BJU International Official journal of the British Association of Urological Surgeons and the Urological Society of Australasia August 2005 - Vol. 96 Issue 3 Page i-469
i Editor's comment Online publication date: 24-Jul-2005
Comments 231 How should we advise patients about the chemoprevention of prostate cancer?
Roger S. Kirby, John M. Fitzpatrick
Online publication date: 24-Jul-2005 232 A proposal for a new classification for operative procedures for stress urinary incontinence
Paul Abrams, Paul Hilton, Malcolm Lucas, Tony Smith
Online publication date: 24-Jul-2005 233 Renal transplantation and manpower issues
Dler Besarani, David Cranston
Online publication date: 24-Jul-2005 234 Is premature ejaculation all in the mind?
John Dean, Ian Eardley, Geoff Hackett, Jeremy Heaton, Roger Kirby
Online publication date: 24-Jul-2005
Mini-reviews 237 Selecting therapy for maintaining sexual function in patients with benign prostatic hyperplasia
Ajay Nehra
Online publication date: 24-Jul-2005 244 Robotic renal and adrenal surgery: present and future
Rajeev Kumar, Ashok K. Hemal, Mani Menon
Online publication date: 24-Jul-2005 250 Targeting bladder outlet obstruction from benign prostatic enlargement via the nitric oxide/cGMP pathway?
André Reitz, Michael Müntener, Axel Haferkamp, Markus Hohenfellner, Brigitte Schurch
Online publication date: 24-Jul-2005 254 The vital role of creativity in academic departments
Jeremy P.W. Heaton
Online publication date: 24-Jul-2005
Great Drug Classes 257 Phosphodiesterase type 5 inhibitors for erectile dysfunction
Culley C. Carson, Tom F. Lue
Online publication date: 24-Jul-2005
Urological Oncology 281 Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma
John T. Leppert, John S. Lam, Allan J. Pantuck, Robert A. Figlin, Arie S. Belldegrun
Online publication date: 24-Jul-2005 286 Therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: biology, clinical results and future development
Brian I. Rini, Jeffrey A. Sosman, Robert J. Motzer
Online publication date: 24-Jul-2005 291 Multidetector computed tomography vs magnetic resonance imaging for defining the upper limit of tumour thrombus in renal cell carcinoma: a study and review
Nathan Lawrentschuk, Johan Gani, Richard Riordan, Steven Esler, Damien M. Bolton
Online publication date: 24-Jul-2005 296 Epothilones and the next generation of phase III trials for prostate cancer
Manish S. Bhandari, Maha Hussain
Online publication date: 24-Jul-2005 303 Tumour markers for managing men who present with metastatic prostate cancer and serum prostate-specific antigen levels of <10 ng/mL
Alison J. Birtle, Alex Freeman, John R.W. Masters, Heather A. Payne, Stephen J. Harland, contributors to the BAUS Section of Oncology Cancer Registry
Online publication date: 24-Jul-2005
308 Age-specific reference levels of serum prostate- specific antigen and prostate volume in healthy Arab men
Elijah O. Kehinde, Olusegun A. Mojiminiyi, Mehraj Sheikh, Kaleel A. Al-Awadi, Abdallah S. Daar, Adel Al-Hunayan, Jehoram T. Anim, Aisha A. Al-Sumait
Online publication date: 24-Jul-2005 313 Analysis of peripheral blood for prostate cells after autologous transfusion given during radical prostatectomy
John T. Stoffel, Linda Topjian, John A. Libertino
Online publication date: 24-Jul-2005 316 New perioperative management reduces bleeding in radical retropubic prostatectomy
Martin Schostak, Klaudia Matischak, Markus Müller, Michel Schäfer, Mark Schrader, Frank Christoph, Kurt Miller
Online publication date: 24-Jul-2005 320 Do all patients with high-grade prostatic intraepithelial neoplasia on initial prostatic biopsy eventually progress to clinical prostate cancer?
Jonathan I. Izawa, Iliana Lega, Donal Downey, Joseph L. Chin, Patrick P. Luke
Online publication date: 24-Jul-2005
324 Increasing the number of biopsy cores improves the concordance of biopsy Gleason score to prostatectomy Gleason score
Christopher L. Coogan, Kalyan C. Latchamsetty, Jason Greenfield, John M. Corman, Barlow Lynch, Christopher R. Porter
Online publication date: 24-Jul-2005 328 Serum thyroid-stimulating hormone is elevated in men with Gleason 8 prostate cancer
Steven Lehrer, Edward J. Diamond, Nelson N. Stone, Richard G. Stock
Online publication date: 24-Jul-2005 330 Inguinal hernia repair with polypropylene mesh during radical retropubic prostatectomy: an easy and practical approach
Alberto Azoubel Antunes, Marcos Dall'oglio, Alexandre Crippa, Miguel Srougi
Online publication date: 24-Jul-2005 334 An office-based immunodiagnostic assay for detecting urinary nuclear matrix protein 52 in patients with bladder cancer
Abdelfattah M. Attallah, Hanem A. Sakr, Hisham Ismail, El-Sayed K. Abdel-Hady, Ibrahim El-Dosoky
Online publication date: 24-Jul-2005
Lower Urinary Tract 341 Detrusor myectomy: long-term results with a minimum follow-up of 2 years
Sunil P.V. Kumar, Paul H. Abrams
Online publication date: 24-Jul-2005
345 Are conventional pressure-flow measurements dependent upon filled volume?
Kanagasabai Sahadevan, Ann S. Leonard, Robert S. Pickard
Online publication date: 24-Jul-2005 350 Validation of a patient-administered questionnaire to measure the severity and bothersomeness of lower urinary tract symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment questionnaire
Darren Clayson, Diane Wild, Helen Doll, Karen Keating, Kathleen Gondek
Online publication date: 24-Jul-2005 360 A novel midstream urine-collection device reduces contamination rates in urine cultures amongst women
Simon R. Jackson, Mathew Dryden, Paul Gillett, Paddy Kearney, Rosemary Weatherall
Online publication date: 24-Jul-2005 365 How do urinary diaries of women with an overactive bladder differ from those of asymptomatic controls?
