difficult to fragment.11

CONCLUSIONS

For the idealized model of the kidney stone our numerical simulations suggest that for direct stress wave induced fragmentation modified shock waves should be as effective as conventional shock waves. Also, with a small interval of 20 microseconds between the pulses tandem pulse lithotripsy using modified or conventional shock waves could be considerably more effective than single pulse lithotripsy for fragmenting kidney stones. Further work is warranted to study ␴ FIG. 5. Contour plots of normal stress ( 22) in spherical kidney the influence of the time between the pulses on the fragmen- stone. Shock wave was incident at stone top and axis of symmetry tation effectiveness of tandem pulse lithotripsy. passed vertically through stone center. Time was measured from instant that first shock wave pulse impacted model. For tandem pulse shock waves 20-microsecond interval separated first and second pulses. A, produced by single pulse conventional shock wave at REFERENCES 11.4 microseconds. B, produced by single pulse modified shock wave at 11.2 microseconds. C, produced by tandem pulse conventional 1. Lingeman JE: Stone treatments: current trends and future shock waves at 27.8 (i) and 31.2 (ii) microseconds. D, produced by tandem pulse modified shock waves at 27.8 (i) and 31.4 (ii) possibilities. J Urol 2004; 172: 1774. microseconds. 2. Dhar NB, Thornton J, Karafa MT and Streem SB: A multivariate analysis of risk factors associated with subcapsular hematoma formation following electromagnetic shock wave lithotripsy. J Urol 2004; 172: 2271. maximum normal stresses at the front of the stones should 3. Evan AP and McAteer JA: Q-effects of shock-wave lithotripsy. also explain the higher overall stress levels produced in the In: Kidney Stones: Medical and Surgical Management. back halves of the stones during tandem pulse lithotripsy. Edited by FL Coe, MJ Favus, CYC Pak, JH Parks and As before, the differences between the stress levels produced GM Preminger. Philadelphia: Lippincott-Raven Publishers by the single and tandem pulses were limited by the atten- 1996. uation of the stress waves of the first shock wave pulses. We 4. Lingeman JE: Bioeffects of shock waves: an overview. In: The expect that the interval between the first and second shock Management of Lithiasis. Edited by J Talati, RAL Sutton, wave pulses was a major factor in determining the degree of F Moazam and M Ahmed. Dordrecht, The Netherlands: attenuation of the first shock wave pulse.11 A shorter inter- Kluwer Academic Publishers 1997. 5. Skolarikos A, Alivizatos G and de la Rosette J: Extracorporeal val should lead to smaller attenuation of the stress wave and shock wave lithotripsy 25 years later: complications and vice versa. their prevention. Eur Urol 2006; 50: 981. The lower overall stress levels produced by the modified 6. Zhou Y, Cocks FH, Preminger GM and Zhong P: Innovations in shock wave pulse compared to those produced by the con- shock wave lithotripsy technology: updates in experimental ventional shock wave pulse was due to the difference in their studies. J Urol 2004; 172: 1892. pressure profiles (fig. 2, A vs B). The modified shock wave 7. Loske AM, Fernandez F, Zendejas H, Paredes M and Castano- ENHANCED KIDNEY STONE FRAGMENTATION BY SHORT DELAY SHOCK WAVES 319

Tostado E: Dual pulse shock wave lithotripsy: in vitro and 14. Chai WW and Liebman M: Oxalate content of legumes, nuts, and in vivo study. J Urol 2005; 174: 2388. grain-based ﬂours. J Food Composition Anal 2005; 18: 723. 8. Bailey MR, Cleveland RO, Blackstock DT and Crum LA: Use of 15. Duck FA: Physical Properties of Tissue: A Comprehensive two pulses to control cavitation in lithotripsy. J Acoust Soc Reference Book. London: Academic Press 1990. Am 1998; 103: 3072. 16. Church CC: A theoretical study of cavitation generated by an 9. Lingeman JE: Extracorporeal shock wave lithotripsy: what extracorporeal shock wave lithotriptor. J Acoust Soc Am happened? J Urol 2003; 169: 63. 1989; 86: 215. 10. Zhu S, Cocks FH, Preminger GM and Zhong P: The role of 17. Loske AM, Prieto FE, Fernandez F and van Cauwelaert J: stress waves and cavitation in stone comminution in shock Tandem shock wave cavitation enhancement for extracor- wave lithotripsy. Ultrasound Med Biol 2002; 28: 661. poreal lithotripsy. Phys Med Biol 2002; 47: 3945. 11. Cleveland RO and Sapozhnikov OA: Modeling elastic wave 18. Xi X and Zhong P: Dynamic photoelastic study of the transient propagation in kidney stones with application to shock stress ﬁeld in solids during shock wave lithotripsy. J Acoust wave lithotripsy. J Acoust Soc Am 2005; 118: 2667. Soc Am 2001; 109: 1226. 12. Mihradi S, Homma H and Kanto Y: Numerical analysis of 19. Lokhandwalla M and Sturtevant B: Fracture mechanics model kidney stone fragmentation by short pulse impingement. of stone comminution in ESWL and implications for tissue JSME Int J 2004; 47: 581. damage. Phys Med Biol 2000; 45: 1923. 13. Myers MA: Dynamic Behavior of Materials. New York: John 20. Eisenmenger W: The mechanisms of stone fragmentation in Wiley & Sons 1994. ESWL. Ultrasound Med Biol 2001; 27: 683. Biomechanical Properties of Vaginal Tissue. Part 1: New Experimental Protocol

Chrystèle Rubod, Malik Boukerrou, Mathias Brieu, Patrick Dubois and Michel Cosson* From the Clinique de Chirurgie Gynécologique, Hôpital Jeanne de Flandre (CR, MB, MC) and Institut de Technologie Médicale, Institut National de la Santé et de la Recherche Médicale U703 (PD), Centre Hospitalier Régional Universitaire de Lille and Ecole Centrale de Lille, Unité Mixte de Recherche Centre National de la Recherche Scientiﬁque 8107 (MB), Lille, France

Purpose: We established a reliable experimental protocol to characterize the biomechanical properties of vaginal tissue and guarantee good test repeatability. Materials and Methods: Because of the large quantities of tissue required to establish the protocol, we worked on ewes according to animal ethics laws. To study the mechanical properties of ewe vaginal tissue we used unidirectional tension tests at a constant deformation rate. Rupture tests were performed under different experimental conditions to analyze the inﬂuence of each condition. Results: Tissue underwent exhaustive tests. The parameters studied were sampling, freezing, preservation conditions, hygrometry and temperature during vaginal tissue tests, and the rate of deformation during tests. As previously noted, vaginal tissue is anisotropic and the collection has been tested previously. We noted that freezing tissue had no consequences on the mechanical response of tissue during unidirectional tension testing. The experimental conditions that we deﬁned (temperature, hygrometry and rate of deformation) allowed us to have reproducible tests. Conclusions: Results and analyses allowed us to determine the best reference protocol. Key Words: vagina, biomechanics, prolapse, sheep, reference values

enital prolapse may be defined by protuberance (per- the type of prosthesis can be chosen each time to match the manent or only appearing upon effort) in the vaginal actual resistance of this tissue as closely as possible. G lumen of all or part of the vaginal walls. Pelvic pro- The behavior of vaginal tissue depends on many factors, lapse affects 1 of 3 women at all ages combined1 and more of which the influence has not yet been assessed to our than 60% of patients older than 60 years.2 Many corrective knowledge. Since it is impossible to study vaginal tissue in surgical techniques for prolapse have been developed but vivo, it is essential to develop a tests protocol that can be their long-term benefits have been poorly evaluated. used to study the influence of all experimental conditions on The vagina is a supporting hammock for the pelvic vis- this tissue before determining the biomechanical properties. cera.3 Thus, the vaginal tissue is the interface where forces We first answered this essential question. are transmitted among pelvic organs. It is largely involved in the prolapse process. MATERIALS AND METHODS Studying the mechanical properties of vaginal tissue may Experimental Technique help develop a mechanical model of the pelvic cavity. This Because tests were required to study impact of the various could be a tool for objective and specific evaluation of pelvic factors likely to influence the behavior of vaginal tissue, a statics, and the precise impact of different surgical treat- huge quantity of tissue was required. Thus, we selected the ments. Vaginal tissue is also largely used for treating pro- vaginal tissue of ewes because it is a conjunctive tissue with lapse and urinary incontinence. However, these techniques a mechanical behavior close to that of the vaginal tissue of have been used without any assessment of the resistance of women, as verified in tests on human vaginal tissue col- vaginal tissue. The biomechanical properties of this tissue 4 lected after approval by the ethics committee (CCPRB). Fur- could explain some failures of surgical techniques and allow thermore, the size of the collected sheep vaginas allowed us a better choice of prostheses simulating these properties. to perform enough tests to assess test reproducibility. Ten The use of prostheses to correct prolapses requires knowl- tests were perform for each series of conditions with tissue edge of the mechanical properties of vaginal tissue, so that collected from the same ewe. We used vaginal tissue from 6 Colombia-Rambouillet ewes. Vaginal tissue was collected from ewes sacrificed after Submitted for publication November 22, 2006. gestation as part of other research and according to animal Study received ethics committee (CCPRB) approval. ethics laws. The ewes were delivered by cesarean section Supported by the Fondation Recherche Médicale, France. after a mean Ϯ SD of 130 Ϯ 3 days of gestation and sacrificed * Correspondence: Clinique de Gynécologie, Hôpital Jeanne de to collect the vagina in the following hour. The ewes were 6 Flandre, 2 ave. Oscar Lambret, CHRU Lille, 59037 Lille Cedex, France (telephone: 33 (0) 320446584; FAX: 33 (0) 320446432; e-mail: years old and had already had 6 gestations. The hormonal [email protected]). status of each animal was the same. Specimens were col-

0022-5347/07/1781-0320/0 320 Vol. 178, 320-325, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.040 BIOMECHANICAL PROPERTIES OF VAGINAL TISSUE 321 lected from the anterior and posterior vaginal wall by the vaginal route. A midline incision was made in the longitudinal axis of the vaginal wall. The bladder or rectum was reflected off of the vaginal wall before the full-thickness vaginal tissue was excised. The tissue was excised in the longitudinal axis of the vagina with the initial midline incision as the medial border. Samples were oriented before being tested. Tissue stresses in women with prolapse are not unidirectional. However, because of the size of the tissue that might be collected in ewes and in women, the unidirectional tension test is the easiest to perform. Thus, the biomechanical study on ewe vaginal tissue consisted of unidirectional tension tests at a constant deformation rate. The histology of vaginal tissue can vary with its thickness, causing variations in total specimen elongation. However, we assumed that the collected tissue was homogeneous. These considerations were accounted for by standard biomechanical calculations. To obtain an area of uniform stress in the center of the test samples during the tension test standardized 25 ϫ 4 mm test samples5 were cut out with a punch from the vaginal tissue of the ewes (fig. 1). Test sample size was determined to be realistic in regard to the size of the human collected tissue. Each test sample was held in grips and stretched at a constant deformation rate. Preliminary tests showed that the tissue ruptured between the 2 plates and not at the edge of the grips. The grips that we developed for such tissue have an automatic tightening system to avoid tissue slippage. The clamping system that we developed holds the tissue without crushing it and no sliding of test samples in the grips has been noted. Therefore, this result FIG. 2. Unidirectional tension test validated the choice of the shape of the test samples since the greatest stress was effectively attained in the center of the samples. Furthermore, stretch measurements were made locally at the center of the sample. Thus, if slippage occurred, it would not be considered in the stretch measurement. Unidirectional tension tests were done on a conventional Instron™ 4302 apparatus (fig. 2). Tension forces were measured with a low capacity 1 kN load cell. All deformation field measurements during the tests were made using an optical extensometer system, providing reliable and contact- free measurement of the deformation in the center of the test samples. The optical extensometer system also guaranteed a constant deformation rate during the tests. The tension test was ended when the test sample ruptured. Before each test thickness of the test samples was mea-

sured to determine the initial cross-sectional area (S0). Due to the optical extensometer system the load cell, deformation (␹) and force (F) in N were recorded. Thus, stress-stretch curves (⌺/␭) were obtained and analyzed to determine stress and stretch at rupture, and the biomechanical behavior of the vaginal tissue.

Test Conditions Rupture tests were done under various experimental conditions to define a study protocol for which we controlled all factors that could alter vaginal tissue results in the considered experimental test. We assessed the influence of certain sample preparation conditions, including the influence of freezing the vaginal tissue, the influence of hygrometry, and FIG. 1. Test sample of vaginal tissue the influence of sample location and orientation. We also 322 BIOMECHANICAL PROPERTIES OF VAGINAL TISSUE assessed the conditions under which the tests were done, including the influence of temperature and of the deformation rate during the tests. The influence of each factor was studied separately and all manipulations were made by the same operator. Except for the parameter tested all the other parameters were kept constant during a given test. Each test was repeated at least 10 times on tissue collected from the same ewe. This number of tests was required to prevent bias. The presented results represent the mean of the different tests. However, the SD is not reported because this was low in each case. We only studied the elastic properties of the tissue before the rupture stage and only show the graphs before rupture and the mean results.

RESULTS FIG. 4. Influence of hygrometry. h, hours. Sample Preparation Conditions Influence of freezing. Measurements were made in the samples were tested within 24 hours and the mechanical same vaginal tissue in the fresh state (at the time of sacri- response was not altered. fice) or after freezing at Ϫ18C for more than a day. When the To decrease the influence of hygrometry and especially tissue had been frozen, samples were defrosted for 9 hours tissue dehydration some tests were done after soaking the before undergoing the tension test. test samples in paraffin oil. No difference was found for tests The mechanical behavior of the vaginal tissue was unaf- at deformation rates of 2 ϫ 10Ϫ2 and 2 ϫ 10Ϫ3 secondϪ1 fected by freezing (fig. 3). Therefore, for tests determining between test samples soaked in paraffin oil and untreated the biomechanical properties of vaginal tissue freezing is not samples (fig. 6). Paraffin oil did not seem to improve hygro- a limiting factor. It even made the tests easier to perform. metric conditions when the tests were done at these rates. All of our tests were then done in previously frozen tissue. We did not use it for this indication in our experiments. Thus, all test samples were cut out at the same time and Influence of hygrometry. A series of measurements were stored in isotonic saline until mechanical testing. Storage in made in previously frozen vaginal tissue left for various isotonic saline enabled us to protect the samples from the times at room temperature and humidity after removal from adverse effects of air and, therefore, increase their life. To physiological solution (isotonic saline solution) to study the have reproducible tests test samples not soaked in paraffin influence of hygrometry. The deformation rate during the oil were studied within 24 hours after cutting out. tests was constant at 2 ϫ 10Ϫ3 secondϪ1. Stretch-stress graphs were plotted (fig. 4). At 50% deformation rigidity Influence of sample location and orientation. Two se- decreased by 34%, 50% and 150% after 1, 2 and 6 hours, ries of measurements were made in samples taken from the respectively, at room temperature. Thus, test sample storing anterior or posterior vagina wall. No difference in mechanical has a major role in test quality. responses was noted in our experimental conditions (fig. 7). The test samples were then cut from previously unfrozen The vaginal tissue of ewes had the same biomechanical vaginal tissue and stored in physiological solution. They behavior whatever its location according to the study were tested immediately after cutting (time 0), and after 1, criteria. 2 and 24 hours of storage in physiological solution (fig. 5). Lastly, 2 series of measurements were made to test the The behavior of the vaginal tissue was stable when the directional behavior of the vaginal tissue, known as anisotropy. A first series of test samples were cut out transversely with respect to the vaginal length and a second was cut longitudinally. The mechanical response showed that for

FIG. 3. Inﬂuence of freezing FIG. 5. Inﬂuence of storage in physiological solution. H, hours. BIOMECHANICAL PROPERTIES OF VAGINAL TISSUE 323

FIG. 6. Influence of paraffin oil lubrication FIG. 8. Influence of orientation (anisotropy) deformation under 50%, which was the same at each tested direction, vaginal tissue seemed to be isotropic but for a less compared to that in tests done at more rapid rates. deformation of 100% or more the behavior varied largely Proceeding to tests at the deformation rate of 2 ϫ 10Ϫ2 with orientation, ie there was strong anisotropy (fig. 8). secondϪ1 ensured constant tissue behavior during the dura- Thus, vaginal tissue is anisotropic and all measurements tion of the test, while proceeding at deformation rates of 2 ϫ were made on test samples cut out in the same orientation 10Ϫ3 secondϪ1 led to long tests (1 to 2 hours) with severe with respect to vaginal length to be interpretable. Otherwise tissue dehydration and changed behavior during the test their location is immaterial. A comparison of the behavior of (fig. 4). Thus, tests performed at 2 ϫ 10Ϫ2 and 2 ϫ 10Ϫ3 tissue collected at the top vs the distal end of the vagina was secondϪ1 could be used. Tests performed at 2 ϫ 10Ϫ1 not performed. secondϪ1 induced few measurements because of sampling frequency, so that we chose to work at the deformation rate Ϫ2 Ϫ1 Test Conditions of 2 ϫ 10 second . However, the behavior of such tissue, Influence of temperature conditions. To overcome possi- which was revealed to be viscoelastic, was highly a function ble temperature bias measurements were made at labora- of the deformation rate and the quantitative results ob- tory room temperature (18C) and in a temperature contained were also a function of the deformation rate. trolled box kept at a constant body temperature of 37C. All measuring conditions were identical except temperature. DISCUSSION There was no significant difference in the mechanical response of the vaginal tissue related to temperature when The definition of the biomechanical properties of vaginal measurements were made at the deformation rate of 2 ϫ tissue is an essential step in the modeling of the pelvic 10Ϫ2 or 2 ϫ 10Ϫ3 secondϪ1 (fig. 9). All tests were then done cavity, which is required to understand the physiopathology at laboratory room temperature. of prolapse. This model could be a method for objective and specific evaluation of pelvic floor dysfunction, choice and Influence of deformation rates. To study different defor- evaluation of the various surgical treatments. Determina- mation rates during tension test in the vaginal tissue we tion of vaginal tissue properties could also provide answers considered certain deformation rates, including 2 ϫ 10Ϫ1, to some surgical failures. In fact, vaginal tissue is sometimes 2 ϫ 10Ϫ2 and 2 ϫ 10Ϫ3 secondϪ1. Figure 10 shows mean used as a corrective support, although its properties are results. No difference in response was found for deformation unknown. New surgical techniques use prostheses of which rates of 2 ϫ10Ϫ1 or 2 ϫ 10Ϫ2 secondϪ1. At the rate of 2 ϫ the mechanical characteristics have not yet been compared 10Ϫ3 secondϪ1 viscosity must have had a major effect to with those of the vagina. The definition of the biomechanical explain the differences observed. Rigidity was almost 30% properties of vaginal tissue is useful in each case.

FIG. 7. Inﬂuence of location FIG. 9. Inﬂuence of temperature conditions 324 BIOMECHANICAL PROPERTIES OF VAGINAL TISSUE

Ettema,7 could theoretically prevent tissue dehydration. In our experimental conditions, in which the test was done rapidly, it seemed to be of doubtful use. Our system of cutting with a punch ensured that identical and normalized test samples were used, which was not the case in the 2 preexisting protocols. Cutting out creates breakage in the connective networks that can affect tissue mechanical properties. However, this phenomenon did not influence our comparative tests. The clamping system that we developed holds the tissue without crushing it. Preliminary tests showed that the tissue ruptured at its center and not close to the Ϫ FIG. 10. Influence of deformation rate. sϪ1, seconds 1. clamping system. Maximum stress is attained at the center of the test samples. This fact did not seem to be noted in the other 2 protocols. To our knowledge 2 mechanical study protocols for vagi- To our knowledge no published study has analyzed the nal tissue are already established.4,6 However, experimental influence of freezing on the vaginal tissue. However, studies conditions are not supported by preliminary study and cer- of the collagen that make up vaginal tissue have been done. tain methodological limits were revealed. In the protocol of Yamamoto et al noted in a study of rabbit tendons that Cosson et al the system of clamping was unreliable and freezing in liquid nitrogen affected the mechanical proper- results varied among and within individuals.4 The protocol ties of collagen.8 The elasticity of the tendon decreased with of Ettema was adapted from measures in skeletal muscle.7 freezing, although the stresses at rupture were not signifi- Linear tension at a constant rate of 0.8 mm per second was cantly different. Also, freezing and thawing at Ϫ20C created combined with sinusoidal vibrations at 50 Hz in tissue pre- artifacts for the interpretation of the biomechanical proper- viously frozen at Ϫ70C.6 This nondestructive method is an ties of pig cartilage under compression.9 In our study freez- alternative to traditional extension tests but the choice of ing at Ϫ18C did not affect the mechanical behavior of vagi- the experimental protocol was not detailed by the investiga- nal tissue and the stress at rupture was unchanged. The tors. observed differences in the effect of freezing were partly Our study provides a new protocol to determine the bio- related to the different freezing methods (preservation liq- mechanical properties of vaginal tissue. It is an alternative uid and temperature) and the different collagen distribu- to those of Cosson4 and Ettema6 et al. All stages used were tions in the tissues studied. Even if freezing tissues altering justified by exhaustive tests in the sample preparation and them and modifies the cellular state, the mechanical re- tests of execution conditions. Vaginal tissue must be frozen sponse (relation between stretch and stress) is not altered. at Ϫ18C in physiological solution and defrosted for 9 hours Thus, to simplify the tests (schedule organization and con- before being tested. All test samples must be cut out along ditioning of samples) we chose to freeze the tissue. the same orientation. They must be stored in physiological Sampling and trimming were performed in a standard- solution for a maximum of 24 hours before being tested. ized way in each ewe. The vaginal wall was excised with a Each test sample must be subjected to a unidirectional ten- various quantity of connective tissue. Since this connective sion test at room temperature at a constant deformation rate tissue has no proper anatomical definition, it is difficult to Ϫ Ϫ of 2 ϫ 10 2 second 1. Under such conditions the reproduc- individualize and dissect it in perioperative conditions. How- ibility of the tests is guaranteed. ever, the integration of this tissue in measurements was not The mechanical anisotropy of vaginal tissue was clearly a bias since it forms part of the local mechanical reality. highlighted in our tests. This property could in part explain However, its involvement is not quantifiable. the intra-individual variability of the results of Cosson et al, who studied nonoriented test samples.4 In ewes we noted no difference in the biomechanical behavior of vaginal tissue CONCLUSIONS from the anterior and posterior walls. However, this result remains to be confirmed in women, who are bipedal. In fact, The biomechanical properties of vaginal tissue have been pressures exerted on the anterior and posterior walls of the poorly studied to date. Since it is inconceivable to study vagina are different while standing and while subjected to vaginal tissue in vivo, we developed a new protocol for study- effort.3 Because of the conditions under which tissue was ing the biomechanical behavior of this tissue. All experimen- collected, we were not able to test the difference between tal conditions were justified by exhaustive tests demonstrat- tissue at the top and at the distal end of the vagina, which ing the pertinence of our choice. This methodology could be may also have induced interesting information. It seems applied to all types of connective tissues. important to do all tests at a deformation rate of 2 ϫ 10Ϫ2 Surgical repair of pelvic floor dysfunction uses prosthe- secondϪ1. This rate allows the test to proceed rapidly, so ses, of which the mechanical characteristics have not been that the response is not influenced by hygrometry and tem- compared with those of vaginal tissue. Determining the me- perature conditions. The tissue has a stable behavior during chanical properties of normal human vaginal tissue could be the short test duration. Tests were performed at room tem- studied in fresh cadavers and become essential for choosing perature. Higher temperatures may alter tissue quality dur- the most suitable prosthesis for correcting prolapse. In this ing a long test because they increase dehydration. However, way the definition of this protocol may help define the one must keep in mind that the deformation rate has a huge behavior of normal and prolapse tissues or ligaments to influence on the response of the materials in regard to its understand more accurately the process of prolapse and behavior. Paraffin oil, which was also used in the protocol of correct it. BIOMECHANICAL PROPERTIES OF VAGINAL TISSUE 325