Mary P. Fitzgerald, Deborah Ayuste, Linda Brubaker
Online publication date: 24-Jul-2005 368 A comparison of the effect of 1.5% glycine and 5% glucose irrigants on plasma serum physiology and the incidence of transurethral resection syndrome during prostate resection
Justin W. Collins, Seamus MacDermott, Richard A. Bradbrook, Francis X. Keeley Jr, Anthony G. Timoney
Online publication date: 24-Jul-2005
Sexual Medicine 373 The management of penile fracture based on clinical and magnetic resonance imaging findings
Ahmad Abolyosr, Alaa E. Abdel Moneim, Atef M. Abdelatif, Medhat A. Abdalla, Hisham M.K. Imam
Online publication date: 24-Jul-2005
Upper Urinary Tract 379 Outcome from percutaneous nephrolithotomy in patients with spinal cord injury, using a single- stage dilator for access
Nathan Lawrentschuk, David Pan, Richard Grills, John Rogerson, David Angus, David R. Webb, Damien M. Bolton
Online publication date: 24-Jul-2005 385 Multimodal management of urolithiasis in renal transplantation
Ben Challacombe, Prokar Dasgupta, Richard Tiptaft, Jonathan Glass, Geoff Koffman, David Goldsmith, Mohammed S. Khan
Online publication date: 24-Jul-2005
Reconstructive Urology 391 Asymptomatic bacteriuria in men with orthotopic ileal neobladders: possible relationship to nocturnal enuresis
Mohamed Abdel-Latif, Ahmed Mosbah, Magdy S. El Bahnasawy, Essam Elsawy, Atallah A. Shaaban
Online publication date: 24-Jul-2005
Paediatric Urology 397 Vesicostomy revisited: the best treatment for the hostile bladder in myelodysplastic children?
Shelby N. Morrisroe, R. Corey O'Connor, Dana K. Nanigian, Eric A. Kurzrock, Anthony R. Stone
Online publication date: 24-Jul-2005 401 Inguinal hernia in female infants: a cue to check the sex chromosomes?
Asma Deeb, Ieuan A. Hughes
Online publication date: 24-Jul-2005 404 Nocturnal enuresis at 7.5 years old: prevalence and analysis of clinical signs
Richard J. Butler, Jean Golding, Kate Northstone, The ALSPAC Study Team
Online publication date: 24-Jul-2005 411 Efficacy of tolterodine as a first-line treatment for non-neurogenic voiding dysfunction in children
Semih Ayan, Kemal Kaya, Kahraman Topsakal, Hakan Kilicarslan, Gokhan Gokce, Yener Gultekin
Online publication date: 24-Jul-2005
Investigative Urology 416 The src-family kinase inhibitor PP2 suppresses the in vitro invasive phenotype of bladder carcinoma cells via modulation of Akt
George J. Chiang, Brian R. Billmeyer, David Canes, John Stoffel, Alireza Moinzadeh, Christina A. Austin, Monika Kosakowski, Kimberly M. Rieger-Christ, John A. Libertino, Ian C. Summerhayes
Online publication date: 24-Jul-2005
423 Sildenafil inhibits the formation of superoxide and the expression of gp47phox NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells
Anthony J. Koupparis, Jamie Y. Jeremy, Saima Muzaffar, Raj Persad, Nilima Shukla
Online publication date: 24-Jul-2005 428 Loss of ryanodine receptor calcium-release channel expression associated with overactive urinary bladder smooth muscle contractions in a detrusor instability model
Hai-Hong Jiang, Bo Song, Gen-Sheng Lu, Qian-Jun Wen, Xi-Yu Jin
Online publication date: 24-Jul-2005
Pharmaceutical review 435 Unseen forces at AUA 2005?
Michael G. Wyllie
Online publication date: 24-Jul-2005
Points of Technique 437 A simple modification to the Albarran deflector enhances endoscopic control
Kevin R. Loughlin
Online publication date: 24-Jul-2005 439 Cystoscopic removal of a JJ stent using a suture 'lasso'
Govind V.S. Murthi, Peter Cuckow
Online publication date: 24-Jul-2005
Letters 440 Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases
Michele Gallucci, Roberta Merola, Costantino Leonardo, Enzo Maria Ruggeri, Anna Maria Cianciulli
Online publication date: 24-Jul-2005 440 Reply
Truls Gårdmark, Per-Uno Malmström
Online publication date: 24-Jul-2005 441 The role of urinary urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects
Alison F. Brading
Online publication date: 24-Jul-2005 441 Laparoscopy for impalpable testes
Stephen J. Griffin
Online publication date: 24-Jul-2005 441 Reply
Steven Lehrer
Online publication date: 24-Jul-2005 441 C-reactive protein is significantly associated with prostate-specific antigen and metastatic disease in prostate cancer
S. Asad Abedin
Online publication date: 24-Jul-2005
442 The incidence and treatment of lymphoceles after radical retropubic prostatectomy
Amrith Raj Rao, Roger O. Plai
Online publication date: 24-Jul-2005
Surgery Illustrated 443 Simplified orthotopic ileocaecal pouch (Mainz pouch) for bladder substitution
Joachim W. Thüroff, Ludger Franzaring, Rolf Gillitzer, Markus Wöhr, Sebastian Melchior
Online publication date: 24-Jul-2005 466 Corrigendum Online publication date: 24-Jul-2005 467 Abbreviations Online publication date: 24-Jul-2005 468 Diary Online publication date: 24-Jul-2005
EDITORIAL
This month sees the arrival of the first in a series of articles entitled ‘Great Drug Classes’
This month sees the arrival of another cite their favourite references (often their pioneering BJU International initiative, the own) or for the pharmaceutical industry to first in a series of articles entitled ‘Great Drug present the most appropriate ‘representative’ Classes’. data? The guidelines established by the BJU International should minimize both of these Over the last two decades, in urology and possibilities. The authors are invited by the sexual health we have seen the arrival of Journal and they must construct the whole many new major drug classes that have article in the context of the above template in revolutionized patient management. ª10 000 words, and using an absolute Although the characteristics of individual maximum of 100 references. In general, drugs are well described (often in relation to statements will be made about the class competitors) in individual papers and reviews, as a whole and only key features of the editorial board felt that there was a void individual drugs will be presented. in the availability and dissemination of easily Hopefully this will be a good way to focus readable information. This has culminated, the mind and the pen, and yet create an after several iterations, in the first of the easily digestible article. series of Great Drug Classes, i.e. that on phosphodiesterase inhibitors. The editorial team would like to thank Tom Lue and Culley Carson for being the willing In this prototype and all subsequent articles in guinea-pigs in establishing this new venture. the series, two eminent authors in the field As you might imagine, this was made (generally one scientist and one clinician) particularly difficult due to the wealth of data have been asked to follow a distinct template and publications available for discussion, covering: Introduction explaining why the dissection and eventual inclusion. drug class is important to healthcare professionals; historical perspective; We at the BJU International look forward to background science; clinical data covering your comments on this style of article and
efficacy, therapeutic ratio, PK-PD relationships suggestions for the future. It is anticipated and including an algorithm on how this fits that the series will on average appear into the contemporary management of the bi-annually. To celebrate the launch of the disease; and finally future prospects, but only Great Drug Classes, one member of the drug as it relates to the primary indication. series is featured on the outside cover.
Is this just an excuse for another unreadable MICHAEL G. WYLLIE lengthy review, giving the authors a chance to Associate Editor
i
KIRBY AND FITZPATRICK
Prostate cancer represents in many ways an HOW SHOULD WE ADVISE PATIENTS ABOUT THE ideal candidate for chemoprevention, because CHEMOPREVENTION OF PROSTATE CANCER? ROGER S. KIRBY and of its high incidence and long latency to clinically significant disease [1]. Because of JOHN M. FITZPATRICK – St George’s Hospital, London, UK and Mater Misericordiae this, increasingly many patients are asking Hospital, Dublin, Ireland their urologist directly what steps they can take to reduce their risk of being affected by the disease. If we as clinicians do not provide Many clinicians have been in the habit of has been evaluated in the Prostate Cancer appropriate evidenced-based advice, then our advising higher doses of vitamin E, often Prevention Trial [6]. In that study 18 882 patients are likely to end up taking an 400 IU/day, but recently published evidence men with a normal DRE and a PSA level expensive cocktail of ‘natural’ preparations, suggests that the recommended dose should of <3.0 ng/mL were randomized to either often purchased at considerable expense from be £150 IU/day. Miller et al. [4] reported a finasteride 5 mg/day or placebo, for 7 years. their local health-food store. meta-analysis of 19 trials, recruiting 135 967 Prostate biopsy was advised if the PSA was participants; nine of 11 trials testing high- >4.0 ng/mL or the DRE became abnormal. So what is the current evidence that there is dosage (<400 IU) vitamin E showed a greater Prostate cancer was detected in 18.4% of anything now available that can safely and risk for all-cause mortality for those on men in the finasteride group and 24.4% effectively reduce the risk of prostate cancer? vitamin E than in controls. The difference in in the placebo group, a 24.8% reduction This is an especially pertinent issue, as ever- mortality risk in high-dosage vitamin E trials (P < 0.001). However, tumours were of increasing numbers of prostate biopsies are was 39 per 10 000 persons (95 CI, 3–74; Gleason score 7–10 in 6.4% of the being taken, and urologists are seeing more P = 0.035). For low-dosage vitamin E trials, finasteride-treated men, compared with men who are deemed ‘high-risk’, either as the risk difference was -16 per 10 000 5.1% of the placebo group (P = 0.005), result of a raised PSA level, prostatic persons (CI -41 to -10; P > 0.2). A dose– and sexual side-effects were more intraepithelial neoplasia, or a positive family response analysis showed a statistically common in the finasteride arm. The history of prostate malignancy. significant relationship between vitamin E explanation for the slight preponderance dosage and all-cause mortality, with of less well-differentiated tumours in the Selenium is a trace nutrient essential for the increased risk for dosages of >150 IU/day men treated with finasteride so far remains activity of glutathione peroxidase, which may (Fig. 1). elusive. Although the result could be reduce oxidative damage to DNA. Several artefactual, because of the known effect studies suggest a useful effect, but the The true safety and effectiveness of selenium of finasteride on prostatic epithelial best (and still indirect) evidence for its and vitamin E should become clearer when architecture, there remains the worrying chemopreventive activity comes from the the results of the SELECT study become possibility that the effect could be real. Until Nutritional Prevention of Cancer Study available. This trial, which is sponsored the position becomes clearer, finasteride Group’s randomized trial of selenium to by the USA National Cancer Institute, is should probably not be recommended as a reduce the recurrence of skin cancer. After a randomized, double-blind, placebo- chemopreventive agent for prostate cancer. 10 years of follow-up (mean time on controlled, population-based clinical trial treatment 4.5 years), men taking selenium designed to test the efficacy of selenium and Dutasteride is a dual inhibitor of both 5a- at a dose of 200 mg/day had a 63–74% vitamin E either alone or combined [5]. The reductase types 1 and 2. As such it results in reduction in the risk of prostate cancer [2]. target accrual is 32 400 individuals and the suppression of dihydrotestosterone by >90%, study duration is planned for 12 years. compared with a suppression of ª70% with Vitamin E is the other supplement for which Unfortunately results are not expected until finasteride. The Reduction of Prostate Cancer there is reasonable, but again indirect, 2013 (SELECT details available at http:// Events trial has just completed recruiting evidence for a genuine chemopreventative www.crab.org/select/). 8000 men to receive either 0.5 mg of effect in this context. In the Alpha-Tocopherol dutasteride or placebo for 4 years [7]. Biopsies Beta-Carotene Cancer Prevention Trial [3] In theory, some of the most logical must be negative within 6 months of accrual there was a statistically significant reduction chemopreventative agents for prostate and repeat biopsies will be taken at 2 and of both prostate cancer incidence and cancer are the 5a-reductase inhibitors. 4 years. The results will not be available for mortality of ª40% in men receiving 50 IU of Finasteride, the first compound developed some time yet, but should throw new light on a-tocopherol daily. in this class, which inhibits isoenzyme type 2, the issue.
© 2005 BJU INTERNATIONAL | 96, 231–236 | doi:10.1111/j.1464-410X.2005.05606–5609.x 231
COMMENTS
Encouragingly, it was recently proposed that FIG. 1. 0.05 the consumption of red wine might be The dose-response relationship protective against prostate cancer [8]. 0.04 between vitamin E Schoonen et al. interviewed 753 middle-aged supplementation and all-cause patients newly diagnosed with prostate 0.03 mortality, in randomized control ifference cancer, and 703 age-matched controls. Their d 0.02 trials. With permission, from [4]. lifelong alcohol habits, choice of beverage and prostate cancer history were assessed using 0.01 an elaborate scoring process. Overall, total 0 alcohol, beer, liquor and white wine -0.01
consumption were not associated with the All-cause mortality risk risk of prostate cancer. However, with red -0.02 wine, every additional glass drunk per week showed a statistically significant 6% decrease -0.03 in relative risk. Men drinking 4–7 glasses/week 10 20 50 100 200 500 1000 2000 were almost 25% less likely to have the Vitamin E dosage, IU/d disease (a relative risk reduction of 48%).