REFERENCES EDITORIAL COMMENT

1. Samuelsson E, Victor F, Tibblin G and Svardsudd K: Signs of There is currently considerable interest in the tissue biome- genital prolapse in a Swedish population of women 20 to 59 chanics of vaginal prolapse. A detailed study of this problem years of age and possible related factors. Am J Obstet Gy- first requires investigation to determine how vaginal tissue necol 1999; 180: 299. must be stored and handled, such that there is minimal 2. Swift S: The distribution of pelvis organ support in a population of female subjects seen for routine gynecologic health care. biasing of results due to the test conditions. Am J Obstet Gynecol 2000; 183: 277. From this study we can conclude that test results are 3. Kamina P: Anatomie Clinique du Petit Bassin et Périnée. Paris: unaffected by testing previously frozen tissue or by testing Editions Maloine 1995. tissue at room temperature (18C) vs body temperature. Con- 4. Cosson M, Lambaudie E, Boukerrou M, Lobry P, Crepin G and Ego versely we can conclude that all future studies of vaginal A: A biomechanical study of the strength of vaginal tissues. tissue biomechanics must control for tissue desiccation, tis- Results on 16 post-menopausal patients presenting with genital prolapse. Eur J Obstet Gynecol Reprod Biol 2004; 112: 201. sue deformation rate and the orientation of vaginal biopsy. 5. Brown RP. Physical Testing of Rubber, 3rd ed. London: Chap- The latter point is significant, in that vaginal tissue is man and Hall 1996. anisotropic. It stretches more transverse to the vaginal axis 6. Ettema G, Goh J and Forwood M: A new method to measure than in the direction of the vaginal axis. This property likely elastic properties of plastic-viscoelastic connective tissue. reflects the underlying tissue architecture and it makes Med Eng Phys 1998; 20: 308. sense when one considers that the vaginal canal must ex- 7. Ettema G: Mechanical behaviour of rat skeletal muscle during pand several-fold during birth. fatiguing stretch-shorten cycles. Exp Physiol 1997; 82: 107. 8. Yamamoto E, Tokura S, Yamamoto N and Hayashi K: Mechan- This essential study provides us with a basic set of guide- ical properties of collagen fascicles from in situ frozen and lines to begin studying the biomechanics of vaginal prolapse. stress-shielded rabbit patellar tendons. Clin Biomech 2000; 15: 284. Christian O. Twiss, Veronica Triaca and Shlomo Raz 9. Willett T, Whiteside R, Wild P, Wyss U, Anastassiades T: Artifacts in the mechanical characterization of porcine Department of Urology articular cartilage due to freezing. Proc Inst Mech Eng University of California-Los Angeles 2005; 219: 23. Los Angeles, California Effects of Tolterodine on Afferent Neurotransmission in Normal and Resiniferatoxin Treated Conscious Rats

Petter Hedlund, Tomi Streng, Tack Lee and Karl-Erik Andersson* From the Department of Clinical and Experimental Pharmacology, Lund University Hospital (PH, TS, TL, KEA), Lund, Sweden, and Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine (KEA), Winston Salem, North Carolina

Purpose: The beneficial effects of antimuscarinics on detrusor overactivity and overactive bladder syndrome are exerted during bladder filling, when there is no parasympathetic outflow from the spinal cord. We tested the hypothesis that, if tolterodine exerts some of its effects on afferent nerves, the functional elimination of C-fiber afferents should affect the actions of the drug on urodynamic parameters. Materials and Methods: The study was performed in normal female Sprague Dawley rats and rats treated with resiniferatoxin to eliminate vanilloid sensitive afferent nerves. Tolterodine was given intravenously to normal and resiniferatoxin treated animals. To test if tolterodine at the doses used affects efferent neurotransmission the drug was given to normal and resiniferatoxin treated animals in which detrusor activity was induced by apomorphine. Results: In resiniferatoxin treated animals (0.3 mg kgϪ1 subcutaneously) the mean micturition interval and volume, and mean residual volume increased significantly compared to those in controls. Baseline and micturition pressures in control and resiniferatoxin treated animals were similar, whereas threshold pressures were higher in resiniferatoxin treated animals. In controls 10 ␮gkgϪ1 tolterodine administered intravenously increased the mean micturition interval, bladder capacity and micturition volume. In resiniferatoxin treated rats 1 and 10 ␮gkgϪ1 tolterodine increased the mean micturition interval, bladder capacity and micturition volume. Subcutaneous administration of 100 ␮gkgϪ1 apomorphine induced detrusor overactivity in all rats. The AUC of intravesical pressure during the initial 10 minutes from the start of detrusor overactivity showed no difference between normal and resiniferatoxin treated rats with or without tolterodine pretreatment. Conclusions: Tolterodine increased the micturition interval and bladder capacity in controls and in resiniferatoxin treated animals, suggesting that these effects were exerted independently of resiniferatoxin sensitive afferents. Tolterodine did not decrease the contractile effects of apomorphine at the doses used, suggesting that the drug had no effect on efferent neurotransmission during voiding. Key Words: bladder; tolterodine; urodynamics; nerve fibers, unmyelinated; rats, Sprague-Dawley

oluntary or involuntary bladder contraction involves dowed with muscarinic receptors and participating in affer- stimulation of the muscarinic receptors on detrusor ent signaling. Extraneuronally generated acetylcholine or V smooth muscle by acetylcholine released from acti- acetylcholine leaking from nerves during the storage phase vated cholinergic nerves.1 Antimuscarinic agents at clini- may further stimulate the contraction of detrusor myocytes, cally recommended doses have little effect on voiding con- which in bladders with detrusor overactivity already have 2 tractions and they act mainly during the bladder storage increased myogenic activity.8 Enhanced myogenic contrac- 3 phase, during which there is normally no parasympathetic tions can generate an enhanced afferent signal, contributing 4 outflow from the spinal cord. Supporting this, antimusca- to urgency and/or initiation of the micturition reflex.3 How- rinic agents were shown to decrease bladder tone during ever, effects on suburothelial interstitial cells (myofibroblasts), 2 storage and increase cystometric bladder capacity. Baseline on which muscarinic receptors can be demonstrated,9 may also release of acetylcholine from nonneuronal (urothelial) as contribute. well as neuronal sources was demonstrated in isolated hu- We tested the hypothesis that, if tolterodine exerts some man detrusor muscle.5,6 It was suggested that this release, of its effects on afferent nerves as suggested,10 the func- which is increased by muscle stretching and in the aging tional elimination of C-fiber afferents should affect the ac- bladder, contributes to detrusor overactivity and overactive tions of the drug on urodynamic parameters. Therefore, we bladder symptoms by eventually increasing bladder afferent treated rats with RTX systemically at a dose that was pre- activity during storage.7 This may be caused by a direct viously shown to functionally eliminate vanilloid sensitive effect on suburothelial afferents or on other structures en- afferents (C fibers). To establish if tolterodine at the doses used had effects on the efferent side of the micturition reflex, Submitted for publication September 27, 2006. we studied the effects of the drug on apomorphine stimu- Study received Lund/Malmö Animal Ethics Committee approval. lated detrusor activity. Apomorphine is believed to activate * Correspondence: Wake Forest Institute for Regenerative Medicine, the bladder independently of afferent activation, initiating Wake Forest University School of Medicine, Medical Center Blvd., Winston Salem, North Carolina 27157 (telephone: 336-713-1195; FAX: activity at a central site of action, and increase the parasym- 336-713-7290; e-mail: [email protected]). pathetic outflow from the spinal cord.11

0022-5347/07/1781-0326/0 326 Vol. 178, 326-331, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.006 EFFECTS OF TOLTERODINE ON AFFERENT NEUROTRANSMISSION 327

METHODS Evaluations and Calculations Urodynamic parameters were investigated, including mic- Animals turition pressure (maximum bladder pressure during mic- A total of 32 female or male Sprague-Dawley rats weighing turition), baseline pressure (the lowest bladder pressure approximately 300 gm were used. The animals were kept during filling), threshold pressure (bladder pressure imme- under clean conditions at the Biomedical Centre animal diately before micturition), bladder capacity (residual vol- facility at Lund University Hospital and they had free access ume at the most recent previous micturition plus the volume to pellets and water during a 12:12-hour dark-light cycle. of infused saline at micturition), micturition volume (volume Experimental procedures were approved by the Lund/ of expelled urine), residual volume (bladder capacity minus Malmö Animal Ethics Committee. micturition volume), the intercontraction interval and the AUC of intravesical pressure. Reproducible micturition cycles, together approximately Surgical Procedures corresponding to a 30-minute period, were recorded before Ϫ1 Rats were anesthetized with ketamine (Ketalar®, 75 mg kg drug administration. They served as baseline values to be Ϫ1 intraperitoneally) and xylazine (Rompun®, 15 mg kg intra- compared with the 3 micturition cycles in the first 30-minute peritoneally), and placed on a thermoregulated surgical area. period after the administration of test substances. Compar- After an abdominal incision was made a polyethylene collar isons of the means of all groups were performed with 1-way fitted PE-50 catheter (Clay-Adams, Parsippany, New Jer- ANOVA (Holm-Sidak). Pairwise comparisons were made by sey) was inserted into the bladder dome and held in place Student’s t test. All statistical calculations were based on with a purse-string suture. The free end of the catheter was the number of individual animals and significant differences sealed. A PE-50 polyethylene catheter was elongated to were considered at p Ͻ0.05. about 1.5 times its original length at the tip of the inserting side and filled with heparinized saline (100 IU mlϪ1). At the RESULTS same time that the bladder catheter was implanted the elongated catheter was inserted into the femoral vein. At Effect of RTX Treatment on Micturition Parameters the same session another PE-50 catheter was filled with After RTX treatment (0.3 mg kgϪ1 subcutaneously) in 22 heparinized saline and introduced subcutaneously from animals 8 showed decompensated bladders with dribbling neck to lower back. All catheters were tunneled subcutane- incontinence. These animals were used only to assess the ously, anchored to the skin of the neck and closed. effects of RTX and tolterodine on apomorphine induced activity. Three rats showed intermittent dribbling incontinence as well as complete voiding cycles. One RTX treated RTX Treatment animal and 1 control were excluded due to catheter prob- To induce C-fiber desensitization RTX (0.3 mg kgϪ1) dis- lems. One RTX treated animal died of postoperative compli- solved in dimethyl sulfoxide was injected subcutaneously cations. into the rats during anesthesia, as described, 3 days before Compared to the 9 controls RTX treatment in 12 rats the experiment. Control animals received corresponding vol- increased the micturition interval (p Ͻ0.001), bladder capac- umes per weight of dimethyl sulfoxide given subcutane- ity (p Ͻ0.0001), micturition volume (p Ͻ0.05), threshold ously. pressure p Ͻ0.05) and residual volume (p Ͻ0.05, fig. 1). There were no significant effects on mean Ϯ SD baseline Ϯ Ϯ pressure, which was 10.2 0.6 and 10.4 0.8 cm H2Oin Experimental Design controls and RTX treated rats, respectively. No statistical Cystometry was performed without anesthesia 3 days after difference was observed for micturition pressure between catheter implantation. The conscious rats were placed in controls and RTX treated rats (98.0 Ϯ 8.6 and 72.2 Ϯ 10.0 cm Ͻ metabolic cages without restraint and the bladder catheters H2O, respectively, p 0.06). were connected via a T tube to a P23 DC pressure transducer (Statham Instruments, Oxnard, California) and a CMA 100 Effect of Tolterodine on Micturition microinjection pump (Carnegie Medicine AB, Solna, Swe- Parameters in Control and RTX Treated Rats den). Micturition volumes were recorded with a fluid collec- In controls intravenous administration of 10 ␮gkgϪ1 toltero- tor connected to an FT03 D force displacement transducer dine increased the mean micturition interval (p Ͻ0.05), (Grass Instrument, Quincy, Massachusetts). Room temper- bladder capacity (p Ͻ0.05), micturition volume (p Ͻ0.05) ature saline was infused into the bladder continuously at a and residual volume (p Ͻ0.05), and decreased micturition rate of 10 ml hour–1. Pressures and micturition volumes pressure (p Ͻ0.001, fig. 2). Baseline pressure was 9.4 Ϯ 1.0 Ϯ were recorded continuously with AcqKnowledge 3.8.1 soft- and 8.4 2.6 cm H2O in 6 rats before and after drug ware and an MP100 data acquisition system (Biopac Sys- administration, respectively. Threshold pressure was also tems, Santa Barbara, California) connected to a Model 7E unaffected by tolterodine in 6 rats (31.2 Ϯ 2.6 and 30.0 Ϯ 1.5 polygraph (Grass Instrument). At the beginning of cystom- cm H2O, respectively). etry the bladder was emptied via the bladder catheter. In 6 RTX treated rats tolterodine (1 ␮gkgϪ1 intrave- Apomorphine (100 ␮gkgϪ1 subcutaneously) was used to nously) increased the mean micturition interval from 10.6 Ϯ stimulate efferent activity and induce detrusor overactivity. 3.7 to 13.6 Ϯ 5.5 minutes (p Ͻ0.05), increased bladder ca- Tolterodine was given intravenously to controls (10 ␮gkgϪ1) pacity from 1.6 Ϯ 0.3 to 1.9 Ϯ 0.3 ml (p Ͻ0.05) and increased and RTX treated (1 and 10 ␮gkgϪ1) animals before and after micturition volume from 1.5 Ϯ 0.3 to 1.8 Ϯ 0.2 ml (p Ͻ0.05, apomorphine administration. The doses chosen were based fig. 3). At 10 ␮g/kg given intravenously in 6 rats the mic- on published information.10 turition interval, bladder capacity and micturition volume 328 EFFECTS OF TOLTERODINE ON AFFERENT NEUROTRANSMISSION

Ϫ FIG. 1. Effects of subcutaneous administration of 0.3 mg kg 1 RTX on micturition parameters in 9 controls (filled bars) and 12 RTX treated rats (open bars). Single asterisk indicates unpaired t test p Ͻ0.05. Double asterisks indicate unpaired t test p Ͻ0.01. Triple asterisk indicate unpaired t test p Ͻ0.001. were also significantly increased (figs. 3 and 4). There were Effect of Tolterodine no significant effects on residual volume, baseline, threshold on Apomorphine Induced and micturition pressures at either investigated tolterodine Overactivity in Control and RTX Treated Rats dose. After 10 ␮gkgϪ1 tolterodine mean baseline pressure Subcutaneous administration of 100 ␮gkgϪ1 apomorphine Ϯ Ϯ was 8.6 1.0 cm H2O in 6 rats in comparison to 10.2 1.4 induced characteristic detrusor overactivity with dribbling cm H2O in 6 without the antimuscarinic agent. Mean incontinence in controls and in RTX treated rats. Mean Ϯ Ϯ threshold pressure was 39.4 5.1 and 37.6 6.4 cm H2O, maximal pressure and AUC were almost identical in con- and micturition pressure was 73.5.4 Ϯ 15.7 and 61.8 Ϯ 18.2 trols and RTX treated animals after apomorphine (100 ␮g ␮ Ϫ1 Ϫ1 ␮ Ϫ1 cm H2O in 6 rats each before and after 10 gkg toltero- kg )(fig. 4). Tolterodine (1 and 10 gkg ) had no effect on dine, respectively. apomorphine induced activity (fig. 5).

FIG. 2. Micturition parameters in 6 controls before (ﬁlled bars) and after (open bars) intravenous administration of 10 ␮g kg tolterodine. Single asterisk indicates paired t test p Ͻ0.05. Double asterisks indicate paired t test p Ͻ0.01. EFFECTS OF TOLTERODINE ON AFFERENT NEUROTRANSMISSION 329

FIG. 3. Original tracings of intravesical pressure and voided volumes during continuous cystometry in 2 RTX treated rats before (A) and after (C) intravenous administration of 1 ␮gkgϪ1 (B) and 10 ␮gkgϪ1 (D) tolterodine.

DISCUSSION myocytes,14 there may be effects not only on afferent nerves. It is well known that RTX desensitizes afferent nerves.15 The current experiments showed that the RTX treatment had significant effects on bladder function, as reflected by However, actions on extraneuronal structures important for cystometric parameters and the development of dribbling afferent signaling and sensitive to muscarinic receptor stim- 16 incontinence in some animals. RTX increased the mean mic- ulation may not undergo desensitization. turition interval, bladder capacity and voided volume, sug- As shown in the current study, tolterodine at the concen- gesting that structures involved in afferent signaling were trations used had no effect on apomorphine induced detrusor affected (desensitized). However, functional elimination of activity. As reported previously, apomorphine is believed to RTX sensitive afferents did not affect the actions of tolterodine, activate the bladder independently of afferent activation, suggesting that they were exerted independently of this type of initiating activity at a central site of action, and increase the C fibers. However, since TRPV1, the receptor for RTX, is parasympathetic outflow from the spinal cord11 with a con- located not only on a subpopulation of afferent nerves,12 but sequent release of large amounts of acetylcholine at the also on urothelium,13 interstitial cells and even on detrusor cholinergic nerve terminals and the direct stimulation of

FIG. 4. Micturition parameters before (black bars) and after (white bars) intravenous administration of 10 ␮g kg tolterodine in 6 rats given 0.3 mg kg RTX subcutaneously. Single asterisk indicates paired t test p Ͻ0.05. 330 EFFECTS OF TOLTERODINE ON AFFERENT NEUROTRANSMISSION

FIG. 5. Apomorphine induced detrusor overactivity in 5 controls and 8 rats treated with 0.3 mg kg RTX subcutaneously before (ﬁlled bars) and after (open bars) intravenous administration of 10 ␮gkgϪ1 tolterodine. s., second.