So how should we advise patients while development of prostate cancer N Engl J ALM, Stanford JL. Alcohol consumption awaiting more data? A combination of Med 2003; 349: 215–24 and risk of prostate cancer in middle-aged selenium 200 mg and vitamin E at £150 IU 7 Andriole G, Bostwick D, Brawley O et al. men. Int J Cancer 2005; 113: 133–40 per day may be effective, and seems unlikely Chemoprevention of prostate cancer in 9 Klein E, Thompson IM. Update on to cause significant side-effects, provided men at high risk: rationale and design chemoprevention of prostate cancer. Curr appropriate doses are used. A glass or two of of the reduction by dutasteride of Opin Urol 2004; 14: 143–9 red wine may be helpful, and tastes good! A prostate cancer events. J Urol 2004; myriad of other remedies are promoted as 172: 1314–7 Correspondence: Roger Kirby/John Fitzpatrick being effective [9], but in the absence of firm 8 Schoonen WM, Salinas CA, Kiemeney e-mail: [email protected] evidence from randomized studies or adequate safety data, patients should be August 2005 discouraged from using compounds that may 963 Comment Article do more harm than good, and that are also A PROPOSAL FOR A NEW CLASSIFICATIONNEW CLASSIFICATION FOR SURGERY FOR FOR STRESS OPERATIVE URINARY INCONTINENCE likely to damage the wallet! PROCEDURES FOR STRESS URINARYABRAMS INCONTINENCE et al. REFERENCES PAUL ABRAMS, PAUL HILTON*, MALCOLM LUCAS† and TONY SMITH‡ – Bristol Urological Institute, Southmead Hospital, Bristol, *Royal Victoria Infirmary, Department 1 Mellon JK. Chemoprevention of prostate cancer comes of age. BJU Int 2004; 93: of Obs & Gynae, Newcastle upon Tyne, †Morriston Hospital, Department of Urology, Swansea, 459–60 ‡St Mary’s Hospital, Department of Obs & Gynae, Manchester, UK 2 Clark LC, Dalkin B, Krongrad A et al. Accepted for publication 3 March 2005 Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. A newcomer to the field of stress element of both, although pure intrinsic Br J Urol 1998; 90: 1219–24 incontinence surgery might be bewildered by sphincter deficiency can be seen in 3 Heinonen OP, Albanes D, Virtamo J et al. the spectrum of surgery offered for this neurological conditions, such as Prostate cancer and supplementation condition, extending from injectables through meningomyelocele, or after cauda equina with alpha-tocopherol and beta- so-called ‘minimally invasive’ procedures and trauma carotene: incidence and mortality in a conventional open procedures, to the artificial controlled trial. J Natl Cancer Inst 1998; urinary sphincter. Over the last 20 years many In recent years, the ‘tension-free’ concept and 90: 440–6 new procedures, some involving implanted the insistence of a ‘mid-urethral position’ for 4 Miller ER, Pastor-Barriuso R, Dalal D devices, have come and gone at regular slings has been much discussed. However, it et al. Meta-analysis: high dosage vitamin intervals. All have promised much, but seems that there is neither evidence for an E supplementation may increase all- regrettably most have failed to fulfil their effective sling being tension-free, nor for cause-mortality. Ann Int Med 2005; 142: promise. In many instances there has been the mandatory position to be mid-urethral. I40 little evidence to support new causal theories What is undoubtedly true is that almost 5 Klein EA, Thompson IM, Lippman SM on which the procedures are said to be based. all urologists and gynaecologists have et al. The Selenium Vitamin E Prevention The two reasonably well accepted theories for recognized the value of ensuring that the Trial. World J Urol 2003; 21: 21–7 female stress incontinence are bladder neck/ urethra is restored to a normal anatomical 6 Thompson IM, Goodman PJ, Tangen CM urethral hypermobility and intrinsic sphincter position, so that the principal aims are to et al. The influence of finasteride on the deficiency. In truth, most women have an prevent descent and to avoid over-elevation.
232 © 2005 BJU INTERNATIONAL
COMMENTS
Therefore, all procedures, be they needle • devices could be added to this classification. The suspension procedures (now largely defunct), • Extra-urethral retropubic devices (e.g. ACT classification should prevent the frequent retropubic bladder neck suspensions, rectus balloon); claims for new theories and mechanisms by sheath slings or the new synthetic tapes, are • Extra-urethral, fixed-resistance perineal which new procedures will be more effective; presently performed at low tension. The devices in men; claims which so often have turned out to be misnomer of ‘tension-free’ has come about • Extra-urethral circumferential variable- further examples of ‘the Emperor’s New from the way synthetic tapes are implanted resistance devices (e.g. the American Medical Clothes’. with the patient supine. However, stress System artificial urinary sphincter). incontinence episodes do not occur when a Correspondence: Paul Abrams, Bristol woman lies flat, unless the urethral function We hope that this classification allows Urological, Institute, Southmead Hospital, is truly dreadful. When the patient stands, established procedures and new techniques to Westbury-on-Trym, Bristol, BS10 5NB, then the anatomical relationships between be viewed according to their proposed mode UK. the procedure (be that suture, tape, etc.) and of action. If new modes of action emerge they e-mail: [email protected] August 2005 its body anchoring points will change for 963 every procedure, and the hammock behind Comment Article RENAL TRANSPLANTATION AND MANPOWER ISSUES the posterior wall of the proximal urethra will BESARANI AND CRANSTON tighten to prevent the caudal and posterior movement of the posterior wall of the bladder RENAL TRANSPLANTATION AND MANPOWER ISSUES neck and proximal urethra. This will apply DLER BESARANI and DAVID CRANSTON – Oxford Radcliffe Hospitals NHS Trust, however the support is created, with the Churchill Hospital, Oxford, UK theoretical exception of injectables and the artificial sphincter. We believe the simple Accepted for publication 29 March 2005 hammock theory of Delancey to be a proper explanation of why female stress incontinence occurs and how a wide range of INTRODUCTION vascular and transplant subsection. procedures cure the condition. Perhaps we The reason for the lack of interest in should call it ‘the unifying theory of female Renal transplantation is the treatment of transplantation by most UK urologists is stress incontinence’. This theory cannot apply choice for patients with end-stage renal entirely clear, but may relate to some of the to men in the same way and perhaps here the failure. In the UK, >5000 patients are waiting factors outlined above. concept of intrinsic sphincter deficiency is for a kidney transplant, but because of the more relevant. We think that most procedures shortage of donor organs and surgeons to The proposal for changes to training in act in two basic ways and would like to undertake the surgery, patients have to urology as part of the modernization of propose the following classification for wait longer for their operation. This is an medical careers will have a further impact discussion. internationally recognized problem. Last on transplantation. Clearly, the changes in year there were 1330 kidney transplant urology to create more generalist and office Urethral/bladder neck-stabilizing operations in the UK (with 47 kidney- urologists to look after the speciality may procedures pancreas operations). Therefore, there is a further decrease the number of those who need to double or triple the number of have an interest in renal transplantation. • Vaginal wall suspension procedure; transplants operations, to reduce the waiting However, with the disappearance of much needle procedures (Peyrera, Stamey, Raz, list. To do this we have to both encourage open surgery, it may create an opportunity for Gittes); organ donation and train more transplant those who still enjoy the challenge of complex suprapubic procedures, open or surgeons. Recently, the speciality has not urological problems sometimes seen after laparoscopic (Marshall Marchetti, Burch, been attractive for most junior surgical renal transplant surgery. In addition to vagino-obturator shelf procedure) trainees [1]. The unattractiveness of the this, the laparoscopic urologist is arguably vaginal procedures (anterior colporraphy). speciality might be a result of several factors, the best-trained person to undertake • Suburethral retropubic space slings e.g. the excessive unsociable working hours, laparoscopic donor nephrectomy. Many biological (autologous, allograft, low potential for financial progress and lack potential living donors are now requesting xenograft) of private work. Nevertheless, there are good laparoscopic surgery, which has several synthetic (e.g. tension-free vaginal tape, opportunities for trainees across the speciality advantages over open nephrectomy in terms SPARC) and many opportunities for research are of postoperative pain, early return to work • Suburethral obturator foramen procedures available. and better cosmetic results [2]. However, biological tapes adequate training and monitoring is essential synthetic tapes (e.g. TOT, Monarch) Traditionally, the renal transplant operation to prevent complications to the donor or has been undertaken by surgeons trained in damage to the kidney. Urethral sphincter augmentation general, vascular or urological surgery. Relatively few renal transplants are done by The Morris report [3] supported the • Intramural urethral injectables urologists in the UK, in contrast to Europe and involvement of urologists with a major • bulking agents (e.g. collagen, North America, which have a much higher commitment to renal transplantation. The hydroxyapatite) urological input. Indeed the AUA has a combination of specialities would provide
© 2005 BJU INTERNATIONAL 233
COMMENTS
career development and access to private offered (as indeed already exists in some M. Renal transplantation surgery. BMJ practice. Such surgeons would be able to take centres). ‘The number of fellowships available Career Focus 2002; 324 (S): 105a on other operations, such as nephron-sparing in any subspeciality will depend on national 3 Morris P. Report of the Working Party to surgery for RCC, and retroperitoneal work. requirements’ [6]. Entry would be by open Review Organ Transplantation. Ann R Coll They would also be able to provide specialist competition but the opportunities for a Surg Engl 1999; 81 (Suppl. 3): 128 support in the transplant team for urological urologist to become involved in 4 Morris-Stiff GJ, Benson S, Casey J, problems in the transplant population. In transplantation are available and would be Darby CR. Transplant surgeons in one audit study in which the Carrel Club welcomed by many units, and those trainees training: is anybody out there? Ann R Coll (an association of trainee surgeons in who still find fulfilment in solving complex Surg Engl 1999; 81: 191–4 transplantation) database was used, 110 problems and who enjoy open surgery would 5 UK Transplant. http://www.uktransplant. trainees were identified in the UK between find it very rewarding. org.uk/ukt/statistics/statistics 2004 1997 and 1998. Interestingly, only 45% 6 Specialist Advisory Committee in intended to apply for a consultancy in Urology. Modernising Medical Careers in transplantation and most trainees (27 of 31) Urology. A report from the Specialist wanted their transplantation commitments to REFERENCES Advisory Committee in Urology, 2004 be combined with a second speciality [4]. 1 Callaghan C, Ali A, Pettigrew G. Correspondence: Dler Besarani, Oxford To perform more organ transplants and care Transplant surgery. BMJ Career Focus Transplant Centre, Churchill Hospital, Oxford for these patients, two or three times more 2004; 329: 23–5 OX3 7LJ, UK. transplant trainees than there are at present 2 Brook N, White S, Veitch P, Nicholson e-mail: [email protected] August 2005 will need to be enrolled in the national 963 training programmes. Transplantation has put Comment comment a heavy demand on surgical services, which DEAN has not been matched by adequate manpower et al. and facilities. The transplant surgeons are often also responsible for creating vascular IS PREMATURE EJACULATION ALL IN THE MIND? JOHN DEAN, or peritoneal access. Overall, resources, IAN EARDLEY, GEOFF HACKETT, JEREMY HEATON and ROGER KIRBY manpower and facilities for transplantation in general are inadequate across the country. To solve the manpower problem, strategic planning is required. There are several ways to INTRODUCTION one couple may be regarded as PE by another. tackle this issue. One approach would be to If this is the case then how can PE be defined have a team which involves urologists and It is generally accepted that premature other than as a condition of perception vascular surgeons in every renal transplant ejaculation (PE) is related to psychological involving poor confidence, low sexual unit in the country to provide a factors and erectile dysfunction is linked with satisfaction or unrealistic expectations? comprehensive input into the management of organic causes. Clinically, the two conditions patients with renal failure. can be differentiated by physical examination, Even when assessing the current ‘branching penile Doppler ultrasonography, penile classifications’, which take into account the Renal transplantation is very cost effective tumescence testing and psychological variable causes of PE, it could be psychogenic, compared with dialysis; in 2002–03, UK assessment [1]. However, this differential arteriogenic, neurogenic, endocrinological Transplant recorded 17 110 people in the UK diagnosis is still insufficient in some cases, and/or cavernosal in origin. Thus perhaps it is with a functioning kidney transplant. In the and there are other examples whereby fairer to say that PE is ‘all in the mind’ of some present year, these patients will save the current definitions and prejudices must patients, reflecting a single sector of the National Health Service £363 million in the be questioned (e.g. psychogenic erectile spectrum of the condition, which incidentally dialysis costs that they would have needed if dysfunction or injury-related PE). So this is probably