detrusor myocytes, resulting in a voiding contraction. Since Kim et al administered muscarinic receptor agonists and the effects of tolterodine and acetylcholine are competitive, antagonists intravesically to rats and were able to separate the amounts of tolterodine used in the current study may not the local inhibitory effects of antimuscarinic agents during have been sufficient to inhibit the acetylcholine effect during the storage phase from a decrease in voiding pressure.17 voiding. The lack of an effect of the antimuscarinic on apo- They found that intravesical instillation of antimuscarinics morphine induced activity supports the assumption that at clinically meaningful concentrations suppressed carba- efferent neurotransmission was not affected. This is differ- chol induced detrusor overactivity. Kim et al concluded that ent from what happens during filling, when only small antimuscarinic agents may be effective for treating overac- amounts of acetylcholine are available to the receptors. This tive bladder, not only by suppression of muscarinic receptor implies that in this situation the tolterodine concentrations mediated detrusor muscle contractions, but also by blocking achieved at the current dose are sufficient to inhibit the muscarinic receptors in bladder-afferent pathways. acetylcholine effects. Since the effects of antimuscarinics are believed to be The finding that the effects of tolterodine were indepen- attributable to a competitive antagonism of acetylcholine at dent of RTX sensitive afferent nerves are in apparent dis- muscarinic receptor sites and the direct involvement of RTX agreement with the results of Yokoyama et al, who con- sensitive afferents seems controversial, possible sites of ac- cluded that the actions of tolterodine depended on the tion other than C fibers may be discussed. M2 and M3 recep- suppression of C-fiber bladder afferent activity.10 They tor immunoreactivity was observed in the urothelium, nerve found in a rat model of increased detrusor activity caused by fibers and detrusor layers in the human bladder.9 A signif- occlusion of the middle cerebral artery that bladder capacity icant increase in suburothelial myofibroblast-like M2 and M3 was markedly decreased after occlusion in RTX at 0.3 mg receptor immunoreactivity was seen in patients with idio- kgϪ1, which is the same dose as in the current investigation, pathic detrusor overactivity. This immunoreactivity signifi- and in vehicle treated rats. Low tolterodine doses of 0.2 and cantly correlated with the urgency score and M2 receptor 2nMkgϪ1 (0.1 and 1 ␮gkgϪ1, respectively) significantly immunoreactivity also correlated with the frequency score. increased bladder capacity in vehicle treated rats without The increase in muscarinic receptor immunostaining in increasing residual volume but had no effects in RTX treated myofibroblast-like cells and its correlation with clinical rats. They suggested that at low doses tolterodine exerts an scores suggested to us a potential role in pathophysiological inhibitory effect on C-fiber bladder afferent nerves, thereby mechanisms and in the therapeutic effect of antimuscarinic improving bladder capacity during the storage phase. The agents. reasons for the discrepancy in results between the current There may be differences in muscarinic receptor distri- study and that of Yokoyama et al are unclear but they may bution, including subtypes, between the rat and the human depend on the models used. bladder. However, muscarinic receptors can be expected in EFFECTS OF TOLTERODINE ON AFFERENT NEUROTRANSMISSION 331 the same structures in the rat bladder as in the human 3. Andersson KE: Antimuscarinics for treatment of overactive bladder. The current results suggest that tolterodine, which bladder. Lancet Neurol 2004; 3: 46. 4. Morrison J, Birder L, Craggs M, de Groat W, Downie J, Drake blocks M2 and M3 receptors, exerted an effect on afferent signaling from the bladder, leading to decreased voiding M et al: Incontinence. In: 3rd International Consultation on frequency, and consequent increases in bladder capacity and Incontinence. Edited by P Abrams, L Cardozo, S Khoury voided volumes independent of RTX sensitive afferents. It and A Wein. Plymouth, United Kingdom: Health Publica- may be assumed that there is a release of small amounts of tion 2005; pp 363–422. 5. Yoshida M, Miyamae K, Iwashita H, Otani M and Inadome A: acetylcholine from nerves or from extraneuronal sources, eg Management of detrusor dysfunction in the elderly: urothelium, during the bladder storage phase5,6 and the changes in acetylcholine and adenosine triphosphate re- released transmitter stimulates afferent signaling. The low lease during aging. Urology, suppl., 2004; 63: 17. concentrations of released acetylcholine can be effectively 6. Yoshida M, Inadome A, Maeda Y, Satoji Y, Masunaga K, counteracted by tolterodine at concentrations that have no Sugiyama Y et al: Non-neuronal cholinergic system in effect on detrusor contraction. However, this is not the case human bladder urothelium. Urology 2006; 67: 425. when there is a massive release of the transmitter, as can be 7. Andersson KE and Yoshida M: Antimuscarinics and the over- expected during apomorphine stimulated voiding. active detrusor—which is the main mechanism of action? Eur Urol 2003; 43: 1. CONCLUSIONS 8. Brading AF: A myogenic basis for the overactive bladder. Urol- ogy, suppl., 1997; 50: 57. The current experiments show that tolterodine increases the 9. Mukerji G, Yiangou Y, Grogono J, Underwood J, Agarwal SK, micturition interval and bladder capacity in controls and in Khullar V et al: Localization of M2 and M3 muscarinic RTX treated animals. Thus, functional elimination of RTX receptors in human bladder disorders and their clinical sensitive afferents did not affect these actions of tolterodine, correlations. J Urol 2006; 176: 367. suggesting that they were exerted independently of this 10. Yokoyama O, Yusup A, Miwa Y, Oyama N, Aoki Y and Akino population of C fibers. This does not necessarily mean that H: Effects of tolterodine on an overactive bladder depend on the effect was not exerted on the afferent side of the mic- suppression of C-fiber bladder afferent activity in rats. turition reflex since A␦-fiber mediated activity may be less J Urol 2005; 174: 2032. affected by RTX treatment, and urothelium and interstitial 11. Kontani H, Inoue T and Sakai T: Effects of apomorphine on urinary bladder motility in anesthetized rats. Jpn J Phar- cells may not be desensitized. Because tolterodine did not macol 1990; 52: 59. decrease the contractile effects of apomorphine, the drug at 12. Avelino A, Cruz C, Nagy I and Cruz F: Vanilloid receptor 1 the doses used seemed to have no effect on efferent neuro- expression in the rat urinary tract. Neuroscience 2002; 109: transmission during voiding. Thus, tolterodine at low doses 787. exerted an inhibitory effect on afferent neurotransmission 13. 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Neu- nary tract: basis for current and future treatments of uri- rourol Urodyn 2006; Epub. nary incontinence. Pharmacol Rev 2004; 56: 581. 17. Kim Y, Yoshimura N, Masuda H, de Miguel F and Chancellor 2. Finney SM, Andersson K-E, Gillespie JI and Stewart LH: MB: Antimuscarinic agents exhibit local inhibitory effects Antimuscarinic drugs in detrusor overactivity: motor or on muscarinic receptors in bladder-afferent pathways. sensory actions? BJU Int 2006; 98: 503. Urology 2005; 65: 238. Intraurethral Transfer of Satellite Cells by Myofiber Implants Results in the Formation of Innervated Myotubes Exerting Tonic Contractions

Constant Lecoeur,* Salem Swieb,* Laurent Zini, Charlotte Rivière, Hélène Combrisson, Romain Ghérardi, Claude Abbou and René Yiou† From the Service d’Urologie, Centre de Recherches Chirurgicales, Centre Hospitalier Universitaire Henri Mondor (CL, SS, CA, RY) and Institut National en Santé et Recherche Médicale E0011, University Paris XII (CL, SS, RG, RY), Créteil, Ecole Nationale Vétérinaire d’Alfort (CL, LZ, HC), Maisons-Alfort, Service d’Urologie, Centre Hospitalier Régional Universitaire de Lille (LZ), Lille and Laboratoire Matières et Systèmes Complexes, Unité Mixte de Recherche Centre Nationale de la Recherche Scientiﬁque 7057, University Paris VII (CR), France

Purpose: We investigated a new method of muscle precursor cell transfer in the urethra for the treatment of urinary incontinence, consisting of implanting myofibers with their satellite cells. Materials and Methods: In preliminary experiments to test the regenerative capacities of satellite cells histological analysis was performed on days 7 and 30 after the implantation of myofiber cores in the urethra of 6 female pigs. In the main experiments 11 pigs underwent baseline urodynamics, followed by endoscopic destruction of the striated urethral sphincter located around the distal urethra (day 0). On day 30 circular myofiber strips in 7 experimental cases and adipocytes in 4 controls were implanted in the proximal urethra. Seven days later (day 37) 1 case was sacrificed to verify satellite cell activation. On day 60 urodynamics were performed without and with curarization. Urethral cryosections were immunostained for desmin (activated satellite cells), fast myosin heavy chain/bungarotoxin (myotubes/acetylcholine receptors), neurofilament/vesicular acetylcholine transporter (nerve endings) and CD45/CD68 (inflammatory response). Results: Preliminary histological studies revealed a myogenic process consisting of myofiber degeneration and satellite cell activation (day 7), followed by myotube formation replacing parental myofibers (day 30). In the main experiments endoscopic injury abolished striated urethral sphincter activity. Implantation of myofiber strips generated a pressure peak that Ϯ Ϯ Ϯ ϭ decreased after curarization (mean SEM 71.5 17.8 vs 33.5 14.8 cm H2O, p 0.031) and reappeared 60 minutes later, revealing that this action was tonic and under neural control. Nerve endings connected to the acetylcholine receptors of myotubes were observed on day 60. An inflammatory response was observed only on day 7 in the myofiber implantation group. Adipocyte implantation resulted in no significant intraurethral pressure changes. Conclusions: Urethral implantation of myofibers regenerates as myotubes that exert tonic activity under neural control. This has potential clinical value as a means to create an additional striated urethral sphincter. Key Words: transplantation; urethra; sphincter insufficiency; muscle precursor cells; satellite cells, myogenic

ransplantation of MPCs into the SUS is a potential The standard MPC grafting technique consists of an injec- new treatment for stress urinary incontinence.1–4 tion of cells that were originally harvested from a muscle bi- T MPCs essentially comprise satellite cells located un- opsy by enzymatic digestion and then cultured under specific der the basal lamina of each skeletal myofiber. Undisturbed conditions to eliminate nonmyogenic cells. However, there is myofibers retain their satellite cells (MPCs) in a quiescent now increasing evidence that these successive steps of MPC state, while myofiber death triggers a myogenic process con- preparation alter their myogenic potential in vivo.8–10 Collins sisting of satellite cell proliferation and fusion into myotubes, et al noted that as few as 7 satellite cells associated with a replacing the parental myofibers. Interestingly the small num- single transplanted myofiber can generate more than 100 new 5 ber of satellite cells contained in each muscle (2 to 10.10 /gm myofibers in an injured muscle provided that they do not come muscle) is sufficient to completely reconstitute all myofibers into contact with disaggregation enzymes.8 After enzymatic 5–7 lost after injury. separation from their parental myofibers satellite cells were found to be several thousand-fold less efficient for generating muscle. Montarras et al found that culture expansion mark- Submitted for publication September 15, 2006. edly decreases the regenerative efficiency of MPCs, suggesting Supported by the Assistance Publique des Hôpitaux de Paris that it is an empty process yielding the same amount of muscle (CIRC Protocol No. 04 027) and Fondation de l’Avenir (Protocol No. 9 ET4-369). as the number of cells from which the culture was initiated. * Equal study contribution. These recent studies advocate the use of fewer but unmanipu- † Correspondence: MCU-PH AP-HP, Service d’Urologie, Centre lated MPCs in cell therapy protocols for muscle diseases. Hospitalier Universitaire Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France (telephone: 33 1 49 81 45 Taking these recent concepts into consideration, we in- 99; FAX: 33 1 49 81 25 52; e-mail: [email protected]). vestigated a novel method of intraurethral MPC transplan-

0022-5347/07/1781-0332/0 332 Vol. 178, 332-337, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.02.044 INTRAURETHRAL TRANSFER OF SATELLITE CELLS BY MYOFIBER IMPLANTS 333 tation consisting of implanting freshly isolated myofibers urethra. We chose an implantation zone deprived of myofi- with their satellite cells. We hypothesized that myofiber bers and at a distance from the SUS to facilitate the assess- death following implantation would induce activation of ment of any UPP changes generated by graft derived myo- their satellite cells in vivo, thus, avoiding the necessity for tubes and avoid confusion with residual SUS activity. The MPC extraction and in vitro expansion. animals were sacrificed after the second urodynamic study and the urethras were removed to determine the presence of MATERIALS AND METHODS myotubes and their innervation. The same protocol was used for a control group of 4 pigs We first implanted muscle cores oriented longitudinally in except strips of abdominal fat tissue of the same size were the pig urethra to prove initial myofiber degeneration, fol- implanted instead of myofibers. We used adipocytes as con- lowed by regeneration from their own satellite cells. We next trols because they do not spontaneously differentiate into attempted to increase the mass of regenerating muscle in a myotubes and, therefore, they were not expected to develop pig model of SUS injury by implanting muscle strips with curare sensitive contractions. myofibers in a circular orientation around the urethra. We investigated the innervation of graft derived myotubes and changes in UPP. Myofiber Preparation and Implantation Figure 1 shows the aspect of myofiber implants. A muscle biopsy obtained from the neck was rinsed in Dulbecco’s General Animal Procedures modified Eagle’s medium (Gibco BRL, Grand Island, New A total of 17, 4-month-old white pigs (Etablissement York) and sliced longitudinally to obtain 2 ϫ 10 mm cores. Grégoire, Campremy, France) weighing 35 to 50 kg were The cores were incubated for 2 hours in a filter sterilized used. The animals were handled in accordance with Univer- suspension of AMNP (Fe ϭ 25 mM) in 0.1 M HEPES at 37C sity Paris XII guidelines for the care and use of animals, and for labeling and washed in Dulbecco’s modified Eagle’s me- housed in animal facilities at Henri Mondor Hospital. dium. AMNP consists of monocrystalline ferrimagnetic All procedures were performed using general anesthesia monodomains of maghemite, which adsorb to the cell surface with propofol (2 mg/kg per hour intravenously) and analge- and are internalized via an endocytotic pathway. AMNP can sia was administered with ketoprofen (2 mg/kg) and be detected by histological staining with Perl’s solution and buprenorphine (0.05 mg/kg intravenously). The animals by magnetic resonance imaging in living animals.12 In the were sacrificed by a lethal injection of pentobarbital (5 gm current study AMNP labeling was done to facilitate histo- intravenously). logical localization of the implants. The results of magnetic resonance imaging are the subject of a separate study. Myo- Experimental Design fiber strips 2 ϫ 10 ϫ 40 mm were prepared and implanted as Preliminary experiments. We first investigated the re- described (fig. 1, B and D). generative capacities of satellite cells implanted with myofibers in the urethra. Six pigs underwent muscle biopsy, from which myofiber cores were isolated, labeled with Urodynamic Studies AMNP for subsequent localization of the implantation zone UPP were recorded using anesthesia with propofol, a drug 13 and immediately implanted into the proximal third of the with minor effects on UPP. A 2-channel catheter (CH 8) urethra (day 0), as described. We previously reported absent was introduced into the bladder through the urethra for striated muscle at this location and in particular the SUS is measuring urethral and bladder pressures simultaneously. found around the distal urethra.11 This allowed the use of Each channel was connected to an electronic pressure trans- antibodies specific for skeletal muscle to detect myotube ducer (Laborie, Mississauga, Ontario, Canada) and perfused formation and avoided confusion between graft derived myo- with isotonic saline (2 ml per minute). UPP was measured tubes and SUS myofibers. while the catheter was withdrawn (5 cm per minute). The animals were sacrificed on days 7 (3) and 30 (3). UCP is defined as UCP ϭ urethral pressure – bladder Urethras were assayed for the presence of AMNP, activated pressure. mUCP was recorded in the proximal and distal satellite cells and myotubes. urethral segments. UPP recordings were repeated 15 minutes and 1 hour (the duration required for curare elimina- Main experiments. Using larger muscle implants we in- tion) after blockage of the neuromuscular junctions by intra- vestigated the possibility of generating a functional circular venous injection of 0.3 mg/kg pancuronium bromide. muscle layer acting like an additional SUS in a previously described model of SUS injury.11 Seven animals underwent Injury to the SUS urodynamic evaluation, followed by endoscopic destruction Deep electrocautery was applied to the ventral aspect of the of the SUS (day 0). On day 30 myofibers strips sized approx- distal urethra using a Storz® Ch 13 pediatric resector. This imately like an SUS were implanted in the proximal ure- injury results in the durable abolition of SUS contrac- thra. One animal was sacrificed 7 days later (day 37) to tions.4,11 verify satellite cell activation at the implantation site. On day 60 UPP was analyzed in 6 subjects before and after curare injection. We previously noted that curarization Histology and Immunostaining temporarily abolishes the intraurethral pressure peak asso- Urethras and myofiber implants were frozen in isopentane ciated with SUS contractions but it has no effect on urethral cooled by liquid nitrogen. A total of 30 consecutive trans- smooth muscle cells.11 Comparison of UPP values before and verse 10 ␮m cryosections collected at 2,000 ␮m intervals after curarization permits quantification of the tonic con- throughout the entire urethra were transferred onto tractions exerted by innervated striated muscle tissue in the silanated glass slides. 334 INTRAURETHRAL TRANSFER OF SATELLITE CELLS BY MYOFIBER IMPLANTS

serum to block nonspecific antibody binding, incubated at 37C with primary antibodies for 1 hour and incubated with secondary antibodies. Primary antibodies for muscle cells were mouse monoclonal anti-MHCf (Novocastra™) at 1:60 to detect mature myotubes and mouse monoclonal anti-human desmin (Dako- Cytomation, Glostrup, Denmark) at 1:100. Desmin is expressed in the cytoplasm of activated satellite cells and young myotubes but not by quiescent satellite cells.14 Neu- ronal markers were rabbit polyclonal anti-VAChT (Sigma®- Aldrich®) at 1:500 and mouse monoclonal anti-human neurofilament protein (DakoCytomation) at 1:200. Anti-VAChT recognizes the functional acetylcholine transporter of the presynaptic vesicles. To study the inflammatory reaction we used the monoclonal mouse anti-human leukocyte common antigen (CD45) and mouse anti-human macrophage (CD68) (DakoCytomation) at 1:100.

FIG. 1. Myofiber preparation and implantation. A, aspect of myofiber core before implantation in urethra. B, aspect of myofiber strip before implantation in urethra. C, surgical procedure for myofiber core implantation. Total of 40, 2 ϫ 10 mm cores were inserted into 1 ml syringe fitted with BD Microlance™ 16 gauge needle. Urethra in same animal was exposed by laparotomy and needle was inserted into smooth muscle layer of proximal urethra parallel to urethra and slowly withdrawn while implanting myofibers at 4 points ven- trally and laterally. SUS was found at distal third of urethra. D, myofiber strip implantation in pig model of SUS injury. Proximal urethra smooth muscle layer (sm) was approached by laparotomy, incised over 1 cm and separated from urethral mucosa (mu) over entire circumference to create space for implantation. Myofiber strip FIG. 2. Histological studies on days 7 and 30 after myofiber core (my) was positioned, so that myofibers formed circular layer in implantation in proximal urethra. A, day 7 detection of AMNP in urethral wall. E, transverse section of myofiber core after AMNP proximal urethra using Perl’s Prussian blue staining solution, coun- staining and needle passage with myofibers oriented longitudinally. terstained with eosin. Scale bar indicates 1 cm. B, on day 7 slowly Staining with Perl’s Prussian blue solution shows AMNP accumu- degenerating myofibers (arrows) surrounded by AMNP (blue areas) lation (blue areas) at core periphery. F, Alexa-Fluor 488 immuno- were observed at higher magnification. Scale bar indicates 100 ␮m. staining for desmin (green areas) and nuclear staining with DAPI C, on day 7 immunostaining for desmin with Alexa-Fluor 488 shows (blue areas) in implant cross-section immediately after isolation cytoplasm (green areas) in adjacent cross-section with numerous reveals absent activated satellite cells. All myonuclei were in pe- activated satellite cells and young myotubes (arrows) in vicinity of ripheral position. Scale bars indicate 50 ␮m. degenerating myofibers (asterisks). Nuclei stained with Hoechst 33342 (red areas). Scale bar indicates 50 ␮m. D, on day 30 persistent AMNP were identified in proximal urethra after myofiber core im- To detect AMNP the cryosections were incubated for 2 plantation with Perl’s Prussian blue staining. Scale bar indicates 1 minutes with Perl’s Prussian stain (2% potassium ferrocya- cm. E, on day 30 immunostaining for MHCf using Alexa-Fluor 488 in adjacent cross-section reveals myotube clusters arranged longi- nide in 2% HCl) to stain AMNP in blue, washed with phos- tudinally like myofibers in implants before injection (fig. 1, E). phate buffered saline and counterstained with eosin. After Nuclei stained with DAPI (blue areas). Scale bar indicates 100 ␮m. revealing AMNP adjacent cryosections were immuno- F, on day 30 larger magnification demonstrates that compared with stained. myofibers before implantation (fig. 1, F) myotubes have nuclei in central position (arrows), providing evidence of myogenic process For immunostaining protocols cryosections were incu- resulting from satellite cell activation and fusion. Scale bar indi- bated in phosphate buffered saline with 20% appropriate cates 50 ␮m. INTRAURETHRAL TRANSFER OF SATELLITE CELLS BY MYOFIBER IMPLANTS 335

parametric test. All tests were done with 2-tailed ␣ consid- mUCP in proximal and distal urethral segments before injury and 30 days after myofiber or adipocyte implantation ered at 0.05. Mean Ϯ SEM Implantation (cm H O) 2 RESULTS mUCP Adipocyte Myofiber p Value Preliminary Experiments Proximal: Baseline 15 Ϯ 6 16.6 Ϯ 3.8 Not significant Numerous desmin expressing cells surrounded by AMNP Day 60 without curare 16.2 Ϯ 7.3 71.5 Ϯ 17.8 0.037 and degenerating myofibers were found on day 7 in the Day 60 after curare 16.5 Ϯ 10 33.5 Ϯ 14.8 Not significant Distal: proximal urethra (fig. 2, A to C). On day 30 immunostaining Baseline 64.2 Ϯ 11.5 62.3 Ϯ 8 Not significant for MHCf revealed the presence of myotubes oriented par- Day 60 without curare 22 Ϯ 4.9 35.1 Ϯ 18.5 Not significant allel to the axis of the urethra. Their myonuclei were in a Day 60 after curare 21.7 Ϯ 4 25.6 Ϯ 8.6 Not significant central position, in contrast to those of the implants imme- Day 60 measurements were performed before and 15 minutes after curare diately after isolation (fig. 2, E and F). No AMNP or myo- injection. tubes were found below the injection site. Leukocytes were found only on day 7 and they essentially comprised macrophages. There was no evidence of abscess formation. Secondary antibodies were Alexa Fluor® 488 (green) or Alexa-Fluor 594 (red) goat anti-mouse IgG, Alexa-Fluor 594 (red) goat anti-rabbit IgG (1:500) (Molecular Probes®) and Urodynamics horseradish-peroxidase rabbit anti-mouse IgG at 1:200 (Da- The table and figure 3 show urodynamic results. Before koCytomation). The latter was revealed with a DAB Kit endoscopic injury a pressure peak was noted in the distal (Vector Laboratories, Burlingame, California). urethra, corresponding to tonic contractions of the SUS. On Nuclei were counterstained with Hoechst-33342 or DAPI day 60 we observed a significant decrease in mUCPdist in the at 1:1,000. The position of the nuclei was the main criterion Ϯ Ϯ ϭ adipocyte (64.2 11.5 vs 22 4.9 cm H2O, p 0.002) and to differentiate myofibers from myotubes, in that the nuclei Ϯ Ϯ ϭ myofiber (62.3 8 vs 35.1 18.5 cm H2O, p 0.011) of myofibers are located in a peripheral position of the cyto- implantation groups compared to baseline. After myofiber plasm under the plasmic membrane, whereas they typically implantation a distinct pressure peak was constantly found occupy the center of the myotubes resulting from MPC fu- 7,8 in the UPP initial segment. Curare injection resulted in a sion. Acetylcholine receptors were detected by incubation significant decrease in mUCP after 15 minutes (71.5 Ϯ ␣ prox with Alexa-Fluor 488 -bungarotoxin (Molecular Probes) at 17.8 vs 33.5 Ϯ 14.8 cm H O, p ϭ 0.031). After 60 minutes the 1:500 for 1 hour at 37C. 2 UPP recovered its initial appearance. The mUCPprox was For double immunostaining (MHCf/VAChT) the second not significantly modified after adipocyte implantation. primary antibody was applied only after the first secondary antibody was developed. Myotubes were considered innervated if they had 1 acetylcholine receptor connected to a Myofiber Strip Regeneration nerve ending. Slides were analyzed using a Zeiss Axioplan® Evidence of satellite cell activation was observed in the 2 microscope. urethra of the 1 pig sacrificed 7 days after myofiber implantation (fig. 4, A). On day 60 a circular layer of myotubes was Statistical Analysis found in the smooth muscle layer of the proximal urethra All data are reported as the mean Ϯ SEM. For statistical (fig. 4, B). There was no evidence of abscess formation. analysis we used SAS®, version 9.13. Comparisons of Leukocytes, mainly macrophages, were found only on day 37 mUCPdist and mUCPprox values before and after implanta- (fig. 4, E). No myotubes were found in the control group tion were performed with the unpaired Mann-Whitney non- (fig. 4, D).

FIG. 3. Urodynamic studies in main experiments. A, UPP in 1 pig before endoscopic injury on day 0. SUS generated peak of intraurethral pressure in distal urethral segment (arrow). B, 1 month after myoﬁber strip implantation or day 60 from SUS injury distinct pressure peak (arrow) was found in proximal urethra, whereas overall SUS activity dramatically decreased. C, second recording 15 minutes after curare injection in same animal shows abolition of intraurethral pressure peak (arrow) in proximal urethra. D, superposition of parts B and C. E, 60 minutes after curare injection (arrow), which is time needed for curare elimination, UPP aspect returned to normal. Intraurethral pressure decrease in proximal urethra after curare injection indicates that graft derived myotubes exerted genuine muscular tonic contraction under neural control. 336 INTRAURETHRAL TRANSFER OF SATELLITE CELLS BY MYOFIBER IMPLANTS

myofiber degeneration and satellite cell activation, followed by myotube formation. Myotubes were oriented in the same direction as the parental myofibers, suggesting that satellite cell fusion was tutored by the tubes of extracellular matrix surrounding each myofiber. We next increased the mass of regenerating muscle with the myofibers oriented circularly in the urethra and found that the graft derived myotubes

increased the mUCPprox and had cholinergic receptors con- ϩ nected to VAChT nerves endings. The mUCPprox reaction to curarization strongly suggests that it results from a genuine muscular tonic activity under neural control because the mechanism of action of curare relies on the existence of functional neuromuscular junctions. Although UPP has poor value to assess urinary incontinence, we consider that the use of curare represents a pertinent tool for assessing the presence of tonic muscular contractions. Adipocyte implantation did not increase the mUCP. Ad- ipose tissue contains stem cells representing a potential therapeutic agent for urinary incontinence.15 The absence of urodynamic modifications may be explained by the fact that stem cells present in the strips were not differentiated toward a myogenic lineage before implantation. Intraurethral injection of stem cells harvested from lipoaspirate results in the formation of smooth muscle cells that may also exert tonic contractions.15 However, this process requires more than 1 month. Therefore, it cannot be excluded that an increase in mUCP associated with adipose stem cell differentiation would have been observed later in this group. The FIG. 4. Evidence of myotube formation in proximal urethra after myofiber strip implantation. A, cross-section of proximal urethra absence of an mUCP change can also be explained by the immunostained for desmin with Alexa-Fluor 488 (green areas) 7 fact that adipocyte strips were implanted surgically without days (day 37) after myofiber implantation shows activated satellite any tension, so that they did not narrow the urethral lumen. cells (arrowheads indicate nuclei of 2 satellite cells) and young This differs from previous trials with endoscopic injection of myotubes oriented longitudinally in urethral wall (arrows indicate nuclei at central position of myotubes). Nuclei counterstained with Hoechst 33342 (red areas). B, immunostaining for MHCf with Alexa-Fluor 488 in proximal urethra 1 month after myofiber implantation (day 60). Nuclei counterstained with DAPI (blue areas). C, lower magnification of urethra immunostained for MHCf with DAB (brown areas) shows myotubes arranged in circular layer close to urethral lumen (asterisk). D, in control group immunostaining for MHCf with DAB shows absent myotube formation in proximal urethra where adipocyte strips were implanted. E and F, assessment of inflammatory response. Seven days after myofiber strip implantation (day 37) immunostaining for CD45 and CD68 showed infiltration of leukocytes that mainly consisted of macrophages (CD68) in proximal urethra. E, immunostaining for CD68 with DAB. F, on day 60 no CD68ϩ cells were found in vicinity of graft derived myotubes stained with DAB. Scale bars indicate 100 ␮m.

Evidence of Myotube Innervation One month after myofiber implantation bundles of nerve fibers expressing neurofilament and VAChT were observed running toward clusters of myotubes (fig. 5). Nerve density was greater in the vicinity of the myotubes than at other urethral areas, where only sparse nerve fibers were ob- FIG. 5. Evidence of myotube innervation by cholinergic nerves in served. Immunostaining of VAChT showed that these proximal urethra on day 60. A, double immunostaining for MHCf with Alexa-Fluor 488 (green areas) and VAChT with Alexa-Fluor nerves fibers were cholinergic. Approximately 30% of the 594 (red areas) reveals bundles of cholinergic nerves fibers running acetylcholine receptors detected on the myotubes of a given toward clusters of graft derived myotubes. Scale bar indicates 100 cross-section appeared to be connected to a nerve ending. ␮m. B, staining with bungarotoxin with Alexa-Fluor 488 and immunostaining for neurofilament with Alexa-Fluor 594 on adjacent cross-section shows acetylcholine receptors connected to nerve fi- DISCUSSION bers (arrowhead), whereas others are not connected (arrow). Scale bar indicates 100 ␮m. C and D, higher magnification shows cross- We investigated a new therapeutic approach to stress uri- sections. Arrows indicate nerve fibers reaching acetylcholine recep- nary incontinence, consisting of the implantation of myofi- tors (arrowheads). Stained with bungarotoxin and Alexa-Fluor 488. C, also immunostained for neurofilament with Alexa-Fluor 594. bers with associated satellite cells to generate a myogenic Scale bar indicates 10 ␮m. D, also immunostained for neurofilament process in the urethra. Muscle core implantation resulted in with VAChT and Alexa-Fluor 594. Scale bar indicates 10 ␮m. INTRAURETHRAL TRANSFER OF SATELLITE CELLS BY MYOFIBER IMPLANTS 337 mature adipocytes, which were aimed at swelling the sub- muscle-derived progenitor cell injection into the denervated mucosa, thus, producing a bulking effect.16 rat urethra. Urology 2003; 62: 958. The process of degeneration of implanted myofibers is 2. Peyromaure M, Sebe P, Praud C, DeRocle G, Potin N, Pinset C comparable to the process after experimental muscle dener- et al: Fate of implanted syngenic muscle precursor cells in vation/devascularization.17 On day 7 there was leukocyte striated urethral sphincter of female rats: perspectives for treatment of urinary incontinence Urology 2004; 64: 1037. infiltration and phagocytosis of degenerating myofibers by 3. Strasser H, Marksteiner R, Margreiter E, Pinggera GM, Mit- macrophages, concurrent with myogenic activation. The use terberger M, Fritsch H et al: Stem cell therapy for urinary of small diameter strips may avoid the risk of extensive incontinence. Urologe A 2004; 43: 1237. necrosis at the center of the implant and subsequent abscess 4. Yiou R, Yoo JJ and Atala A: Restoration of functional motor formation. units in a rat model of sphincter injury by muscle precursor Myofiber implantation clearly exerted a trophic effect on cell autografts. Transplantation 2003; 76: 1053. the urethral nervous system, resulting in the development of 5. Morgan JE and Partridge TA: Muscle satellite cells. Int J Bio- a dense network of nerve fibers running toward myotubes. chem Cell Biol 2003; 35: 1151. The cellular signaling pathways inducing nerve sprouting in 6. Zammit PS, Heslop L, Hudon V, Rosenblatt JD, Tajbakhsh S, the urethra are currently under investigation at our labora- Buckingham ME et al: Kinetics of myoblast proliferation show that resident satellite cells are competent to fully regenerate tory. They likely imply the presence of neurotrophic growth skeletal muscle fibers. Exp Cell Res 2002; 281: 39. factors produced by regenerating myotubes, degenerating 7. Yiou R, Lefaucheur JP and Atala A: The regeneration process 18,19 myofibers and extracellular matrix. To our knowledge of the striated urethral sphincter involves activation of our results are original, in that they describe a nerve sprout- intrinsic satellite cells. Anat Embryol (Berl) 2003; 206: 429. ing process at a location initially deprived of myofibers and 8. Collins CA, Olsen I, Zammit PS, Heslop L, Petrie A, Partridge motoneurons. TA et al: Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell CONCLUSIONS niche. Cell 2005; 122: 289. 9. Montarras D, Morgan J, Collins C, Relaix F, Zaffran S, The concept of MPC delivery that we developed differs from Cumano A et al: Direct isolation of satellite cells for skeletal other ongoing cell therapy protocols3 because it implies a muscle regeneration. Science 2005; 309: 2064. surgical approach. However, this procedure allows the 10. Smythe GM and Grounds MD: Exposure to tissue culture proper orientation of myotube formation in the urethra, a conditions can adversely affect myoblast behavior in vivo in factor that is not controlled with MPC injection. Its objective whole muscle grafts: implications for myoblast transfer is also different because it attempts to generate an addi- therapy. Cell Transplant 2000; 9: 379. 11. Zini L, Lecoeur C, Swieb S, Combrisson H, Delmas V, Gherardi tional sphincter instead of reinforcing the original one by R et al: The striated urethral sphincter of the pig shows MPC injection. In that sense the described procedure is close morphological and functional characteristics essential for to a transposition of gracilis muscle with preserved neuro- the evaluation of treatments for sphincter insufficiency. 20 vascular pedicle (graciloplasty). The fundamental differ- J Urol 2006; 176: 2729. ence resides in the degeneration/regeneration process asso- 12. Wilhelm C, Billotey C, Roger J, Pons JN, Bacri JC and Gazeau ciated with myofiber implantation, resulting in the F: Intracellular uptake of anionic superparamagnetic nano- innervation of regenerated myotubes by urethral nerves. particles as a function of their surface coating. Biomaterials Further studies are warranted to compare the effects of 2003; 24: 1001. myofiber implantation vs MPC injection or graciloplasty. 13. Combrisson H, Robain G and Cotard JP: Comparative effects of xylazine and propofol on the urethral pressure profile of healthy dogs. Am J Vet Res 1993; 54: 1986. ACKNOWLEDGMENTS 14. Rantanen J, Hurme T, Lukka R, Heino J and Kalimo H: Dr. Geoffrey Liu critically read the manuscript, and Philippe Satellite cell proliferation and the expression of myogenin Druelle and Philippe Mario provided animal care and man- and desmin in regenerating skeletal muscle: evidence for two different populations of satellite cells. Lab Invest 1995; aged surgical procedures. 72: 341. 15. Jack GS, Almeida FG, Zhang R, Alfonso ZC, Zuk PA and Rodriguez LV: Processed lipoaspirate cells for tissue engi- Abbreviations and Acronyms neering of the lower urinary tract: implications for the treatment of stress urinary incontinence and bladder recon- AMNP ϭ anionic magnetic nanoparticles ϭ struction. J Urol 2005; 174: 2041. DAPI 4,6-diamidino-2-phenylindole 16. Haab F, Zimmern PE and Leach GE: Urinary stress inconti- MHCf ϭ fast myosin heavy chain ϭ nence due to intrinsic sphincteric deficiency: experience MPC muscle precursor cell with fat and collagen periurethral injections. J Urol 1997; mUCP ϭ maximal UCP ϭ 157: 1283. mUCPdist distal urethral segment mUCP ϭ 17. Lefaucheur JP and Sebille A: The cellular events of injured mUCPprox proximal urethral segment mUCP muscle regeneration depend on the nature of the injury. SUS ϭ striated urethral sphincter ϭ Neuromuscul Disord 1995; 5: 501. UCP urethral closure pressure 18. English AW: Cytokines, growth factors and sprouting at the UPP ϭ urethral pressure profilometry ϭ neuromuscular junction. J Neurocytol 2003; 32: 943. VAChT vesicular acetylcholine transporter 19. van Mier P and Lichtman JW: Regenerating muscle fibers induce directional sprouting from nearby nerve terminals: REFERENCES studies in living mice. J Neurosci 1994; 14: 5672. 20. Janknegt RA, Baeten CG, Weil EH and Spaans F: Electrically 1. Cannon TW, Lee JY, Somogyi G, Pruchnic R, Smith CP, Huard stimulated gracilis sphincter for treatment of bladder J et al: Improved sphincter contractility after allogenic sphincter incontinence. Lancet 1992; 340: 1129. hSMR3A as a Marker for Patients With Erectile Dysfunction

Yuehong Tong, Moses Tar, Val Monrose, Michael DiSanto, Arnold Melman and Kelvin P. Davies* From the Institute of Smooth Muscle Biology, Department of Urology, Albert Einstein College of Medicine, Bronx, New York, New York

Purpose: We recently reported that Vcsa1 is one of the most down-regulated genes in the corpora of rats in 3 distinct models of erectile dysfunction. Since gene transfer of plasmids expressing Vcsa1 or intracorporeal injection of its mature peptide product sialorphin into the corpora of aging rats was shown to restore erectile function, we proposed that the Vcsa1 gene has a direct role in erectile function. To determine if similar changes in gene expression occur in the corpora of human subjects with erectile dysfunction we identified a human homologue of Vcsa1 (hSMR3A) and determined the level of expression of hSMR3A in patients. Materials and Methods: hSMR3A was identified as a homologue of Vcsa1 by searching protein databases for proteins with similarity. hSMR3A cDNA was generated and subcloned into the plasmid pVAX to generate pVAX-hSMR3A. pVAX-hSMR3A (25 or 100 ␮g) was intracorporeally injected into aging rats. The effect on erectile physiology was compared histologically and by measuring intracorporeal pressure/blood pressure with controls treated with the empty plasmid pVAX. Total RNA was extracted from human corporeal tissue obtained from patients undergoing previously scheduled penile surgery. Patients were grouped according to normal erectile function (3), erectile dysfunction and diabetes (5) and patients without diabetes but with erectile dysfunction (5). Quantitative reverse-transcriptase polymerase chain reaction was used to determine the hSMR3A expression level. Results: Intracorporeal injection of 25 ␮g pVAX-hSMR3A was able to significantly increase the intracorporeal pressure-to- blood pressure ratio in aging rats compared to age matched controls. Higher amounts (100 ␮g) of gene transfer of the plasmid caused less of an improvement in the intracorporeal pressure-to-blood pressure ratio compared to controls, although there was histological and visual evidence that the animals were post-priapitic. These physiological effects were similar to previously reported effects of intracorporeal injection of pVAX-Vcsa1 into the corpora of aging rats, establishing hSMR3A as a functional homologue of Vcsa1. More than 10-fold down-regulation in hSMR3A transcript expression was observed in the corpora of patients with vs without erectile dysfunction. In patients with diabetes associated and nondiabetes associated erectile dysfunction hSMR3A expression was found to be down-regulated. Conclusions: These results suggest that hSMR3A can act as a marker for erectile dysfunction associated with diabetic and nondiabetic etiologies. Given that our previous studies demonstrated that gene transfer of the Vcsa1 gene and intracorporeal injection of its protein product in rats can restore erectile function, these results suggest that therapies that increase the hSMR3A gene and product expression could potentially have a positive impact on erectile function. Key Words: penis; diabetes; impotence; gene transfer techniques; rats, Sprague-Dawley

National Institutes of Health consensus panel defined Penile erection is a neurovascular process that relies on a ED as the inability to achieve or maintain erection concerted action of the nervous system, the vascular system A sufficient for satisfactory sexual performance. The and cavernous smooth muscle tissues. ED is attributable to development of ED is multifactorial and there are several inability of the cavernous smooth muscle tissue to undergo risk factors for ED. Depending on the cause ED can be relaxation. It might be expected that different types of ED broadly classified as organic, psychogenic or mixed.1 Because that have overlapping pathophysiological mechanisms may of the multifactorial nature of ED, it has been difficult to identify also have common biochemical pathways contributing to a universal molecular marker for organic ED. Two of the most ED. However, microarray studies of different models of ED, common risk factors for organic ED are diabetes and aging.2 such as diabetes4 and post-radical prostatectomy models,5 Diabetic men are 3 times as likely to have ED as nondiabetic men only serve to highlight that ED involves changes in a diverse and men 50 to 90 years old are at 10 times greater risk for ED set of molecular pathways that do not overlap. However, we than those younger than 50 years.3 and others recently reported that the Vcsa1 transcript (variable coding sequence a1 gene, also known as a submandibular rat 1 gene) is one of the most down-regulated genes in Submitted for publication August 23, 2006. the corpora of rats in 3 distinct models of ED, including Study received approval from the Albert Einstein College of Med- diabetic, age related and neurogenic (bilaterally ligated cav- icine Animal Use Committee and the AECOM/Montefiore Hospital ernous nerve) ED models.5,6 These reports led to the sug- Internal Review Board. Supported by National Institutes of Health, National Institute of gestion that Vcsa1 is a potential marker for ED. Diabetes and Digestive and Kidney Diseases Grants P01-DK060037 Vcsa1 encodes a precursor protein that gives rise to 3 and K01-DK67270 (KPD). peptide products, including an undecapeptide, a hexapep- * Correspondence: Department of Urology, Albert Einstein Col- 7 lege of Medicine, Bronx, New York 10461 (telephone: 01 718 430 tide and a pentapeptide. The final mature peptide is the 3201; e-mail: [email protected]). pentapeptide, named sialorphin. There are several lines of

0022-5347/07/1781-0338/0 338 Vol. 178, 338-343, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.004 hSMR3A AS ERECTILE DYSFUNCTION MARKER 339 evidence that sialorphin has a role in male rat sexuality Cloning of hSMR3A since there is 100 to 500 times greater circulating sialorphin and Construction of pVAX-hSMR3A peptide levels in adult male rats than in females and dorsal We PCR amplified the full length gene from human corpo- tail injection of sialorphin modulates male rat sexual behav- real cell cDNA using the primers SMR3AF (5=-ggatgaaat- ior.8,9 In addition, when Vcsa1 was intracorporeally injected cactgacttggatc-3=) and SMR3AR (5=-gtatttagggtgcaggag- into aging rats, there was improved erectile function at taggg-3=), and cloned hSMR3A into the pPCR-4-TOPO lower doses and priapism occurred at higher doses, leading vector. After sequencing the insert to confirm the correct to the suggestion that the Vcsa1 gene product has a direct sequence we subcloned hSMR3A into the pVAX vector (In- role in erectile function. Indeed, it was subsequently shown vitrogen™) to create pVAX-hSMR3A. that the mature peptide product of Vcsa1, sialorphin, can also restore erectile function in the aging rat, mediated Measurement of ICP/BP through smooth muscle tissue relaxation.10 A total of 17 Sprague-Dawley retired breeder rats at ages 9 Homologues with close identity to the Vcsa1 gene were to 10 months weighing greater than 500 gm were used to reported in mice (mSG1, mSG2 and mSMR2), cows (bovine determine the effect of intracorporeal injection of pVAX- P-B) and humans (hSMR3A).11,12 The human homologue hSMR3A or the empty vector pVAX on erectile physiology, 6 hSMR3A has 34% identity with Vcsa1 over the entire amino essentially as previously described. All study protocols acid sequence and 55% identity in the first 38 amino acids of were approved by the Animal Use Committee at the the protein, which encodes the functional mature peptide Albert Einstein College of Medicine. For gene transfer experiments vectors/plasmids were mi- sialorphin. The similarity of the sequences suggests that the croinjected into the rat corporeal tissue, essentially as pre- 2 proteins may perform similar physiological roles. There- viously described.6 Briefly, the rats were anesthetized with fore, we determined if hSMR3A is a functional homologue of pentobarbital sodium (35 mg/kg intraperitoneally). An incision Vcsa1, and if patients with ED have decreased hSMR3A was made through the perineum, the corpus spongiosum was expression. hSMR3A might then serve as a marker for or- identified and a window was made in the corpus spongiosum ganic ED in patients and potentially as a target for its to identify the corpus cavernosum. Using an insulin syringe treatment. all microinjections consisted of a bolus injection of naked plasmid DNA into the corporeal tissue. The final volume of all microinjections was 150 ␮l. MATERIALS AND METHODS For cavernosometry determining the ICP response to CN stimulation the rats were anesthetized with pentobarbital so- Sequence Analysis and Comparison dium (35 mg/kg intraperitoneally). An incision was made in the The Basic Local Alignment Search Tool, available from perineum and a window was made in the ischiocavernosus the National Center of Biotechnology, National Institutes muscle to expose the corpus cavernosum. The CNs were iden- of Health, was used to search for gene and protein se- tified adjacent to the prostate gland. The CN was directly quences with similarity to Vcsa1. Sequences were aligned electrostimulated with a delicate stainless steel bipolar hook using MultiAlin,13 available on-line from Institut National electrode attached to a multijointed clamp. Each probe was de la Recherche Agronomique. 0.2 mm in diameter and the 2 poles were separated by 1 mm.