a better representation of the they did not have a functioning kidney leaves an unanswered question; is PE a argument. transplant [5]. condition of perception, or organic, or both? Looking also at the neurophysiology of To answer this question we examine the ejaculation, whereby neurological control CONCLUSIONS historical and current definitions of PE. of the sexual response occurs at the According to Kaplan [2], PE is caused by poor supra-spinal, spinal and infra-spinal levels, Currently the discrepancy between the voluntary control over the timing of primary PE (i.e. PE since puberty) can be workload and the number of transplant ejaculation. Current definitions, including caused by developmental delay of this control surgeons is large, and will become even those proposed by the American Psychiatric mechanism. There is also evidence to suggest greater in future if no action is taken. Association [3], continue with this ‘line of that it is a conditioned response relating to However, the new training programme in thinking’, by emphasising the emotional and this process, and those with an early onset urology may offer a way forward. interpersonal nature of the condition. There is may be unable to regain ‘normal’ ejaculatory Subspecialist training could include renal also greater promotion of the couples’ control later in life. In these patients, the transplantation and a fellowship could be perception of PE, i.e. what may be normal for neurological control may be no different to
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those without PE, but the results are; so is this perception’ contributes to PE, and it has been penile hypersensitivity; recent studies suggest the true definition of an ‘all in the mind’ the poor understanding of the causes of PE that it is not a major contributing factor to PE, condition? that has contributed to neglect in this area. e.g. in one study of 18 patients with lifelong The multifactorial nature of the condition PE there was no significant (P < 0.05) PE is commonly associated with psychological is highlighted by the WHO consensus [7]. difference in sensitivity of the glans penis, causes (e.g. anxiety disorders, stress, In this consultation document, several dorsum or frenulum compared with controls interpersonal conflicts, guilt and fears); these pathophysiologies are described as [10]. However, topical anaesthetics have been problems are very real but historically there contributing to PE, which includes very effective in this context; in one study of has been little to link them with an organic psychogenic causes such as anxiety and early 42 men the intravaginal ejaculatory latency cause of PE. In one survey of 789 men and 979 sexual experiences; however, the WHO panel time increased from 1.49 to 8.45 min women, PE was frequently associated with acknowledge that the evidence-base (P < 0.001) after treatment with topical anxiety (odds ratio 3.1), whereas organic supporting these causes was weak. lidocaine-prilocaine [11]. These anomalies diseases such as insulin-dependent diabetes suggest that larger studies are needed to mellitus were more strongly associated with There is also a distinction between mind assess the impact of organic causes on PE, erectile dysfunction (odds ratio 6.9) [4]. and brain, which is often overlooked. The and diagnostic techniques may also need to neurological control of ejaculation, even in come under closer scrutiny. In the light of this, perhaps the argument patients with the primary condition, is one of has become one of classification. Having cognition not perception, and this in itself However, further condemnation for the mind identified an inorganic form of PE, when represents an organic control mechanism. In theory comes from the effectiveness of can this type of PE be distinguished from patients with PE this mechanism has not treatment with antidepressants, particularly performance anxiety or psychogenic adapted (or responded) normally to external selective serotonin re-uptake inhibitors. This erectile dysfunction? These conditions are stimuli, and it is this that separates PE from suggests that PE may be a result of a acknowledged in the medical literature, and normal ejaculation. neurotransmitter imbalance (e.g. serotonin), the high, worldwide prevalence of these which may also account for the high conditions supports their existence. There is Furthermore, there is evidence to support association between the condition and also a significant association between several organic causes of PE, including illness, psychological disorders. A recent pilot study psychopathological conditions and other injury (spinal), surgery and medication use showed that fluoxetine was effective at sexual dysfunctions. For example, several (side-effects or abuse). This breaks the myth treating both panic disorder and comorbid PE psychopathological conditions have been that PE has psychological causes. However, in the same patients. In this open-label study, identified with erectile dysfunction (and the existing evidence still lends itself to 10 patients were given fluoxetine 20 mg for organic causes are not always established). distinguishing between primary premature 8 weeks; there were significant improvements These include depressive disorders (18–35% and secondary (late-onset) ejaculation, largely in PE at 2 weeks, and in panic and sexual have PE), anxiety disorders (37%), or in terms of ‘organic’ vs ‘psychogenic’. The satisfaction at 4 weeks [12]. It is assumed that psychotic disorders (46–47%) [5]; these two are characterized by differences in other agents (e.g. tricyclic antidepressants) findings also lend weight to the existence of bulbocavernosus reflex, latency time, history will have similar properties. ‘all in the mind’ conditions relating to sexual and demonstrable organic illness [8]. PE can function. ‘run in families’, which is suggestive of an In summary, PE is a complex condition. If the inherited condition where the underlying view that it is ‘all in the mind’ refers to its link Further evidence for the ‘all in the mind’ cause has not been identified, and these with psychological disorders, emotional argument comes from studies in which patients could be those wrongly considered to disturbances or situations, then there is patients continue to improve after therapy have an ‘all in the mind’ condition. evidence to show that, in some cases, has stopped. In a study of 65 men with there are established underlying causes psychogenic erectile dysfunction who The comorbid nature of PE (i.e. it is evident (e.g. neurotransmitter imbalances). Even were treated with sildenafil for 6 weeks, with many other conditions such as considering the differences between primary a significant proportion (89%) showed an depression or hypogonadotrophic and secondary PE, a multifactorial approach improvement. After treatment was stopped, hypogonadism) is also indicative of a causal is needed to effectively diagnose and 66% still maintained their gains 6 weeks later link, albeit one that has not been readily differentiate the two, and this is also the case [6]. Does this represent