TABLE 1. Patient information Failure Intracavernous Diabetes Pt—Age Phosphodiesterase-5 Injection MUSE® Mellitis Other Disease Smoker Previous Pelvic Surgery Prosthesis

0A—26 No No No 0B—35 No No No 0C—51 No No No 1—62 Yes No No Yes Hypertension No Radical retropubic Semirigid prostatectomy ϩ colon 2—66 No No No Yes Hypertension, congestive No No Semirigid heart failure, hypercholesterol 3—64 Yes No No Yes Benign prostatic No Prostate Ca Inflatable hyperplasia, brachytherapy gastroesophageal reflux disease 4—65 No No No Yes Hypertension, peripheral No No Semirigid vascular disease 5—68 Yes Yes Yes Yes No No No Semirigid 6—72 No No No No Peripheral vascular disease, Yes No Inflatable osteoporosis 7—45 No No No No Hypercholesterol Yes No Inflatable 8—79 No No No No Hypothyroidism Yes No Inflatable 9—72 No No No No Gout, no family history No Penile revascularization Inflatable 10—59 Yes No No No Prostate Ca No Laparoscopic radical Inflatable prostatectomy Automobile accident, sex change surgery and penile cancer surgery in patients 0A, 0B and 0C, respectively. 340 hSMR3A AS ERECTILE DYSFUNCTION MARKER

Monophasic rectangular pulses were delivered by a signal roform. After mixing, the aqueous phases were separated by generator that was custom made with a built-in constant centrifugation at 12,000 ϫ gravity for 15 minutes at 4C and current amplifier. Stimulation parameters were frequency they were then transferred to a clean tube. RNA was pre- 20 Hz, pulse width 0.22 milliseconds, duration 1 minute, and cipitated from the aqueous phase by the addition of isopro- current 0.75 and 4 mA. Changes in ICP and systemic BP pyl alcohol and pelleted by centrifugation at 12,000 ϫ grav- were recorded at each intensity of stimulation. Mean Ϯ SD ity for 15 minutes at 4C, washed once with 75% ethanol and ICP/BP and ANOVA were calculated for each treatment again pelleted at 12,000 ϫ gravity for 15 minutes. Ethanol group. Significant differences between treatment groups was aspirated and the RNA pellet was dried and then dis- were determined by Student’s t test. solved in sterile water. Total RNA (1 ␮g) was reverse transcribed to first strand Patient Samples cDNA primed with oligo(deoxythymidine) using the Super- Human corporeal tissue was procured from several patients script™ First-Strand Synthesis System for real-time PCR. during penile prosthetic implant surgery according to proto- RNA was denatured for 5 minutes at 65C and immediately cols approved by the AECOM/Montefiore Hospital Internal cooled on ice. RNA was then combined with Superscript II Review Board. Table 1 lists the conditions and ages of pa- RT, 40 U RNaseOUT™ recombinant ribonuclease inhibitor tients 1 to 10. Tissue samples were immediately flash frozen and RT reaction buffer. cDNA synthesis was then performed after removal in liquid nitrogen and stored at –70C until for 50 minutes at 42C. RT products were amplified using RNA and cDNA preparation. SYBR® Green 2X PCR Master Mix. Real-time quantitative PCR analysis was performed using a 7300 real-time PCR sys- Isolation of Patient RNA and Quantitative RT-PCR tem (Applied Biosystems™). The primers for hSMR3A were Total RNA was extracted from frozen tissue with TRIzol® forward 5=-CTATGGTCCAGGGAGATTTCC-3= and reverse according to manufacturer instructions. Briefly, approxi- 5=-GAGGAGGAAGAGAGTGTGATTG-3=. GAPDH (forward mately 50 mg tissue were added to 1 ml TRIzol reagent and primer 5=-GCCGCCTGCTTCACCACCTTCT-3= and reverse homogenized using a Polytron™ homogenizer for 30 sec- primer 5=-GCATGGCCTTCCGTGTTCCTACC-3=) served as an onds. Homogenized tissues were incubated for 5 minutes at endogenous control. PCR reactions for all samples were per- room temperature, followed by the addition of 200 ␮l chlo- formed in 96-well plates with 1 ␮l cDNA, 100 nM of each

FIG. 1. Nucleotide sequence comparison of Vcsa1 and hSMR3A with consensus sequence and amino acid sequence comparison of Vcsa1 and hSMR3A with consensus sequence. Bold, green and underlined text indicates primers used to speciﬁcally amplify hSMR3A gene. hSMR3A AS ERECTILE DYSFUNCTION MARKER 341

␮g are injected intracorporeally but higher amounts of plas- TABLE 2. ICP/BP measurements in retired breeder rats 6 after pVAX or pVAX-hSMR3A gene transfer mid results in priapism. To confirm that hSMR3A is a and CN electrostimulation functional homologue of Vcsa1 these experiments were repeated to determine if hSMR3A has comparable physiolog- Mean Ϯ SD ICP/BP Intracorporeal No. ical effects on the penis. Injection (dose) Rats Baseline 0.75 mA 4 mA When 25 ␮g pVAX-hSMR3A were intracorporeally in- Control pVAX 8 0.063 Ϯ 0.02 0.22 Ϯ 0.12 0.33 Ϯ 0.06 jected into retired breeder rats, there was significant im- (100 ␮g) provement in the erectile response, as indicated by an in- pVAX-hSMR3A: 25 ␮g 3 0.153 Ϯ 0.06 0.28 Ϯ 0.07* 0.61 Ϯ 0.02* creased ICP-to-BP ratio compared with that in control rats 100 ␮g 5 0.102 Ϯ 0.05 0.13 Ϯ 0.07 0.39 Ϯ 0.01* treated with the empty vector pVAX (table 2). The values * Significantly different vs control (Student’s t test p Ͻ0.05). obtained were similar to those in published experiments, in which the effect of gene transfer of pVAX-Vcsa1 into the corpora of retired breeders was investigated for an effect on 6 primer and 12.5 ␮l SYBR® Green in a 25 ␮l reaction volume. erectile function. 6 Cycling conditions were SYBR Green DNA polymerase acti- Also similar to reported experiments for Vcsa1, higher vation at 95C for 10 minutes, 40 cycles of denaturation at doses of the pVAX-hSMR3A plasmid resulted in only slight 95C for 15 seconds and annealing/extension at 60C for 1 improvement in ICP-to-BP ratios (table 2), although there minute. Real-time PCR results are presented as threshold was visible and histological evidence of a priapitic episode. cycles normalized to that of the GAPDH gene according to a The histological appearance of 4 of the 5 animals treated previously described method.6 The relative quantified value with pVAX-hSMR3A showed visible indications of edema, for each target gene is expressed as 2Ϫ(Ct Ϫ Cc), where Ct and which is a possible indication of a vasocongested state, Cc represent mean threshold cycle differences after normal- whereas in untreated control animals corporeal morphology izing to GAPDH. Transcript expression was analyzed using appeared normal. Histological examination and comparison the comparative Ct method, also known as the 2–␦␦Ct to control animals also suggested that SMR3A causes method. This method was applicable because the efficiency changes in penile morphology, which might have been a of the SMR3A primers for generating products was found to result of the vasocongested (priapism-like) state (fig. 2). The be close to that of the housekeeping gene GAPDH, which dorsal vein was greatly enlarged. This would occur if there was used to normalize samples. was increased blood flow or post-penile obstruction, which was not observed. In addition, there was evidence of sinusoidal congestion of blood in animals treated with hSMR3A RESULTS but not in control animals. Overall the occurrence of vaso- DNA and Sequence Analysis congestion (a priapism-like state) has not been observed in We searched GenBank™ for human proteins with the great- the history of animal experiments at our department in est similarity to Vcsa1. The closest human gene with homol- which vasodilating drugs or genes were injected into the ogy to Vcsa1 was identified as hSMR3A, which has 34% corpora. identity with Vcsa1 at the protein level (fig. 1). In the first 38 The sequence and functional similarity of Vcsa1 to amino acids of the protein, which encodes the functional hSMR3A suggests that they are indeed the homologues of mature peptide sialorphin, there is 55% identity. This level each other. Since we proposed that Vcsa1 is a marker for ED of identity suggests that the proteins perform similar phys- in rats,6 we performed analysis of human corporeal samples iological roles. to determine if hSMR3A is present in patients with no reported ED and down-regulated in patients with ED. Effect of Intracorporeal pVAX-hSMR3A Injection Into Retired Breeders on Erectile Physiology Detection of SMR3A in Human Corpora We previously reported that pVAX-Vcsa1 injection into re- Although the rat Vcsa1 gene was originally isolated from the tired breeder rats can improve erectile physiology when 25 rat submandibular gland (hence, the original designation

FIG. 2. Histological comparison of distal sections of normal penis and that of rat treated with 100 ␮g pVAX-hSMR3A. Reduced from ϫ4. 342 hSMR3A AS ERECTILE DYSFUNCTION MARKER

SMR1) and it is highly expressed in that tissue, it appears to our knowledge we report for the first time that hSMR3A is be expressed in various other tissues.12 We recently reported expressed in human corpora tissue and it is down-regulated its presence in rat corpus cavernosum tissue. Therefore, we in patients with ED. Down-regulation of hSMR3A is highly determined if hSMR3A is similarly present in human corpo- significant despite the small number of control patient sam- real tissue. Corporeal samples were available from patients ples that could be obtained for this study. The addition of 0A, 0B and 0C, who did not report ED (table 1). In these 3 more control patients may have to wait for a less invasive patients hSMR3A was clearly detectable using quantitative assay, for example an immunoassay, in which the protein RT-PCR. To our knowledge this is the first demonstration product of hSMR3A is measured in the bloodstream. How- that the gene is expressed in human corporeal tissues. ever, the current study indicates that hSMR3A acts as a marker for human ED. Decreased hSMR3A Expression in Patients Although in the rat Vcsa1 and hSMR3A appear to have a With ED Compared to That in Patients Without ED direct role in erectile function since intracorporeal injection We recently reported that the rat homologue of Vcsa1 was of plasmids expressing the gene can improve erectile func- down regulated in animals with ED.6 We determined tion in an aging model of ED, down-regulation of the gene hSMR3A levels in patients undergoing prosthetic implant could be a cause or an effect of ED. In the rat Vcsa1 gene surgery (table 1 and fig. 3). hSMR3A expression in the expression is regulated by androgens, which can cause 100 patients was normalized to GAPDH and the expression level to 200-fold enhancement of Vcsa1 in the acinar cells of rat 9,14 was compared to that in patient 0A without ED. In patients submandibular glands during puberty. To our knowledge with ED there were significantly lower levels of expression it remains to be determined if the regulation of hSMR3A compared to those in the 3 control patients (more than a expression is also under hormonal regulation. 10-fold decrease, Student’s t test p Ͻ0.5), suggesting that, as We recently noted that the mature peptide product of in the rat model, hSMR3A is a marker for erectile function. Vcsa1, sialorphin, was able to directly improve erectile func- 10 We also grouped the patients with ED into those with and tion in the aging rat. Sialorphin acts as an inhibitor of rat 15 without diabetes. The 2 groups had significantly lower levels membrane bound NEP. We proposed that the ability of of hSMR3A expression compared to control patients (Stu- sialorphin to prolong the activity of agonists that are nor- dent’s t test p Ͻ0.5). However, compared to the control mean mally broken down by NEPs causes heightened smooth mus- age of 37 years the median age in the 2 ED groups with and cle relaxation in the corpora cavernosa, leading to penile without diabetes was higher (each mean 65). Therefore, in erection. Given the similarity of the amino acid sequence these groups of patients it was not possible to distinguish if and the fact that SMR3A and Vcsa1 are down-regulated the reported ED was a result of diabetes or age. However, with ED, it is likely that hSMR3A also gives rise to peptide overall down-regulation of hSMR3A expression is a marker products that act as NEP inhibitors and, thereby, cause for ED caused by several factors. human corporeal smooth muscle tissue relaxation. Recently PROL1, another member of the Vcsa1 gene family found in DISCUSSION humans, was shown to give rise to a protein product called opiorphin, which is secreted in saliva. This protein also acts as We provide evidence that hSMR3A is the human homologue an NEP inhibitor, suggesting that the physiological effect of of the Vcsa1 gene. This conclusion is based on sequence com- this family of proteins is mediated through NEP inhibition.16 parison and gene transfer of hSMR3A by intracorporeal injec- The identification of hSMR3A as a marker for ED has tion into an aging rat model. Similar to Vcsa1, hSMR3A can applications as a diagnostic tool for organic ED and in the improve erectile function when 25 ␮g are intracorporeally development of novel therapies. In the era of agents that are injected and it can cause priapism at higher amounts.6,10 To noninvasive and successful for treating ED the quest to establish an etiological diagnosis has been downplayed. However, the potential ability to suggest to the patient that the condition is reversible, ie psychogenic if the level is normal, with an accurate but invasive test (diagnostic corporeal biopsy) or with the development of a noninvasive immunoassay would be of significance to the physician and patient, particularly young men who are convinced that they have a nonreversible physical problem, as well as for reimbursement issues for therapy by insurance companies.17 In addition, it is increasingly recognized that ED is an important marker of vascular disease and there is growing evidence that ED and cardiovascular disease share common mechanisms of development through vascular endothelial dysfunction.18 Indeed, it has been recommended that patients with ED should be investigated for cardiovascular disease.19 The development of a test for organic ED in men who approach physicians for treatment represents an enormous potential for prescreening and the prevention of more FIG. 3. hSMR3A transcript expression was analyzed using compar- serious vascular complications. In conclusion, given that our –␦␦Ct ative Ct method, also known as 2 method, which was applicable previous studies demonstrated that gene transfer of the because SMR3A primer efficiency for generating products was close to that of housekeeping gene GAPDH used to normalize samples. Vcsa1 gene and its protein product in rats can restore erec- Expression level is compared to that in patient 0A. tile function,6,10 these results suggest that therapies that hSMR3A AS ERECTILE DYSFUNCTION MARKER 343 increase the expression of the hSMR3A gene or other genes basic cleavage sites. Salivary and bloodstream secretion in the Vcsa1 gene family, resulting in peptide products that products. Eur J Biochem 1994; 219: 765. act as NEP inhibitors, could have a positive impact on erec- 8. Messaoudi M, Desor D, Nejdi A and Rougeot C: The endoge- tile function. nous androgen-regulated sialorphin modulates male rat sexual behavior. Horm Behav 2004; 46: 684. 9. Rosinski-Chupin I, Huaulme JF, Rougeot C and Rougeon F: The transcriptional response to androgens of the rat VCSA1 Abbreviations and Acronyms gene is amplified by both binary and graded mechanisms. BP ϭ blood pressure Endocrinology 2001; 142: 4550. CN ϭ cavernous nerve 10. Davies KP, Tar M, Rougeot C and Melman A: Sialorphin (the Ct ϭ crossing threshold mature peptide product of Vcsa1) relaxes corporal smooth ED ϭ erectile dysfunction muscle tissue and increases erectile function in the ageing GAPDH ϭ glyceraldehyde-3-phosphate rat. BJU Int 2007; 99: 431. dehydrogenase 11. Isemura S and Saitoh E: Molecular cloning and sequence anal- hSMR3A ϭ human homologue of SMR1 ysis of cDNA coding for the precursor of the human salivary ICP ϭ intracorporeal pressure proline-rich peptide P-B. J Biochem (Tokyo) 1994; 115: NEP ϭ neutral endopeptidase 1101. PCR ϭ polymerase chain reaction 12. Isemura S, Watanabe S, Fujiwara S and Sanada K: Tissue RT ϭ reverse transcriptase distribution and nucleotide sequence of bovine mRNA for SMR1 ϭ submandibular rat 1 gene salivary proline-rich protein P-B. Arch Oral Biol 2004; 49: Vcsa1 ϭ variable coding sequence a1 gene 881. 13. Corpet F: Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res 1988; 16: 10881. REFERENCES 14. Rosinski-Chupin I, Tronik D and Rougeon F: High level of accumulation of a mRNA coding for a precursor-like protein 1. Lizza EF and Rosen RC: Definition and classification of erectile in the submaxillary gland of male rats. Proc Natl Acad Sci dysfunction: report of the Nomenclature Committee of the U S A 1988; 85: 8553. International Society of Impotence Research. Int J Impot 15. Rougeot C, Messaoudi M, Hermitte V, Rigault AG, Blisnick T, Res 1999; 11: 141. 2. Korenman SG: Epidemiology of erectile dysfunction. Endocrine Dugave C et al: Sialorphin, a natural inhibitor of rat mem- 2004; 23: 87. brane-bound neutral endopeptidase that displays analgesic 3. Shabsigh R, Perelman MA, Lockhart DC, Lue TF and Brod- activity. Proc Natl Acad SciUSA2003; 100: 8549. erick GA: Health issues of men: prevalence and correlates of 16. Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Unge- erectile dysfunction. J Urol 2005; 174: 662. heuer MN et al: Human opiorphin, a natural antinocicep- 4. Sullivan CJ, Teal TH, Luttrell IP, Tran KB, Peters MA and tive modulator of opioid-dependent pathways. Proc Natl Wessells H: Microarray analysis reveals novel gene expres- Acad SciUSA2006; 103: 17979. sion changes associated with erectile dysfunction in dia- 17. Melman A, Fogarty J and Hafron J: Can self-administered betic rats. Physiol Genomics 2005; 23: 192. questionnaires supplant objective testing of erectile func- 5. User HM, Zelner DJ, McKenna KE and McVary KT: Micro- tion? A comparison between the International Index of array analysis and description of SMR1 gene in rat penis in Erectile Function and objective studies. Int J Impot Res a post-radical prostatectomy model of erectile dysfunction. 2006; 18: 126. J Urol 2003; 170: 298. 18. Muller A and Mulhall JP: Cardiovascular disease, metabolic 6. Tong Y, Tar M, Davelman F, Christ G, Melman A and Davies syndrome and erectile dysfunction. Curr Opin Urol 2006; KP: Variable coding sequence protein A1 as a marker for 16: 435. erectile dysfunction. BJU Int 2006; 98: 396. 19. Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, 7. Rougeot C, Rosinski-Chupin I, Njamkepo E and Rougeon F: Moinpour CM and Coltman CA: Erectile dysfunction and Selective processing of submandibular rat 1 protein at di- subsequent cardiovascular disease. JAMA 2005; 294: 2996. Infertility and Hypergonadotropic Hypogonadism as First Evidence of Hereditary Apolipoprotein A-I Amyloidosis

Tiziano Scalvini, Paola Rossana Martini,* Laura Obici, Regina Tardanico, Luciano Biasi, Gina Gregorini, Francesco Scolari and Giampaolo Merlini From the Departments of Endocrinology and Andrology (TS, PRM) and Pathology (RT) and Divisions of Infectious Diseases (LB) and Nephrology (GG, FS), Spedali Civili, Brescia and Amyloid Centre, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo (LO, GM), Pavia, Italy

Purpose: We report that primary infertility and hypergonadotropic hypogonadism in young patients may be caused by testicular amyloidosis and it is associated with the presence of a mutation in the apoA-I gene, resulting in the replacement of proline for leucine at residue 75 of the protein. Materials and Methods: Ten patients presenting with infertility, gynecomastia, decreased libido, erectile dysfunction or a family history of amyloidosis underwent clinical evaluation, hormone assays, semen analysis, ultrasonographic investigation of the testicles, testicular biopsy and DNA sequencing of the apoA-I gene. Results: All patients showed azoospermia and 9 had increased testicular volume. Massive amyloid deposition was observed in all testicular biopsies and the apoA-I mutation of replacement of proline for leucine at residue 75 of the protein was noted. Five patients showed hypergonadotropic hypogonadism and 5 had normal testosterone values with high gonadotropin levels. Conclusions: Nonobstructive azoospermia and macro-orchidism with or without hypogonadism may be caused by hereditary apoA-I amyloidosis in young patients. Testicular amyloidosis can be the ﬁrst manifestation of this systemic disease. Speciﬁc staining for amyloid deposits and genetic analysis of apoA-I mutations are recommended in young, infertile patients with macro-orchidism. Finally, surveillance in asymptomatic mutation carriers is suggested to evaluate the opportunity to implement sperm retrieval and start androgen replacement therapy when necessary. Key Words: testis; apolipoprotein A-I; infertility, male; amyloidosis; hypogonadism

ystemic amyloidosis consists of a group of diseases systemic amyloidosis has been occasionally reported, mani- characterized by the progressive extracellular deposi- festing as hypogonadism, sterility and macro-orchidism.5–7 S tion of soluble plasma proteins as insoluble fibrils, However, in most of these cases it was never formulated as disrupting tissue integrity, which leads to organ dysfunc- a diagnosis based on the biochemical nature of the amyloid tion.1 Of the diseases AL and AA are the most frequent. deposits. Schrepferman et al described secondary infertility Acquired AL is generated by the deposition of Ig light-chain due to testicular amyloid deposition as the only clinical fragments produced by clonal plasma cells, AA is a long- finding in a patient heterozygous for an apoA-I variant.8 term complication of several chronic inflammatory condi- Similarly testicular biopsy showed amyloid deposits several tions and some systemic types of amyloidosis are inherited years before the occurrence of severe amyloid cardiomyopa- and present as autosomal dominant diseases. In hereditary thy in a patient carrying the leucine 174 serine mutation of amyloidosis amyloid fibrils derive from a mutated form of 1 apoA-I.9 of certain proteins, including transthyretin, lysozyme, ApoA-I, the major component of high density lipoproteins, ␣ apoA-I, apolipoprotein A-II, fibrinogen A chain, cystatin C can cause systemic amyloidosis at the presence of specific and gelsolin. amino acid replacements. A total of 12 amyloidogenic apoA-I Clinically systemic amyloidosis is characterized by renal, variants have been identified to date.10 The natural history of heart, liver and peripheral nerve involvement that is iso- the disease consists of progressive liver and kidney involve- lated or variably associated, leading to progressive organ ment with restrictive cardiomyopathy observed in some vari- failure and ultimately to death. Testicular amyloid localiza- ants. We recently referred to an amyloidogenic variant of tion, resulting in azoospermia and hypogonadism, is rarely apoA-I associated with a predominantly sporadic presenta- observed in the context of AL,2 while it is more frequently tion, in which the leucine residue at position 75 is replaced described in AA, especially in patients with familial Medi- by proline (Leu75Pro).11 In the first 2 series of patients in terranean fever.3,4 Testicular amyloidosis as a first sign of whom the diagnosis was confirmed by genetic and immunohistochemical analyses surgically treated Gyn was reported 11,12 Submitted for publication September 14, 2006. in a few, suggesting testicular localization of the dis- Study received Institutional Review Board approval. ease. However, no additional studies were performed in * Correspondence: Department of Endocrinology and Andrology, these subjects. University of Brescia, Spedali Civili of Brescia, p. le Spedali Civili 1, 25123 Brescia, Italy (telephone: ϩ39-0303995251; FAX: ϩ39-030- To our knowledge we report for the first time a detailed 3388147; e-mail: [email protected]). characterization of apoA-I testicular amyloidosis in a novel

0022-5347/07/1781-0344/0 344 Vol. 178, 344-348, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.005 INFERTILITY AND HYPOGONADISM IN ApoA-1 AMYLOIDOSIS 345 series of patients. Furthermore, this proves that the early deposition of amyloid in the testes leading to infertility is a peculiar feature of this form of the disease.