the introduction of identified. There are other outstanding for distinguishing between PE and erectile a positive-behavioural cycle (i.e. improved problems, e.g. many patients have been dysfunction. In addition, pharmacological sexual functioning = improved self- successfully treated for hypogonadism but treatments are effective at treating PE, confidence = improved sexual functioning) or they retain their PE. In one study of 10 including that of a psychogenic nature does it indicate a previously unknown organic patients treated by aromatase inhibition (as shown by the success with sildenafil). cause? Indeed, how did sildenafil induce such (anastrazole), hormone levels (testosterone However, patients still fare better if they are a significant response in patients with a and oestradiol) returned to normal after given a more ‘holistic’ treatment strategy, largely psychogenic, inorganic cause in the 2 weeks but the PE remained [9]. We could often involving experimentation with first place? argue that this supports a mind-based behavioural therapy, partner involvement, condition, but it suggests that the link counselling and pharmacological However, there is also much evidence to between the conditions has not yet been intervention. Tailoring the diagnostic suggest that something other than ‘mind or identified. Not dissimilar is the case with expertise and treatment strategies will greatly
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benefit from large-scale trials based on some 2 Kaplan HS. The New Sex Therapy: Active Health Organization, (WHO), International of findings described above. Treatment of Sexual Dysfunctions. New Consultation on Urological Diseases York: Brunner/Maazel, 1974 (ICUD) and Societe Internationale ACKNOWLEDGEMENT 3 APA. Diagnostic and Statistical Manual of d’Urologie (SIU). Paris, July 1–3 1999, Mental Disorders 4th edn. Text Revision. 2000: 713 This article was based on a debate held at this Washington DC: American Psychiatric 8 Godpodinoff ML. Premature ejaculation. year’s European Society for Sexual Medicine Association, 2000 Clinical subgroups and etiology. J Sex in London. The debate was sponsored by the 4 Dunn KM, Croft PR, Hackett GI. Martial Ther 1989; 15: 130–4 BJU International, Janssen-Cilag, Johnson & Association of sexual problems with 9 Holbrook JM, Cohen PG. Aromatase Johnson Pharmaceutical Services LLC, Ortho- social, psychological, and physical inhibition for the treatment of idiopathic McNeil and Urodoc Ltd. problems in men and women: a cross hypogonadotropic hypogonadism in men sectional population survey. J Epidemiol with premature ejaculation. South Med J CONFLICT OF INTEREST Community Health 1999; 53: 144–8 2003; 96: 544–7 5 Farre JM, Fora F, Lasheras MG. Specific 10 Paick JS, Jeong H, Park MS. Penile None declared. Source of funding: BJU aspects of erectile dysfunction on sensitivity in men with premature International, Janssen Cilag, J&J, Ortho: psychiatry. Int J Impot Res 2004; 16 ejaculation. Int J Impot Res 1998; 10: McNeil, Urodoc Ltd. (Suppl. 2): S46–9 247–50 6 van Lankveld JJ, van den Hout MA, 11 Busato W, Galindo CC. Topical REFERENCES Spigt MG et al. Cognitive changes predict anaesthetic use for treating premature continued recovery of erectile functioning ejaculation: a double-blind, randomized, 1 Oguzhanoglu N, Ozdel O, Oguzhanoglu versus relapse after discontinuation of placebo-controlled study. BJU Int 2004; A et al. The complementary role of sildenafil treatment for male erection. 93: 1018–21 different neurophysiological methods to Psychosom Med 2003; 65: 709–18 12 Kindler S, Dolberg OT, Cohen H et al. demonstrate organicity in male with 7 Jardin A, Wagner G, Khoury S The treatment of comorbid premature premature ejaculation and erectile et al. Recommendations of the 1st ejaculation and panic disorder with dysfunction. Electromyogr Clin International Consultation on Erectile fluoxetine. Clin Neuropharmacol 1997; Neurophysiol 2003; 43: 437–41 Dysfunction. Co-Sponsored by The World 20: 466–71
236 © 2005 BJU INTERNATIONAL Mini rev Article THERAPY FOR MAINTAINING SEXUAL FUNCTION IN BPH NEHRA
In the first of these mini–reviews Selecting therapy for maintaining the selection of therapy for the maintenance of sexual function in sexual function in patients with patients with BPH is outlined, benign prostatic hyperplasia along with an explanation of how altered regulation of AJAY NEHRA neurotransmitters, especially Department of Urology, Mayo Clinic, Rochester, MN, USA noradrenaline, may underlie the Accepted for publication 18 April 2005 syndrome of LUTS and sexual dysfunction. KEYWORDS Dutch men, of whom 9–20% were determined to have BPH, ED prevalence rates were 3% in Other mini-reviews outline the BPH, LUTS, adrenoceptors, a-blocker, 5a- men aged 50–54 years and 26% in men aged current status of robotic surgery to reductase inhibition, sexual function 70–78 years, and EjD prevalence was 3–35% treat renal and adrenal disorders, [10,11]. A multinational study involving both community and clinic cohorts showed and its future applications, and INTRODUCTION ED prevalence rates of 53% and 60%, the potential use of the nitric respectively, and EjD prevalence rates of 47% oxide/cGMP pathway as a potential In patients with BPH, LUTS can diminish and 62%, respectively, among patients with LUTS [12]. A study in 1274 European men with target to treat BOO associated quality of life (QoL) by interfering with sexual function [1–3], which has been shown to be LUTS showed prevalence rates for ED of 62% with benign prostatic enlargement. an important component of QoL among men and EjDs of 63%, with both being highly even in their later years [4,5]. As QoL becomes bothersome to patients, even in advanced Finally, the capacity to be creative more of a consideration in managing BPH, the age [12]. effects of BPH treatment on sexual function in academic departments is need to be included in patient management extolled as a core property of decisions. PATHOPHYSIOLOGY OF BPH, LUTS AND academicians, and its surfacing SEXUAL DYSFUNCTION described as having the potential EPIDEMIOLOGY OF LUTS, BPH AND BPH AND LUTS to revitalize individuals and SEXUAL DYSFUNCTION departments. The development of BPH requires the In a cohort of 80 774 Dutch men aged elaboration of testosterone by the testes. Men ≥45 years [6], the incidence rate of LUTS was castrated before puberty do not develop 5 per 1000 man-years and increased with age, BPH, and BPH is rare in men castrated in while the overall prevalence rate was 10.3%. It adulthood. Within the prostate, testosterone was reported that more than half of men aged is converted to 5a-dihydrotestosterone (DHT) >60 years have BPH, with 15–30% of such by 5a-reductase. DHT is important both for men experiencing LUTS [7]. the development of the prostate and for its enlargement later in life. The prevalence of sexual dysfunction, including erectile dysfunction (ED) and The prostate has a large complement of a- ejaculatory disorders (EjDs), also increases adrenoceptors, particularly in the prostatic with age [8]. ED has a reported global capsule, with varying concentrations in prevalence of 18.9–69.2% [9]. In a the bladder neck region and maximum community-based, longitudinal study of 3924 concentrations in the trigone. The two classes