MATERIALS AND METHODS Of 1,400 infertile men examined in a 13-year period at the Department of Endocrinology at University of Brescia 10 were found to have testicular amyloidosis due to the hereditary Leu75Pro mutation of Apo A-I. In all patients the testicle was the ﬁrst or single organ involved. Mean patient age Ϯ SD was 35.7 Ϯ 6.3 years (range 29 to 45) at diagnosis and all were included in the study. Patients were examined due to rLib, ED, gynecomastia, infertility or a family history of amyloidosis that was isolated or variably associated (see table). All patients underwent testicular biopsy after collecting the personal and family medical history as well as physical examination of the genitals and breast, ultrasonographic investigation of the abdomen and testicles, and semen analysis. Blood samples for hormonal assays, hepatic and renal function parameters, and DNA sequencing of the apoA-I gene were also taken. For the medical history particular attention was given to

libido, erectile function, past urological pathologies, infertil- LH (mU/ml) FSH (mU/ml) T (ng/ml) fT (pg/ml) SHBG (nmol/L) ity, the number of children and patient age at conception. Assessment of the hormonal profile was performed at 9:00 a.m. with the patient fasting. The parameters measured at a centralized laboratory were LH, FSH, SHBG, T and calcu- Vol (ml) Rt Lt 34 24 45 75 1.8 23.0 60 lated fT. Vermeulen’s formula was used to calculate fT ac- Testicular cording to published criteria.13 At ultrasonographic investigation testicular volume was calculated with the Taskinen and Schiff formula, 0.71 ϫ length ϫ width ϫ depth.14 Echographic examinations were performed by the same physician usinga7to12MHzlinear multifrequencing Sequoia Siemens™ instrument. In the lit- Patient characteristics erature a testicular volume of between 15 and 25 ml is consid- rLib, ED ered normal.15 All data are presented as the mean Ϯ SD. Semen analysis was performed by the same specialist according to the WHO manual definition. Histological evaluation was done by the same physician according to standard techniques. The search for amyloid deposits was done by Congo red staining, followed by microscopic examination under polarized light. Immunohistochemical characterization of amyloid deposits was made on paraffin embedded sections using a panel of antibodies against ␬ and ␭ chains, serum amyloid-A, fibrinogen and apoA-I (Dako, Milan, Italy). This last reaction was visualized with the alkaline phosphatase RED method. All patients provided written informed consent and the study was approved by the Institutional Review Board. Ge- Pt Age at netic testing was performed on DNA extracted from periph- Conception Past Testicular Pathology Presenting Features eral blood using standard procedures. Screening for apoA-I mutations was done by direct sequencing of polymerase chain reaction amplified fragments, as previously described.11 No. Children

RESULTS The table lists patient initial clinical characteristics. Previ- ous testicular pathologies were present in 3 cases, including 7—438—459—45 1 0 2 36 27, 30 None None Orchio-epididymitis Gyn, rLib, ED rLib, ED Gyn, rLib, ED 27 34 22 39 37 32 44 36 29 60 71 0.3 72 3.2 5.8 1.2 30.0 20.0 30 89 40 1—362—293—324—315—296—33 0 0 0 0 0 0 None Varicocele, funicular torsion None Varicocele Inf None None Gyn, rLib, ED Inf 35 Inf 19 Family history Gyn, family 34 history, 35 12 37 35 43 31 18 43 28 26 8 14 16 36 4.2 20 20 4.0 26 97.3 4.1 65.2 4.3 3.9 27 99.2 75.2 47 84.0 26 43 30 varicocele, orchio-epididymitis and funicular torsion, respec- Pt—Age at 10—34 1 31 None Gyn, rLib, ED 19 20 22 21 1.5 29.0 32 tively. Two patients had a family history of amyloidosis. Two No. Diagnosis 346 INFERTILITY AND HYPOGONADISM IN ApoA-1 AMYLOIDOSIS patients had fathered a child before diagnosis and 1 had gonadism. Patient 9 with hypogonadism and patients 2 and fathered 2 children at the ages indicated (see table). 4 with normal testosterone levels showed only a few Leydig At physical examination 1 or 2 testicles appeared smooth, cells without precise tissue organization. Finally, patients 1, markedly enlarged and toughened in patients 1 to 9. These 3 and 5 with normal testosterone and patient 10 with hypo- findings were confirmed by a homogeneous solid appearance gonadism had few aggregates of Leydig cells, which retained on ultrasound with a mean volume of 31.4 Ϯ 6.7 ml (range 19 normal tissue architecture. At immunohistochemical analy- to 39) for the right testicle and 32.0 Ϯ 9.3 ml (range 19 to 44) sis amyloid deposits were intensively and specifically immu- for the left testicle. No additional pathological findings were noreactive with anti-apoA-I antibody but not with the other revealed by abdominal ultrasound screening. antibodies tested (part B of figure). All patients were completely azoospermic. Patient 2 un- Genetic analysis performed through direct DNA sequenc- derwent previous semen analyses due to infertility, which ing showed that all 10 patients were heterozygous for a revealed normospermia (32 ϫ 106 spermatozoa per ml) thymine to cytosine transition at nucleotide 1772 of the 23 months before the diagnosis of amyloidosis and severe apoA-I gene, resulting in a leucine to proline amino acid oligospermia (60 ϫ 103 spermatozoa per ml) 6 months pre- replacement at residue 75 of the mature protein. No patients viously. had different apoA-I variants, a normal apoA-I genotype or Hepatic and renal function was normal in all patients. other sequence variations. Hypergonadotropic hypogonadism was present in patients 6 Ϯ to 10 with low androgen levels, including T 1.6 1.1 ng/ml DISCUSSION (normal at our laboratory 3.5 to 9) and fT 21.6 Ϯ 9.7 pg/ml (normal 75 to 124), and high gonadotropin values, including The current study demonstrates that testicular failure is a LH 33.8 Ϯ 8.7 mU/ml (normal 0.5 to 6) and FSH 59.7 Ϯ 22.4 typical finding in hereditary apoA-I amyloidosis, especially mU/ml (normal 0.5 to 6). In contrast, patients 1 to 5 in association with the Leu75Pro variant of this protein. showed normal androgen values with T 4.1 Ϯ 0.2 ng/ml Testicular involvement can be the first or the single mani- and fT 84.2 Ϯ 14.5 pg/ml but increased levels of LH and festation of the disease and it evolves with time. FSH at 13.7 Ϯ 3.9 and 25.6 Ϯ 6.5 mU/ml, respectively. All To our knowledge this is the first series of patients with except patient 9 had SHBG concentrations within the apoA-I amyloidosis in which the clinical and pathological normal range (13 to 71 nMol/l). basis of testicular amyloid involvement was characterized in Histological analysis of testicular biopsies showed abun- detail. These data strengthen and expand previous descrip- dant deposits of amorphous eosinophilic material, strongly tions of single patients in whom testicular failure was re- suggestive of amyloid (part A of figure). Congo red staining ported in the medical history several years before a diagno- confirmed the presence of pathognomonic apple-green bire- sis of cardiac9 or visceral11,12 apoA-I amyloidosis was made. fringence under polarized light. Amyloid deposits were The Leu75Pro mutation of the apoA-I gene leads to found around the basement membrane of the seminiferous asymptomatic, long-standing, mild to moderate renal fail- tubules, narrowing or obstructing the lumen in any case. ure, and increased alkaline phosphatase and ␥-glutamyl- Patients 3 to 10 had a germinal epithelium that was com- transferase levels.11,12 Compared to other variants this is pletely replaced by amyloid without Sertoli’s cells. Patients associated with a mild phenotype due to the slower progres- 1 and 2 presented with mixed tissue morphology, showing sion of kidney and liver deposits. The lack of a family his- areas with complete replacement of the germinal epithelium tory, advanced patient age at renal or hepatic biopsy and the scattered with tubules with only Sertoli’s cells as well as limited evidence of disease related mortality strengthen this areas at all stages of spermatogenesis. view. The current study proves that this disease occurs Amyloid deposits were also found in the interstitium, in earlier than expected and it may be responsible for the the walls of arteries, capillaries and veins. They increased dramatic impairment of fertility from the third decade of wall thickness with a decreased lumen in all patients, lead- life. ApoA-I amyloidosis should be suspected in patients with ing to complete obstruction in some men. No Leydig cells azoospermia, a normal or decreased testosterone level and were seen in the biopsies of patients 6 to 8, who had hypo- normal or high testicular volume even in the absence of an informative family history. The frequency of this rare genetic condition still remains to be defined. A possible founder effect likely justifies the high incidence in our population. However, the same variant was reported in a patient with a different ethnic background, suggesting more widespread distribution.16 Our study shows the characterization of the pathological basis for testicular apoA-I amyloidosis and the possible molecular mechanisms of this disease. Biopsies revealed a germinal epithelium that was completely replaced by amyloid fibrils or Sertoli’s cells only. Amyloid deposits are also present in the vessel walls, leading to narrowing or obstruc- A, testicular biopsy reveals massive peritubular deposition of amor- tion, and in the interstitium with partial or complete Leydig phous material with complete loss of germinal epithelium (yellow cell substitution. In patients 1 and 2 there coexisted areas of arrows). Interstitial amyloid deposits are visible focally (white ar- complete germinal epithelium replacement, areas with Ser- ϫ rows). H & E, reduced from 25. B, immunohistochemical analysis toli’s cells only and areas at all stages of spermatogenesis. of testicular biopsy by anti-Apo A-I antibody shows intense immunostaining of peritubular and interstitial amyloid deposits, in particular Repeat semen analyses in patient 2 during the 23 months focal interstitial deposits (yellow arrows). Reduced from ϫ25. before diagnosis revealed rapid evolution from normosper- INFERTILITY AND HYPOGONADISM IN ApoA-1 AMYLOIDOSIS 347 mia to oligospermia and azoospermia. The progressive im- through the adenosine triphosphate-binding cassette trans- pairment of spermatogenic function is due to the gradual porter-A1 receptor and it supplies cholesterol to steroido- deposition of amyloid, which causes parenchymal replace- genic cells through the scavenger receptor class B type-I. It ment, and it seems to reflect the mixed histological profile. is possible that conformational changes occurring during the Our findings agree with previous results, reflecting similar process of lipid exchange might contribute to the proteolytic observations in AA and AL.4,17 remodeling of the protein when mutated, promoting the To date different hypotheses have been formulated on the generation of N-terminal peptides and triggering the fibril- mechanisms that cause the impairment of spermatogenic logenetic process. function by amyloid. A hypothesis is that azoospermia can be due to the obliteration of intratesticular canaliculi or to the disruption of sperm production through a direct effect on CONCLUSIONS the seminiferous tubules by amyloid deposits.3,4 Özdemir et al proposed that the narrowing and obstruction of vessels This study clearly points out that infertility with or without may cause long-term hypoxia, leading to disruption of the complete hypogonadism is an early and clinically relevant germinal epithelium with spermatogenic arrest.17 Vascular finding in hereditary Apo A-I amyloidosis, particularly in compression was proposed to be caused by amyloid deposi- association with the Leu75Pro variant of this protein. Tes- tion in the vessel tunica propria or by interstitial fluid from ticular involvement is associated with normal or high testic- damaged and more permeable vessels. ular volume and it may be the first or single manifestation of In all patients testicular biopsies showed increased vessel disease in young patients. Dramatic impairment of fertility wall thickness and partial or complete replacement of the may occur from the third decade of life. Progression of sper- germinal epithelium by amyloid deposits, indicating that matogenic deterioration to complete azoospermia may hap- tubular and vascular obstructions are probably the end pen in about 2 years. Thus, semen analysis should be ad- stages of the same process. Amyloid fibrils were also found vised annually in young, asymptomatic carriers of the in the interstitium, causing partial or complete Leydig cell mutation, whereas testicular biopsy is suggested at the on- replacement. This explains the low level of T and fT, and the set of spermatogenic impairment to increase the chance of high level of gonadotropins in patients 6 to 10. In patients 1 sperm retrieval. Moreover, evaluation of gonadic function to 5, in whom Leydig cells appeared less disrupted, high should be done annually, also in older patients with known FSH and LH values were able to maintain normal testoster- renal or hepatic damage, to start testosterone administra- one levels, indicating early and subclinical gonadic dysfunction when necessary. In cases of infertility, nonobstructive tion. Histological findings also support clinical and hor- azoospermia and macro-orchidism with complete or subclin- monal data, suggesting that testicular failure results from ical hypogonadism apoA-I amyloidosis must be suspected progressive parenchymal replacement by amyloid deposits, even in the absence of a significant family history. first compromising spermatogenesis in 100% of the patients and then endocrine function in 50%. In the literature it is known that the onset of hypergonad- Abbreviations and Acronyms otropic hypogonadism can follow nonobstructive azoospermia in primary testicular failure.15 Tubular dysfunction AA ϭ reactive amyloidosis ϭ may occur with normal testosterone production initially due AL Ig light-chain amyloidosis Apo ϭ apolipoprotein to higher sensitivity to damage to seminiferous tubules ϭ 18 ED erectile dysfunction rather than Leydig cells. FSH ϭ follicle-stimulating hormone In this series testicular volume was normal or high com- fT ϭ free testosterone pared to that in other pathological conditions associated Gyn ϭ gynecomastia with impaired spermatogenesis that lead to micro-orchid- Inf ϭ infertility ism, including primary hypogonadism due to congenital ab- Leu75Pro ϭ leucine 75 proline normalities, Klinefelter’s syndrome, myotonic dystrophy, LH ϭ luteinizing hormone ϭ cryptorchidism and abnormal karyotypes. These findings rLib decreased libido ϭ confirm previous case report data on the size of amyloidotic SHBG sex hormone binding globulin T ϭ total testosterone testicles.5–8,19 Briefly, testicular involvement appears to be an early and clinically relevant feature of apoA-I amyloidosis compared to other systemic forms of the disease. In the literature histological data indicate a similar dis- REFERENCES tribution of amyloid deposits in the testicular parenchyma apart from the protein precursor involved.17 To our knowl- 1. Merlini G and Bellotti V: Molecular mechanisms of amyloidosis. edge the reasons for the peculiar tissue targeting of apoA-I N Engl J Med 2003; 349: 583. amyloid deposits are presently unknown. In particular no 2. Kyle RA and Gertz MA: Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995; association with any previous testicular pathology was 32: 45. found. We hypothesize that the high concentration of the 3. Ben-Chetrit E and Levy M: Reproductive system in familial amyloid precursor in the testicular extracellular milieu Mediterranean fever: an overview. Ann Rheum Dis 2003; might be due to the specific functional and metabolic prop- 62: 916. erties of apoA-I. In fact, this protein has a key role in cho- 4. Haimov-Kochman R, Prus D and Ben-Chetrit E: Azoospermia lesterol trafficking, particularly in steroidogenic tissues.20 due to testicular amyloidosis in a patient with familial ApoA-I removes excess cholesterol from Sertoli’s cells Mediterranean fever. Hum Reprod 2001; 16: 1218. 348 INFERTILITY AND HYPOGONADISM IN ApoA-1 AMYLOIDOSIS

5. Handelsman DJ, Yue DK and Turtle JR: Hypogonadism and 13. Vermeulen A, Verdonck L and Kaufman JM: A critical evalu- massive testicular infiltration due to amyloidosis. J Urol ation of simple methods for the estimation of free testoster- 1983; 129: 610. one in serum. J Clin Endocrinol Metab 1999; 84: 3666. 6. Bonacina R, Virgili G, Rosi P, Vespasiani G, Capodicasa E and 14. Schiff JD, Li PS and Goldstein M: Correlation of ultrasono- Micali F: Testicular and cardiac amyloidosis. Scand J Urol graphic and orchidometer measurements of testis volume Nephrol 1992; 26: 297. in adults. BJU Int 2004; 93: 1015. 7. Kanada DJ and Sharma OP: Long-term survival with diffuse 15. Griffin JE and Wilson JD: Disorders of the testes and the male interstitial pulmonary amyloidosis. Am J Med 1979; 67: reproductive tract. In: Williams Textbook of Endocrinology, 879. 10th ed. Edited by PR Larsen, HM Kronenberg, S Melmed 8. Schrepferman CG, Lester DR and Sandlow JI: Testicular amy- and KS Polonsky. Philadelphia: WB Saunders 2003; chapt loid deposition as a cause of secondary azoospermia. Urol- 18, pp 709–770. ogy 2000; 55: 145i. 16. Coriu D, Dispenzieri A, Stevens FJ, Murphy CL, Shuching W, 9. Obici L, Bellotti V, Mangione P, Stoppini M, Arbustini E, Wiess DT et al: Hepatic amyloidosis resulting from depos- Verga L et al: The new apolipoprotein A-I variant iting of the apolipoprotein A-I variant Leu75Pro. Amyloid: Leu174¡Ser causes hereditary cardiac amyloidosis, and the J Protein Folding Disord 2003; 10: 215. amyloid fibrils are constituted by the 93-residue N-terminal 17. Özdemir BH, Özdemir OG, Özdemir FN and Özdemir AI: Value polypeptide. Am J Pathol 1999; 155: 695. 10. Murphy CL, Wang S, Weaver K, Gertz MA, Weiss DT and of testis biopsy in the diagnosis of systemic amyloidosis. Urol- Solomon A: Renal apolipoprotein A-I amyloidosis associ- ogy 2002; 59: 201. ated with a novel mutant Leu64Pro. Am J Kidney Dis 2004; 18. Winters SJ: Male hypogonadism. In: Endocrinology and Me- 44: 1103. tabolism. Edited by A Pinchera, X Bertagna, J Fischer, 11. Obici L, Palladini G, Giorgetti S, Bellotti V, Gregorini G, Ar- L Groop, J Schoemaker and M Serio. New York: McGraw- bustini E et al: Liver biopsy discloses a new apolipoprotein Hill 2001; chapt 40, pp 399–412. A-I hereditary amyloidosis in several unrelated Italian 19. Casella R, Nudell D, Cozzolino D, Wang H and Lipshultz LI: families. Gastroenterology 2004; 126: 1416. Primary testicular amyloidosis mimicking tumor in a crypt- 12. Gregorini G, Izzi C, Obici L, Tardanico R, Röcken C, Viola BF orchid testis. Urology 2002; 59: 445. et al: Renal apolipoprotein A-I amyloidosis: a rare and 20. Marcel YL and Kiss RS: Structure-function relationships of usually ignored cause of hereditary tubulo-interstitial ne- apolipoprotein A-I: a flexible protein with dynamic lipid phritis. J Am Soc Nephrol 2005; 16: 3680. associations. Curr Opin Lipidol 2003; 14: 151. Urological Survey

URO-SCIENCE

TMPRSS2:ERG Gene Fusion Associated With Lethal Prostate Cancer in a Watchful Waiting Cohort F. Demichelis, K. Fall, S. Perner, O. Andren, F. Schmidt, S. R. Setlur, Y. Hoshida, J. M. Mosquera, Y. Pawitan, C. Lee, H. O. Adami, L. A. Mucci, P. W. Kantoff, S. O. Andersson, A. M. Chinnaiyan, J. E. Johansson and M. A. Rubin, Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, and Bioinformatics Group, SRA, ITC-IRST, Trento, Italy Oncogene Jan 22, 2007; Epub.

The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratioϭ2.7, PϽ0.01, 95% confidence intervalϭ1.3–5.8). Quantitative reverse-transcription-polymerase chain reaction demonstrated high estrogen-regulated gene (ERG) expression to be associated with TMPRSS2:ERG fusion (PϽ0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression. Editorial Comment: TMPRSS2:ERG fusion has been reported to be associated with aggressive forms of prostate cancer. The data presented in this article suggest that TMPRSS2:ERG may provide a marker of progression to aid in decision making for patients interested in expectant treatment of their cancer. If further studies validate the observation, it would be an important contribution to prostate cancer management. Timothy L. Ratliff, Ph.D.

Application of Genomic Technologies to Human Prostate Cancer S. Li, S. Bhamre, J. Lapointe, J. R. Pollack and J. D. Brooks, Department of Urology, Stanford University School of Medicine, Palo Alto, California OMICS 2006; 10: 261–275.

Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in U.S. males and has a broad spectrum of clinical behavior ranging from indolent to lethal. Microarray technology has provided unprec- edented opportunity to explore the genetic processes underlying prostate cancer by providing a comprehensive survey of a cell’s transcriptional landscape. Prostate cancer, however, has posed significant challenges that have contributed to inconsistent results between studies and difficulty replicating findings. Despite these challenges, several important insights have been gained along with new clinical biomarkers of diagnosis and prognosis. Continued improvements in methods of tissue preparation, microarray technology and data analysis will overcome existing challenges and fuel future discoveries. Editorial Comment: This is a good review of the use of modern technology for identification of markers in prostate cancer. Timothy L. Ratliff, Ph.D.

0022-5347/07/1781-0349/0 349 Vol. 178, 349-351, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.086 350 ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE Five-Year Follow-Up of Trial of Replication-Competent Adenovirus-Mediated Suicide Gene Therapy for Treatment of Prostate Cancer S. O. Freytag, H. Stricker, J. Peabody, J. Pegg, D. Paielli, B. Movsas, K. N. Barton, S. L. Brown, M. Lu and J. H. Kim, Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan Mol Ther 2007; 15: 636–642. Replication-competent adenovirus-mediated suicide gene therapy is an investigational cancer treatment that combines the oncolytic actions of human adenoviruses with the cytotoxic effects of chemo-radiosensi- tizing genes. Previously, we reported the short-term effects of this therapy in men with local recurrence of prostate cancer after definitive radiotherapy. With a median prostate-specific antigen (PSA) follow-up of 5 years, we report here the effect of the gene therapy on prostate-specific antigen doubling time (PSADT), a surrogate end point with significant prognostic power. When considering all evaluable subjects, the PSADT increased following the gene therapy from a mean of 17 to 31 months (median 16 to 22 months) (Pϭ0.014). Assuming that salvage androgen suppression therapy androgen suppression therapy (AST) was uniformly initiated at a PSA of 15 ng/mL, the gene therapy would have delayed the projected onset of salvage therapy by an average of 2 years. The results indicate that replication-competent adenovirus- mediated suicide gene therapy may provide a potential long-term benefit to patients, as shown by a lengthening of the PSADT, and delay in when salvage therapy is indicated. Given the high morbidity associated with AST, we believe this approach could provide an attractive treatment option for selection of patients experiencing PSA relapse following definitive therapy. Editorial Comment: The authors analyzed the response of patients with prostate cancer to a replication competent adenovirus therapy. The data suggest a positive effect of treatment. Timothy L. Ratliff, Ph.D.

ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE

Hypertension in Page (Cellophane-Wrapped) Kidney is Due to Interstitial Nephritis V. Vanegas, A. Ferrebuz, Y. Quiroz and B. Rodriguez-Iturbe, Renal Service, Hospital Universitario, Instituto de Investigaciones Biomedicas, Universidad del Zulia, Maracaibo, Venezuela Kidney Int 2005; 68: 1161–1170.

Background: Cellophane wrapping of the kidneys (Page kidney) induces perinephrits and hypertension, assumed to be due to renal ischemia resulting from parenchymal compression by the fibrous hull surrounding the kidneys. We investigated if interstitial nephritis, rather than plasma angiotensin activity, played a role in the development of hypertension in the Page kidney model. Methods: We followed for 7 weeks rats with bilateral cellophane wrapping of the kidneys that received 20 mg/kg/day of the immunosuppressive antiproliferative drug mycophenolate mofetil (MMF) (two-kidney wrap/MMF) (N ϭ 10) or vehicle (two- kidney wrap) (N ϭ 10), and sham-operated rats (N ϭ 10). Results: The two-kidney wrap group had progressive increment in blood pressure, inflammatory damage occupying 25% to 50% of the renal tubulo- interstitial region and increased number of angiotensin II-positive cells, angiotensin II content, and oxidative stress in the kidney. MMF treatment prevented the development of hypertension and renal inflammation without modifying the perinephritic hull or the increment it induced in the intrarenal pressure. The plasma levels of angiotensin II were similar in the two-kidney wrap group, the two-kidney wrap/MMF group and the sham-operated animals and unchanged from baseline, despite the blood pressure increase in the two-kidney wrap group. Conclusion: Our results indicate that renal wrap hypertension is unrelated to plasma angiotensin II levels and related to the inflammatory damage caused by the external compression of the kidney. Editorial Comment: This is an interesting study in rats, which addresses the mechanism of hypertension in a Page kidney. In the clinical situation a Page kidney usually occurs as a result of a perinephric hematoma that consolidates and becomes fibrotic, compressing the renal parenchyma. I have tended to remove these kidneys, thinking them to be unsalvageable. My former colleague, Robert Krane, told me of his experience of decorticating such a kidney, with BENIGN PROSTATIC HYPERPLASIA 351 return of function and normalization of blood pressure. This article suggests that the mechanism of injury is related to interstitial nephritis rather than overproduction of angiotensin II, which, depending on degree, might be reversible. It is unclear whether, in fact, the situation is similar in humans, compared to the animal model in this study. I have always wondered whether one should attempt to preserve such kidneys with the prospect of returning blood pressure to normal and preserving renal function. Perhaps we should try. W. Scott McDougal, M.D.

BENIGN PROSTATIC HYPERPLASIA

CYR61, a Cellular Proliferation Marker in Dogs With Prostatic Disease K. S. Oliveira, E. G. Araujo, L. B. Menezes, A. D. Damasceno, M. C. Fioravanti and R. L. Amorim, Escola de Veterinaria/Universidade Federal de Goias, Campus Samambaia II, Goiania, Goias, Brazil Theriogenology 2006; 66: 1618–1620. The life expectancy of dogs is increasing and is associated with a greater frequency of age-related disease, including that of the prostate gland. A marker of cell proliferation, CYR61, may be detected in a number of conditions in humans, including hyperplasia and neoplasia. The objective of the present study was to investigate the degree of CYR61 expression in a number of different prostate diseases in dogs in order to understand the potential of this marker for diagnosis of prostatic disease. Immunohistochemistry with a CYR61 antibody was performed on prostatic tissue from 22 dogs with different diseases. Intense stromal staining was observed in cases of prostatic dysplasia and benign prostate hyperplasia. In contrast, CYR61 staining was very intense in alveolar epithelial cells in cases of epithelial benign prostate hyperplasia and one case of adenocarcinoma. An obvious CYR61 staining pattern was absent in cases of prostatitis. In conclusion, CYR61 may be a useful marker of cell proliferation in a number of prostatic pathologies, although further studies of normal tissue are warranted. Editorial Comment: CYR61 is a heparin binding, cysteine rich protein from the vasculogenic and angiogenic regulator gene family, CCN. The CYR61 marker is associated with growth factors related to the extracellular matrix and cellular surface. In this study different pathological conditions within the dog prostate, as well as different locales within the prostate, resulted in varying degrees of expression of the CYR61 marker. In ﬁbrous and nodular benign prostatic hyperplasia CYR61 was stained intensely within the stroma. In contrast, epithelial overgrowth of benign prostatic hyperplasia was associated with intense staining within the alveolar epithelial cells. Interestingly, this pattern of staining was also found in a case of prostate cancer. Ultimately, use of markers such as these will gain a stronger foothold only if they can consistently discern between benign and malignant prostate growth. Steven A. Kaplan, M.D. Letters to the Editor/Errata

Re: Can Restaging Transurethral e-mail: [email protected] and Resection of T1 Bladder Cancer Select Patients for Immediate Cystectomy? Michael A. S. Jewett Department of Surgery, Division of Urology University of Toronto H. W. Herr, S. M. Donat and G. Dalbagni Toronto, Ontario, Canada J Urol 2007; 177: 75–79. 1. Nieder AM, Brausi M, Lamm D, O’Donnell M, Tomita K, Woo H et al: Management of stage T1 tumors of the bladder: Inter- To the Editor. We read with interest the article by Herr national Consensus Panel. Urology, suppl., 2005; 66: 108. et al showing that restaging transurethral resection can 2. Nieder AM, Simon MA, Kim SS, Manoharan M and Soloway identify patients at high risk for tumor progression, and, MS: Radical cystectomy after bacillus Calmette-Guerin for thus, can be used to stratify which patients should be offered high-risk Ta, T1, and carcinoma in situ: defining the risk of early cystectomy. The T1 bladder cancer guidelines, which initial bladder preservation. Urology 2006; 67: 737. the authors cite, were written after extensive discussion to provide strictly evidence based assessments and recommendations for the treatment of bladder cancer.1 We believe that Herr et al unfortunately misinterpreted Re: Expression of Major Heat one of our guidelines. We enthusiastically agree with the Shock Proteins in Prostate Cancer: authors that restaging transurethral resection of bladder Correlation With Clinicopathological tumor should be performed in all patients with high grade T1 bladder cancer, and this is a grade B recommendation.1 Outcomes in Patients Undergoing However, we disagree with the statement that we recom- Radical Prostatectomy mend cystectomy only for those who have failed 2 previous cycles of intravesical therapy. In fact, we maintain that T. Kurahashi, H. Miyake, I. Hara and M. Fujisawa “cystectomy and intravesical [bacillus Calmette-Guerin] are J Urol 2007; 177: 757–761. both acceptable primary therapies for high grade T1 disease and both options should be discussed.”1 Most of our panel To the Editor. Considering the numerous functions of heat agrees with Herr et al that early cystectomy is an appropri- shock protein 27 (HSP27) as a survival and antiapoptotic ate option for patients at high risk for progression. Unfor- molecule, it is not surprising that it can be involved in tumor tunately, we can only give this recommendation a grade C, progression and the development of treatment resistance. since no prospective randomized studies have compared Clinically, in breast cancer, ovarian cancer, osteosarcoma, early cystectomy to intravesical therapy. While our study endometrial cancer and leukemias an increased and overac- 1 was unable to demonstrate solid evidence indicating when tive amount of HSP27 has been detected. Consequently, the bladder preservation should be abandoned, previous studies timely article of Kurahashi et al, suggesting that HSP27 have shown that for those who choose an initial bladder may be involved in the progression of early stage prostate sparing approach if 2 cycles of bacillus Calmette-Guerin are cancer, heralds the possibility that a routine search of pros- unsuccessful, the patients are unlikely to be salvaged with tatic biopsy tissue could be included with Gleason score as an aid for improving detection of malignant tissue with further intravesical therapy and should be counseled to un- enhanced cell proliferative activity and aggressive behavior. dergo cystectomy. In fact, some of us consider a single However, could it be opportune to translate other frag- 3-month trial sufficient. ments of these results to the clinic at present? In the diag- The authors should be congratulated on attempting to strat- nostic area HSP serology is now possible.2 However, since it ify high risk cases. We recently reviewed our cystectomy data- detects the presence of extracellular HSP (involved in an base, and were unable to determine at which point patients immunological role but not related to carcinogenesis), it is who had received bacillus Calmette-Guerin should have pro- useless, at least with the current technology. In the preven- 2 ceeded to cystectomy. This article significantly contributes tive area what can perhaps be inferred from this study is to the literature, and further helps document the serious- that there are at least 2 practical suggestions for patients at ness of high grade T1 bladder cancer. risk for prostate cancer, namely to avoid actions that may generate up-regulation of HSP27, and to promote down- Respectfully, regulation of this molecule. Alan M. Nieder and Mark S. Soloway Recent research indicates that androgens inhibit up-reg- Department of Urology ulation of HSP27.3,4 This association is in keeping with the University of Miami Miller School of Medicine well-known association in which biologically aggressive 4306 Alton Rd. #3014 prostate cancers exist in a low androgen (particularly dihy- Miami Beach, Florida 33140 drotestosterone) environment.5 It is also reminiscent of the

0022-5347/07/1781-0352/0 352 Vol. 178, 352-355, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.050 LETTERS TO THE EDITOR 353 results obtained in the Prostate Cancer Prevention Trial, Voiding Function and where reduction of dihydrotestosterone with the use of finasteride yielded a higher incidence of high grade tumors de- Dysfunction, Bladder Physiology and spite being an effective chemopreventive agent in low grade Pharmacology, and Female Urology prostate cancers.6 Meanwhile, we gain an improved outlook on this theme. For example, based on the results of the A. J. Wein ongoing REDUCE trial,7 it might be prudent to avoid anti- J Urol 2007; 177: 230–233. androgen use in patients without serious ailments, such as administration of finasteride for male baldness. To the Editor. In the rapidly changing science of pelvic Neutralizing HSP27 seems to be an attractive strategy floor reconstruction Wein has provided an important service for prostate anticancer therapy. However, up to now, only in reviewing 3 well respected publications. He concludes the synthetic inhibitors of HSP90 have been available for clini- last review with a quote from Cardozo, who reminds practical testing. Nevertheless, we know that quercetin (a natural tioners “to remain judicious and withhold implantation of flavonoid) can inhibit HSP27, although its mechanisms of unproven mesh materials until manufacturers have con- action have not been characterized.8 It is noteworthy that firmed their efficacy and safety.” I think we can do better. quercetin can be obtained from several vegetables, such as Drug and device manufacturers are being examined under a infusions of green tea.9 One is tempted to speculate that microscope because of numerous reports of deception of pa- ingestion of this dietary compound (at useful doses) may tients and physicians regarding the efficacy and complica- have chemopreventive value in some prostate cancers (with- tions of their products. Turn on the television news or pick out known important side effects). Undoubtedly, to be actu- up a New York Times, Washington Post, New England Jour- nal of Medicine, Journal of the American Medical Associa- ally useful, this conjecture needs to be addressed tion or Lancet and there is frequently a prominent story of experimentally. deception with significant harm experienced by patients, with subsequent removal of the product from the market Respectfully, and impending liability claims. It cannot be left to industry Salvador Vale to inform us about their mesh materials. Departamento de Investigación We should demand that new products should be evalu- Laboratorios Trinidad Mexico ated by regulatory agencies free of industry influence, with- Allori 35, Mexico out the loopholes that bypass such evaluation, and that e-mail: [email protected] there be a registry for each material for every implant as well as for every result. This practice should be extended to 1. Schmitt E, Gehrmann M, Brunet M, Multhoff G and Garrido C: include all new implants of previously approved materials. Intracellular and extracellular functions of heat shock pro- The public deserves to be protected from spurious manu- teins: repercussions in cancer therapy. J Leukoc Biol 2007; facturers rather than having the responsibility of confirm- 81: 15. 2. Birnie DH, Vickers LE, Hillis WS, Norrie J and Cobbe SM: ing efficacy and safety placed in their hands. There is Increased titres of anti-human heat shock protein 60 predict already a sad history of injured patients from faulty im- an adverse one year prognosis in patients with acute cardiac planted materials for pelvic floor reconstruction and chest pain. Heart 2005; 91: 1148. stress incontinence. 3. Rocchi P, So A, Kojima S, Signaevsky M, Beraldi E, Fazli L et al: Heat shock protein 27 increases after androgen ablation and Respectfully, plays a cytoprotective role in hormone-refractory prostate Gerald Frankel cancer. Cancer Res 2004; 64: 6595. Center for Bladder and Prostate Disorders 4. Park KM, Cho HJ and Bonventre JV: Orchiectomy reduces Medical Center of McKinney susceptibility to renal ischemic injury: a role for heat shock McKinney, Texas proteins. Biochem Biophys Res Commun 2005; 328: 312. 5. Nishiyama T, Ikarashi T, Hashimoto Y, Suzuki K and Takahashi K: Association between the dihydrotestosterone level in the Reply by Author. I agree. My interpretation of the quote prostate and prostate cancer aggressiveness using the was that the originator ensured the safety and efficacy via Gleason score. J Urol 2006; 176: 1387. well done clinical trials of adequate length (followup) by 6. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, established and impartial investigators who were experi- Ford LG et al: The influence of finasteride on the develop- enced clinicians and with access to all data, and reported ment of prostate cancer. N Engl J Med 2003; 349: 215. these objectively. So I think Frankel is correct, and I agree 7. Andriole G, Bostwick D, Brawley O, Gomella L, Marberger M, with him. Tindall D et al: Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol 2004; 172: 1314. Re: Choices 8. Westerheide SD and Morimoto RI: Heat shock response modulators as therapeutic tools for diseases of protein conforma- M. I. Resnick tion. J Biol Chem 2005; 280: 33097. 9. de Vries JH, Janssen PL, Hollman PC, van Staveren WA and J Urol 2006; 176: 2342. Katan MB: Consumption of quercetin and kaempferol in free-living subjects eating a variety of diets. Cancer Lett To the Editor. The description by Resnick of his dilemmas 1997; 114: 141. facing treatment decisions resonates with all patients who 354 LETTERS TO THE EDITOR are faced with a disease process that offers more than one recent Commentary in Pediatrics I detailed and documented possibility for therapy. There is some measure of partner- the evidence of these circumcision advantages.3 My original ship and camaraderie for a patient when a physician, who, article in The Journal and my responses to the letters also after all, is supposed to have an inside track on information contain references to key articles on these medical benefits regarding treatment choices for a particular disease process, of circumcision,1,2 although these citations were ignored. voices that he, too, experienced the burden of uncertainty Instead of documentation, Elder offers personal opinions and apprehension. and cites the anecdotal material of Denniston, a longstand- I would like to comment on the question most frequently ing anti-circumcision activist who has equated circumcision asked by patients concerning a treatment option direction, a with removal of the eyelids and is one of the letter writers to subject that is noted in this editorial: “Doc, what would you whom I responded.2 do if you were me?” I believe every physician, while recogniz- Elder states that the “the risk for circumcision complica- ing that patient dispositions vary and that hardwiring to- tions is significant.” The word “significant” implies statistics ward one direction vs another can be extraordinarily differ- and values but no references or prevalence data are given. ent, tries legitimately to examine what he or she would The 1989 and 1999 reports of the American Academy of really do based on extensive experience and knowledge Pediatrics state that the prevalence of medical circumcision concerning the choices the patient faces. Nevertheless, complications is less than 1%, and that complications are however carefully this hypothetical decision making effort usually minor.4,5 The 60% rate cited by Elder under- is pondered, it does not include the powerful visceral estimates the prevalence of circumcision in the United reaction that is experienced when the bad news is received States. This figure includes only those infants circumcised at personally. Angst, trepidation and fear generate powerful the birth hospital, with the procedure being properly coded. emotional forces that can have a significant role in deci- It has been shown that about 15% of newborn hospital sion making. A sports analogy would be the practice field, circumcisions are not coded. Furthermore, an additional 7% where a drill is conducted to ensure predictable perfor- to 10% of males are circumcised for medical or personal mance, and the playing field, where a number of unantic- reasons after newborn hospital discharge. As a result, mul- ipated factors can alter sequence and outcome. The mes- tiple observational studies around the country show that sage is that when physicians respond to “the question” 80% to 85% of United States males are circumcised.3 This they realize that they are doing so in an artificial con- prevalence has been confirmed by a recent report from the struct, and that their personal responses may not be re- National Health and Nutritional Examination Studies, Cen- produced and confirmed in real time. ters for Disease Control and Prevention, which found that 79% of United States males are circumcised.6 Among non- Respectfully, Hispanic whites the figure is 89%.6 Paul F. Schellhammer The final conclusions of Elder are particularly trouble- Department of Urology some. Despite compelling evidence of preventive health ben- Eastern Virginia Medical School efits, he considers circumcision to be solely a “cosmetic” Norfolk, Virginia procedure. Cosmetic surgery is aimed at improving the appearance of the patient. Circumcision would have no cosmetic advantage unless we lived in a nude society where a circumcised penis was considered more attractive. Re: Circumcision—Are You With Us Of much more concern is the call for insurance companies and the government to stop paying for circumcision. Here or Against Us? Elder is echoing the decades long campaign of the activist lay anti-circumcision organizations, including the Na- J. S. Elder tional Organization of Circumcision Information Resource J Urol 2006; 176: 1911. Centers, the National Organization to Halt the Abuse and Routine Mutilation of Males and Doctors Opposing Cir- To the Editor. The editorial by Elder in the November cumcision, which Denniston founded. Years ago these or- 2006 issue of The Journal of Urology® misrepresents my ganizations were initially successful in getting some insur- circumcision cost analysis study published in the March ance companies to drop coverage for circumcision. However, 2006 issue,1 as well as my responses to Letters to the Editor, because of the strong support of the American public for which also appeared in the November issue.2 I do not uncircumcision, and the fear of losing subscribers, these com- derstand how Elder could have read my article and my panies quickly relented and reestablished payment. None- replies and concluded that circumcision is simply a cosmetic theless, poor uninsured parents have no such power, and procedure that should not be paid for by insurance compa- here the anti-circumcision groups have had more success. By nies or the government. There are multiple well docu- lobbying state legislatures and health departments, they have mented, preventive health benefits of circumcision, includ- convinced 16 states, including California, to stop covering new- ing longstanding evidence (much of it provided by urologists) born circumcision for Medicaid patients. This policy denies of protection against penile cancer, infant urinary tract in- poor parents the same freedom to choose a proved preventive fections, balanoposthitis and phimosis. More recently, there health procedure for their sons that is exercised by more afflu- has been compelling and accumulating documentation pub- ent parents who have insurance coverage. lished in leading peer reviewed medical journals that cir- Up until now these unfair and extreme policies have been cumcision also helps to prevent HIV, human papillomavirus considered the sole purview of activist lay anti-circumcision and Chlamydia infections, and decreases the prevalence of groups, which dominate the media and the Internet, and cervical cancer in the partners of circumcised men. In a have little credibility. However, Elder is a Section Editor of LETTERS TO THE EDITOR 355

The Journal, which gives him special medical status and cision.5 With new data pertaining to the risk of sexually trans- lends strength to the bogus claims of these fringe organiza- mitted diseases in uncircumcised men it is time for a reassess- tions. The Journal of Urology and American urologists ment by the American Academy of Pediatrics or an analysis by should distance themselves from the unwarranted recom- an American Urological Association guidelines panel. mendations expressed by Elder. 1. Schoen EJ, Colby CJ and To TT: Cost analysis of neonatal circumcision in a large health maintenance organization. Respectfully, J Urol 2006; 175: 1111. Edgar J. Schoen 2. Schoen EJ: Re: Cost analysis of neonatal circumcision in a large Department of Pediatrics health maintenance organization (author reply). J Urol Kaiser Permanente Medical Center 2006; 176: 2317. Oakland, California 3. Schoen EJ: Ignoring evidence of circumcision benefits. Pediat- rics 2006; 118: 385. Reply by Author. As indicated in my editorial, and as 4. American Academy of Pediatrics: Report of the Task Force on reflected in the Letters to the Editor that stimulated the Circumcision. Pediatrics 1989; 84: 388. editorial, circumcision is a highly polarizing issue in this 5. Circumcision policy statement. American Academy of Pediat- country for physicians. Families typically request circumci- rics. Task Force on Circumcision. Pediatrics 1999; 103: 686. sion for religious reasons, or because of a perceived benefit in 6. Xu F, Markowitz L, Sternberg M and Aral S: Prevalence of cir- terms of hygiene (ie easier to keep clean), and/or because cumcision in men in the United States: data from the National they want their son to look like other boys in the locker room Health and Nutrition Examination Survey (NHANES), 1999- (cosmetic). The most recent analysis by the American Acad- 2002. XVI International AIDS Conference. Available at emy of Pediatrics Task Force on Circumcision found existing http://www.iasociety.org/abstract/show.asp?abstract_idϭ evidence insufficient to recommend routine neonatal circum- 2193307. Book Review

Operative Urology at the Cleveland Clinic A. C. Novick, J. S. Jones, I. S. Gill, E. A. Klein, R. Rackley and J. H. Ross, Totowa, New Jersey: Humana Press, 576 pages, 2006 I would like to take this opportunity to congratulate Novick and his stellar editorial staff for providing this “comprehensive and practical” resource for residents and practicing physicians interested in examining the signiﬁcant surgical alternatives for several urological diseases and conditions. As Novick states in the preface, the illustrations and detailed explanations of the different surgical techniques ultimately are meant to improve treatment outcomes for the urological patient. Operative Urology at the Cleveland Clinic is a thorough examination of all of the innovative surgical procedures that have changed the face of urology in the last 10 years, as well as those operations considered the gold standard for treatment. Although there are other similar respected texts detailing operative procedures for urological surgery, this book has incorporated the expertise of the faculty at the Cleveland Clinic along with current techniques, integrating laparoscopic surgery into the material when relevant. The book has been divided into 7 parts, including kidney and adrenal, retroperitoneum, malignant disease of the bladder, benign disease of the bladder, prostate, penis and urethra, and genitalia, so that the reader can easily identify and select the area of surgical interest. The editors have chosen to organize the material in each of the 50 chapters into a familiar format, reviewing the anatomy, indications/contraindications, preoperative evaluations and operative approaches. Chapter 1 presents a brief but detailed, well illustrated description of the various surgical incisions used for urological procedures. Although many of the technical details are written in easy to follow, understand- able language, it might have been helpful to include information on the surgical anatomy of the various incisions. The other chapters in part I of the text provide an overview of open and laparoscopic approaches to malignant and benign kidney and adrenal disorders. These chapters will be useful to residents and fully trained urologists who enjoy comparing their technique to others. It is easy to continue to perform procedures the same way each time. However, even when the success rate is good it is not unusual to learn some technical aspects that make a particular procedure easier or improve outcome. This is particularly true with laparoscopy, which is a rapidly evolving area. The chapter on renal trauma is a bit disappointing, since there is limited information on diagnosis and preoperative management. The remainder of the sections on benign and malignant management of the bladder, as well as those on the prostate, penis, urethra and scrotum, are all well illustrated, with brief but adequate detail. The sections on open and laparoscopic radical prostatectomy are particularly well described and detailed. In any subsequent editions the editors may wish to include 2 additions, namely more operative photographs and a description of the endoscopic management of bladder tumors, which is the foundation for treatment decisions in bladder cancer. Overall, I found the textbook to be user friendly and reﬂective of the wide variety of contemporary approaches to any given urological problem. I think that this would be an excellent addition to the library of any resident or practicing physician because of its illustrations and clear descriptions. Mark Soloway, M.D. Department of Urology University of Miami Miller School of Medicine Miami, Florida

0022-5347/07/1781-0356/0 356 Vol. 178, 356, July 2007 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.03.148 Home Study CME Enrollment Form

Program Description and Objectives: The Journal of Urology®Home Study Course is a comprehensive learning activity developed by a team of educators, academicians and clinicians. After completing the program, urologists will be able to demonstrate an increase in or affirmation of their knowledge of clinical medicine. They will also be able to evaluate the appropriateness of clinical data and apply it to their practice and the provision of patient care. Program Format: Two volumes of the The Journal of Urology® are published annually. Each volume is comprised of 6 issues. Five clinically relevant articles are selected by the editor to be offered for CME in each issue of The Journal. For CME credit, the participant must read the articles and answer 5 related questions on the examination; enroll in the home study program; and choose to submit answers either online or on a paper answer sheet that will be sent to you with a return envelope. Accreditation: The American Urological Association Education and Research, Inc. is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education (CME) for physicians. The American Urological Association Education and Research, Inc. takes responsibility for the content, quality and scientific integrity of this CME activity. CME Credit: The American Urological Association Education and Research, Inc. designates this educational activity for a maximum of 24 AMA PRA Category 1 Credits™. Completion of each test and a score of 80% or above qualify for 2 credits of AMA PRA Category 1 Credits™ with up to a maximum of 24 credits annually. Each physician should only claim credit commensurate with the extent of their participation in the activity. Estimated time to complete each month’s activity is 2 hours. AUA Disclosure Policy: As a provider accredited by the ACCME, the American Urological Association Education and Research, Inc., must insure balance, independence, objectivity and scientific rigor in all its activities. All faculty participating in an educational activity provided by the American Urological Association Education and Research, Inc. are required to disclose to the audience any relevant financial relationships with any commercial interest to the provider. The intent of this disclosure is not to prevent faculty with relevant financial relationships from serving as faculty, but rather to provide members of the audience with information on which they can make their own judgments. The Program Planners and Scientific Planning Committee must resolve any conflicts of interest prior to the commencement of the educational activity. It remains for the audience to determine if the faculty’s relationships may influence the educational content with regard to exposition or conclusion. When unlabeled or unapproved uses are discussed, these are also indicated. Program Enrollment: There are 3 convenient ways to enroll in The Journal of Urology® Home Study Course. ● Complete the form below and return by MAIL including a check or credit card information ● Complete the form below and return by FAX including your credit card information ● Enroll online at www.auanet.org. Choose The Journal of Urology®. ● You will need your AUA identification number, password and credit card to purchase this home study product. For any of these enrollment options you must choose one method to submit your home study answers–either online or by mail on a provided paper answer sheet. The cost for the home study is $60 per year for 2005 to 2007, which includes volumes 173 to 178. Previous home study volumes may be ordered by calling 1-866-746-4282, ext 3747. See page 359 for questionnaire

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CME QUESTIONS FOR JULY 2007 ISSUE OF THE JOURNAL OF UROLOGY®

1. STANDARD VERSUS LIMITED PELVIC LYMPH NODE DISSECTION FOR PROSTATE CANCER IN PATIENTS WITH A PREDICTED PROBABILITY OF NODAL METASTASIS GREATER THAN 1% (vol. 178, pp. 120–124) With regard to standard vs limited pelvic lymph node dissection (PLND) for prostate cancer which of the following statements is true? a) limited PLND retrieves a lower nodal count but the positivity rate is comparable to standard PLND b) limited PLND retrieves a nodal count and positivity rate comparable to standard PLND c) limited PLND retrieves a comparable nodal count but a higher positivity rate than standard PLND d) the anatomical template for limited PLND includes the obturator fossa and hypogastric nodal groups e) standard PLND retrieves a higher nodal count and positivity rate than limited PLND

2. POPULATION BASED INCIDENCE AND AGE DISTRIBUTION OF SPERMATOCYTIC SEMINOMA (vol. 178, pp. 125–128) All of the following are true about spermatocytic seminoma except: a) incidence is 0.4 cases per million b) there may be increasing trends in incidence c) 25% of cases occur in men aged 40 years or less d) most cases occur in the elderly e) orchiectomy and surveillance are usually sufﬁcient management

3. EJACULATORY DISORDERS MAY AFFECT 1 IN 2 MEN UNDERGOING SCREENING FOR PROSTATE CANCER (vol. 178, pp. 232–238) What is the rate of associated severe bother related to ejaculatory pain in the entire cohort? a) 11% b) 28% c) 44% d) 77% e) 89%

4. THE VOLUME AT WHICH WOMEN LEAK FIRST ON URODYNAMIC TESTING IS NOT ASSOCIATED WITH QUALITY OF LIFE, MEASURES OF URETHRAL INTEGRITY OR SURGICAL FAILURE (vol. 178, pp. 193–196) Which of the following is associated with the ﬁrst volume at which women demonstrate stress incontinence on urodynamic testing? a) maximal urethral pressure b) Valsalva leak point pressure c) persistent urodynamic stress incontinence following sling procedure d) low intravesical pressure e) none of the above

5. URACHAL CARCINOMA: CONTEMPORARY SURGICAL OUTCOMES (vol. 178, pp. 74–78) Surgical cure of urachal cancer is best achieved by: a) pelvic cystectomy b) pelvic lymph node dissection c) extended partial cystectomy and complete removal of the urachus d) omentectomy e) transurethral resection Publication date: July 2007 Expiration date: July 2010 News and Announcements

AUA Board of Directors

PRESIDENT —DR.PAUL F. SCHELLHAMMER, Interstate Corporate Center, 6333 Center Drive, Bldg. 16, Norfolk, Virginia 23502-4106 PRESIDENT-ELECT —DR.JOHN M. BARRY, Oregon Health & Sciences University, Urology, CH10U, 3303 SW Bond Ave., Portland, Oregon 97239 PAST PRESIDENT —DR.LAWRENCE S. ROSS, Department of Urology, M/C 955, University of Illinois, 820 S. Wood St., Chicago, Illinois 60612-7316 SECRETARY —DR.ROBERT C. FLANIGAN, Department of Urology, Loyola University Medical College, Maywood, Illinois 60153 TREASURER —DR.WILLIAM F. GEE, 3204 Hobcaw Lane, Lexington, Kentucky 40502-3523 HISTORIAN —DR.SAKTI DAS, 1890 Via Ferrari, Lafayette, California 94549

SECTION REPRESENTATIVES TO THE BOARD OF DIRECTORS

MID-ATLANTIC SECTION —DR.THOMAS J. ROHNER,JR., Milton S. Hershey Medical Center, Pennsylvania State University, P. O. Box 850, MC H055, Hershey, Pennsylvania 17033-0850 NEW ENGLAND SECTION —DR.RICHARD K. BABAYAN, Department of Urology, Boston University School of Medicine, 720 Harrison Ave. Ste. 606, Boston, Massachusetts 02118-2334 NEW YORK SECTION —DR.MAJID ESHGHI, 11 Shady Lane, Chappaqua, New York 10514 NORTH CENTRAL SECTION —DR.RICHARD A. MEMO, 602 Parmalee Ave., Ste 300, Youngstown, Ohio 44510-1653 NORTHEASTERN SECTION —DR.DATTA G. WAGLE, Main Urology Associates, 6645 Main St., Williamsville, New York 14221-5934 SOUTH CENTRAL SECTION —DR.CHARLES W. LOGAN, Arkansas Urology, 1300 Centerview Dr., Little Rock, Arkansas 72211-4349 SOUTHEASTERN SECTION —DR.B.THOMAS BROWN, 545 Health Blvd., Daytona Beach, Florida 32114-1493 WESTERN SECTION —DR.JOHN C. PRINCE, 3622 E. Westridge Dr., Orange, California 92867-2044

SECTIONS

Mid-Atlantic

PRESIDENT —DR.DOUGLAS E. MCKINNEY, 636 Rivendell Drive, Bridgeport, West Virginia 26330-1358 SECRETARY-TREASURER —DR.MARGUERITE C. LIPPERT, Department of Urology, University of Virginia Health System, Box 800422, Charlottesville, Virginia 22908-0422 EXECUTIVE DIRECTOR —MR.STAN ALGER, 900 Cummings Center, Suite 221-U, Beverly, Massachusetts 01915

New England

PRESIDENT —DR.W.SCOTT MCDOUGAL, 39 Proctor St., Manchester, Massachusetts 01944- 1447 SECRETARY —DR.KEVIN R. LOUGHLIN, Urology, Brigham & Women’s Hospital, 75 Francis St., Boston, Massachusetts 02115 TREASURER —DR.MARK KENNETH PLANTE, 111 Colchester Ave., ACC 5th Floor East, Urology, Burlington, Vermont 05401-1473 EXECUTIVE DIRECTOR —MS.AURELIE M. ALGER, 900 Cummings Center, Suite 221-U, Beverly, Massachusetts 01915

New York

PRESIDENT —DR.GOPAL BADLANI, Department of Urology, North Shore-Long Island Jewish Health System, 270-05 76th Ave., New Hyde Park, New York 11040-1496 SECRETARY —DR.MUHAMMAD S. CHOWDHURY, Department of Urology, New York Medical College, Munger Pavilion, Valhalla, New York 10595

TREASURER —DR.HARRIS M. NAGLER, Beth Israel Medical Center, PACC, Department of Urology, Suite 3A, 10 Union Square East, New York, New York 10003 EXECUTIVE DIRECTOR —MICHELE PAOLI, 4100 Duff Place, Lower Level, Seaford, New York 11783-1324 North Central

PRESIDENT —DR.DENNIS A. PESSIS, 376 Hazel, Highland Park, Illinois 60035 SECRETARY —DR.STEPHEN Y. NAKADA, Division of Urology, University of Wisconsin, 600 Highland Ave. G5/339 Clinical Science Center, Madison, Wisconsin 53792- 3236 TREASURER —DR.PETER M. KNAPP,JR., 1801 N. Senate Blvd., Suite 655, Indianapolis, Indiana 46202-1228 EXECUTIVE DIRECTOR —MS.WENDY J. WEISER, 1111 N. Plaza Drive, Suite 550, Schaumburg, Illinois 60173-4946 Northeastern

PRESIDENT —DR.BARRY A. KOGAN, Urological Institute of Northeastern NY, 23 Hackett Blvd., Albany, New York 12208-3436 SECRETARY —DR.EDWARD M. MESSING, Department of Urology, University of Rochester Medical Center, 601 Elmwood Ave., Box 656, Rochester, New York 14642 TREASURER —DR.ANNE-MARIE HOULE, Pediatric Urology, Sainte-Justine Hospital, 3175 Cote St. Catherine, A-4, Montreal PQ H3T 1C5 Canada EXECUTIVE DIRECTOR —MR.DREW SHIFFLET, 1000 Corporate Blvd., Linthicum, Maryland 21090 South Central

PRESIDENT —DR.ARTHUR I. SAGALOWSKY, Department of Urology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9110 SECRETARY —DR.RANDALL BROWNING MEACHAM, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Box C-319, Rm. 5415, Denver, Colorado 80262 TREASURER —DR.JOHN B. FORREST, Urologic Specialist of Oklahoma, 10901 E. 48th St., Tulsa, Oklahoma 74146-5830 EXECUTIVE DIRECTOR —MS.WENDY J. WEISER, 1111 N. Plaza Drive, Suite 550, Schaumburg, Illinois 60173-4946 Southeastern

PRESIDENT —DR.EDWARD O. JANOSKO, II, Eastern Urological Assoc., PA, 275 Bethesda Dr., Greenville, North Carolina 27834-7217 SECRETARY —DR.RAJU THOMAS, 3920 Wheat Dr., Metairie, Louisiana 70002-1302 TREASURER —DR.THOMAS F. STRINGER, Citrus Urology Associates, 609 W. Highland Blvd., Inverness, Florida 34452-4638 EXECUTIVE DIRECTOR —MS.WENDY J. WEISER, 1111 N. Plaza Drive, Suite 550, Schaumburg, Illinois 60173-4950 Western

PRESIDENT —DR.SCOTT K. SWANSON, Mayo Clinic Scottsdale, 13400 E. Shea Blvd., Scottsdale, Arizona 85259-5404 SECRETARY —DR.FRED GOVIER, Virginia Mason Medical Center, 1100 9th Ave., Seattle, Washington 98101-2756 TREASURER —DR.ERIC J. ZEIDMAN, 202 E. Earll Drive, Ste. 360, Phoenix, Arizona 85012- 2648 EXECUTIVE DIRECTOR —MR.FRANK J. DESANTIS, 1950 Old Tustin Ave., Santa Ana, California 92705-7812 362 NEWS AND ANNOUNCEMENTS

SECTION MEETINGS AUA FOUNDATION SUMMER RESEARCH CONFERENCE: CLINICAL TRIALS AND MID-ATLANTIC — Southampton Princess, Bermuda, OUTCOMES October 19–21, 2007 NEW ENGLAND — Seaport Hotel, Boston, Massachusetts, August 2–4, 2007. Los Angeles, California. For details e-mail September 26–30, 2007 [email protected] (Internet: www.auafoundation.org). NEW YORK — Hilton Buenos Aires, Buenos Aires, Argentina, November 10–16, 2007 CURRENT CONCEPTS IN MEN’S HEALTH 2007 NORTH CENTRAL — The Westin Diplomat Resort and Spa, August 3–5, 2007. The Sagamore Resort, Bolton Landing, Hollywood, Florida, October 29– New York. For details telephone 518-262-3296 (e-mail: November 3, 2007 [email protected]). NORTHEASTERN — Hyatt, Rochester, New York, September 5–9, 2007 SEGURA ANNUAL UROLITHIASIS AND SOUTH CENTRAL — The Broadmoor, Colorado Springs, ENDOUROLOGY UPDATE Colorado, September 5–9, 2007 August 10–11, 2007. Westin Chicago River North, Chicago, SOUTHEASTERN — Manchester Grand Hyatt, San Diego, California, March 6–9, 2008 Illinois. For details telephone 800-908-9414 (e-mail: [email protected]). WESTERN — Hyatt Gainey Ranch, Scottsdale, Arizona, October 28–November 1, 2007 AUA CODING HOT TOPICS SEMINAR

GET THE MEMBER ADVANTAGE August 11, 2007. Gallery One, DoubleTree Hotel, Fort Lau- derdale, Florida. For details telephone 800-908-9414 (e-mail: Practicing urologists and researchers are invited to apply for [email protected]). membership to the American Urological Association. Details may be obtained from www.auanet.org or by contacting the AUA FRIDAY FORUM—PROSTATE AND RENAL AUA Member Services Department at membership@ CANCER SERIES auanet.org, telephone 410-689-3933 (FAX: 410-689-3939 or 9940). August 17, 2007. Seattle, Washington. For details telephone 800-908-9414 (e-mail: [email protected]). ANNUAL MEETINGS OF AUA RUNNING AN EFFECTIVE INFUSION CLINIC MAY 17–22 — 2008–Orange County Convention August 21, 2007. Audio/Web Conference 8:00–9:30 p.m. Center, Orlando, Florida EST. For details telephone 800-908-9414 (e-mail: APRIL 25–30 — 2009–McCormick Place, Chicago, [email protected]). Illinois ANNUAL INTERNATIONAL MEETING OF EUROPEAN SYMPOSIUM ON UROLITHIASIS UROLOGY—FFFCMPA July 4–7, 2007. Hotel Cascais Miragem, Lisbon, Portugal. August 23–25, 2007. Sheraton Hotel, Porto Alegre, Brazil. For details telephone 351-217957175 (e-mail: info@ For details telephone 55 51 3328 2328 (e-mail: eulis2007.com; Internet: www.eulis2007.com). [email protected]).

DR. F. K. MOSTOFI UROLOGICAL PATHOLOGY FLORIDA UROLOGICAL SOCIETY ANNUAL AND RADIOLOGY MEETING July 16–21, 2007. Crowne Plaza Hotel, Silver Spring, Mary- August 31–September 2, 2007. Loews Miami Beach Hotel, land. For details telephone 202-782-2634 (e-mail: sutton@ Miami Beach, Florida. For details telephone 847-517-7249 aﬁp.osd.mil). (e-mail: [email protected]).

AUA CODING HOT TOPICS SEMINAR INTERNATIONAL CONGRESS ON HYPOSPADIAS SURGERY July 21, 2007. Hilton San Diego Mission Valley, San Diego, California. For details telephone 800-908-9414 (e-mail: September 2–5, 2007. Grand Hotel, Prishtina University, [email protected]). Prishtina, Kosova, Albania. For details telephone 377 44 126 637 (e-mail: [email protected]; Internet: www. FILING INSURANCE APPEALS—HOW TO kosovapedsurg.com). PREPARE AND WIN SOCIÉTÉ INTERNATIONALE D’UROLOGIE July 24, 2007. Audio/Web Conference 2:00–3:30 p.m. EST. For details telephone 800-908-9414 (e-mail: registration@ September 2–6, 2007. Palais des Congrès de Paris, Paris, auanet.org). France. For details visit www.siu-urology.org.

AUA FRIDAY FORUM—PROSTATE AND RENAL SOCIETY OF LAPAROENDOSCOPIC SURGEONS CANCER SERIES CONGRESS AND ENDO EXPO July 27, 2007. Minneapolis, Minnesota. For details telephone September 5–8, 2007. Hyatt Regency, San Francisco, Cali- 800-908-9414 (e-mail: [email protected]). fornia. For details visit www.sls.org. NEWS AND ANNOUNCEMENTS 363

AUA FRIDAY FORUM—PROSTATE AND RENAL AMERICAN ACADEMY OF PEDIATRICS SECTION CANCER SERIES ON UROLOGY MEETING September 7, 2007. Charlotte, North Carolina. For details October 26–31, 2007. San Francisco, California. For details telephone 800-908-9414 (e-mail: registration@auanet. telephone 800-433-9016 x 7668. org). NATIONAL CONGRESS OF THE MEXICAN LCA POLICIES—REVIEW AND CURRENT SOCIETY OF UROLOGY REGULATIONS November 9–14, 2007. Moon Palace Hotel, Cancun, Mexico. September 18, 2007. Audio/Web Conference 8:00–9:30 p.m. For details e-mail [email protected] (Internet: www. EST. For details telephone 800-908-9414 (e-mail: smu.org.mx). [email protected]). PHYSICIAN COMPENSATION STRATEGIES AUA CODING HOT TOPICS SEMINAR November 13, 2007. Audio/Web Conference 8:00–9:30 p.m. September 22, 2007. Hyatt Regency Tech Center, Denver, EST. For details telephone 800-908-9414 (e-mail: Colorado. For details telephone 800-908-9414 (e-mail: [email protected]). [email protected]).

HANDS-ON LAPAROSCOPY: A PROBLEM- HAND-ASSISTED LAPAROSCOPY—AUA SURGICAL ORIENTED APPROACH—AUA SURGICAL LEARNING CENTER COURSE LEARNING CENTER COURSE November 17–18, 2007. Marriott Houston Medical Center, September 29–30, 2007. Marriott Houston Medical Center, Houston, Texas. For details telephone 800-904-9414 Houston, Texas. For details telephone 800-908-9414 (e-mail: ([email protected]). [email protected]). BENIGN PROSTATIC HYPERPLASIA—AUA INNOVATION AND EBM IN UROLOGY SUBJECT-ORIENTED SEMINAR October 4–7, 2007. Astir Palace Hotel, Athens, Greece. For November 30–December 1, 2007. Grand Hyatt San Fran- details telephone 30-210-7257693 (e-mail: n.dargonakis@ cisco, San Francisco, California. For details telephone 800- erasmus.gr; Internet: www.urology-ebm.com). 908-9414 (e-mail: [email protected]).

HANDS-ON ULTRASOUND—AUA SURGICAL SOCIETY OF UROLOGIC ONCOLOGY MEETING LEARNING CENTER COURSE November 30–December 1, 2007. Natcher Conference Cen- October 6–7, 2007. Doubletree Hotel Dallas-Campbell Cen- ter, National Institutes of Health, Bethesda, Maryland. For ter, Dallas, Texas. For details telephone 800-908-9414 (e- details e-mail [email protected] (Internet: www.societyofurolog- mail: [email protected]). iconcology.org).

PROSTATE CANCER UPDATE—AUA SUBJECT- ADVANCES IN UROLOGY 2007 ORIENTED SEMINAR November 30–December 1, 2007. InterContinental Buck- October 12–13, 2007. Dallas Solana Marriott, Dallas, Texas. head, Atlanta, Georgia. For details telephone 404-727-0468 For details telephone 800-908-9414 (e-mail: registration@ (e-mail: [email protected]). auanet.org). SEXUAL MEDICINE SOCIETY OF NORTH BLADDER AND KIDNEY CANCER—AUA SUBJECT- AMERICA ANNUAL MEETING ORIENTED SEMINAR December 5–9, 2007. The Westin River North, Chicago, Illi- October 19–20, 2007. Loews New Orleans Hotel, New Or- nois. For details telephone 847-517-7225 (e-mail: leans, Louisiana. For details telephone 800-908-9414 (e- [email protected]). mail: [email protected]).

BENCHMARKING—PULSE POINTS TO DIAGNOSE AUA FRIDAY FORUM—PROSTATE AND RENAL YOUR PRACTICE’S HEALTH CANCER SERIES October 23, 2007. Audio/Web Conference 8:00–9:30 p.m. December 7, 2007. Oklahoma City, Oklahoma. For details EST. For details telephone 800-908-9414 (e-mail: telephone 800-908-9414 (e-mail: [email protected]). [email protected]). PHYSICIAN RECRUITMENT—CONTRACTING AND EVIDENCE-BASED CLINICAL PRACTICE—A SELECTION STRATEGIES WORKSHOP FOR UROLOGISTS December 11, 2007. Audio/Web Conference 8:00–9:30 p.m. October 26–27, 2007. Linthicum, Maryland. For details tele- EST. For details telephone 800-908-9414 (e-mail: phone 800-908-9414 (e-mail: [email protected]). [email protected]). 364 NEWS AND ANNOUNCEMENTS

SEXUAL MEDICINE—AUA SUBJECT-ORIENTED authors the principal requirements for the acceptability of a SEMINAR paper. The Editors wish to offer to as many authors as possible December 14–15, 2007. Ritz-Carlton, Washington, D. C. For an opportunity to publish their work if it meets the estab- details telephone 800-908-9414 (e-mail: registration@ lished standards of excellence. The Editors will judge a auanet.org). paper primarily on the basis of originality and accuracy of content, and after that on the simplicity, clarity and brevity INFORMATION FOR AUTHORS of a good grammatical style. Information for Authors is printed in the February, Because of the increasing number of manuscripts of varying April, June, August, October and December issues. The length and complexity submitted to The Journal of page number for Information for Authors is listed in the Urology®, the Editorial Board has listed for the beneﬁt of contents.