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of adrenoceptors, a-1 and a-2, are also Ureters FIG. 1. selectively distributed: a-1s are more The anatomical distribution of abundant in the lower urinary tract and in the a1-adrenoceptor subtypes. blood vessels. (The a-1 and a-2 also have Adapted with permission from differing effects on male sexual function, as Bladder detrusor m. Schwinn [13]. discussed below). Three subtypes of a1- adrenoceptors, 1A, 1B and 1D, are also selectively distributed in the prostate, penis Urinary bladder and urinary tract, and these distributions vary with age. Trigone of the bladder
The preponderance of adrenoceptors in the Prostatic urethra smooth muscle of the prostate suggests that Prostate gland stimulating the receptors could cause an increase in smooth muscle tone in the External urethra sphincter prostate, thereby increasing pressure on the Penile urethra urethra and resulting in BOO or acute urinary retention (Fig. 1) [13]. In fact, a-blockers have been shown to relax prostatic smooth muscle, with improvements in both irritative and obstructive symptoms. a 1A - Adrenergic receptors predominate SEXUAL DYSFUNCTION (ED AND EJD) a 1D -Adrenergic receptors predominate
Penile erection is a complex neurovascular event involving the sympathetic, parasympathetic and somatic nervous ‘very important’ [2]. Both voiding and storage parasympathetic tracts, may also be involved systems, which mediate psychogenic and symptoms have been associated with sexual in LUTS as well as in sexual function and reflexogenic erections via the spinal cord. This dysfunction [17]. dysfunction [20]. process involves a balance of pro-erectile and anti-erectile neurotransmitters, e.g. Other age-related changes that may influence noradrenaline, serotonin, dopamine and the relationship between LUTS/BPH and MEASURES TO EVALUATE SYMPTOMS g-amino butyric acid. sexual dysfunction include declines in AND SEXUAL FUNCTION IN PATIENTS circulating androgen levels and the effects of WITH LUTS AND BPH The normal process of ejaculation proceeds some medications likely to be used in elderly initially with stimulation by the sympathetic patients. The bothersome effect of obstructive Several well-validated symptom scoring nervous system, which results in contraction and irritative symptoms, and negative scales have been developed for evaluating of the prostate, vas deferens, epididymis and expectations related to sexual performance, LUTS/BPH, and there are generic or disease- seminal vesicles, and ends with the flow of can impair sexual performance and QoL specific QoL instruments. With the seminal fluid into the urethra. EjD may occur among patients with LUTS/BPH [18]. recognition that treatments for BPH may in the presence of any pathological disorder affect sexual function, several instruments that involves the lower urinary tract Sexual dysfunction and incontinence often have been used to evaluate sexual function structures in the ejaculation pathway, occur in conjunction with LUTS [19], and this among patients with LUTS/BPH, including the including the prostate. In addition, raises the possibility of a shared mechanism International Index of Erectile Function, the neurological and psychological factors may involving similar noradrenergic and/or other Brief Sexual Function Inventory, the BPH- also be implicated in the development of neurotransmitter pathways. BPH can be Health-related Quality of Life scale, the ICSsex EjD [14]. marked by increases in the concentrations questionnaire and the Danish Prostatic and distribution patterns of a1 receptor Symptom Score questionnaire. subtypes in the prostate, and these same LUTS, BPH AND SEXUAL DYSFUNCTION receptor subtypes have been located within Although evaluations of sexual dysfunction penile tissue, where they play an anti-erectile have traditionally focused on ED, sexual A link between LUTS/BPH and sexual function role. It is possible that alterations in these functioning encompasses many domains, [15] is emerging despite the perception that receptor populations may occur in the penis including satisfaction with intercourse, BPH per se does not adversely affect sexual and contribute to the development of sexual ejaculation, sexual desire and overall function. Sexual dysfunction can profoundly dysfunction. Autonomic modulation of a1- satisfaction. Clinical experience with sexual affect older men [16], as many still engage in receptors and their subtypes at sites outside function scales shows a strong relationship sexual activity [3]; in one survey, 42% of men the genitourinary tract, including the human between LUTS and sexual difficulties [14,21]; aged >50 years considered sex ‘important’ or spinal cord and in both sympathetic and in addition, sexual satisfaction progressively
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decreases as the severity of LUTS advances treatments on sexual function are less so. The reductions appear to occur in men with larger from mild to severe [22–25]. Even when age- following represents a summary of clinical prostates at the initiation of therapy. adjusted, patients who score higher on the data. Finasteride has also yielded an improvement IPSS have poorer sexual function, as defined in urinary flow rates and in symptom relief. by the Brief Sexual Function Inventory [23] or WATCHFUL WAITING AND SURGERY other sexual function scales [24]. When Finasteride is associated with significant patients and their partners are asked about Watchful waiting is often used in patients adverse effects on sexual function in ª10% the history of urinary symptoms and sexual with mild symptoms or symptoms that are of subjects [30,36,38], which has led to dysfunction, they generally recall both not particularly bothersome. For the many discontinuation of patients from the drug problems as starting concurrently [25]. patients who eventually require treatment, in several studies [36,38]. In a 2-year, Studies using these measurement TURP is the most common surgical procedure. prospective, double-blind trial of finasteride instruments show that men with ED are twice Although highly effective, it is associated with 5 mg/day, 15.8% of finasteride-treated as likely to have LUTS as are men without significant morbidity and sexual dysfunction subjects developed ED, 10% reported ED [3]. (EjD in 25–55% of cases; ED in 13%) [30–32]. decreased libido and 7.7% developed EjD. Open prostatectomy, used especially in men Not all men will be bothered to the same with large prostates (>60 g), also has a high DUTASTERIDE degree by the same symptoms. Both the success rate but is associated with frequent prevalence and the bothersomeness of sexual complications, including deleterious effects Dutasteride is an inhibitor of both 5a- disorders have been shown to be strongly on sexual function. Prospective studies reductase isozymes and has been shown to associated with the severity of LUTS, even evaluating the impact of minimally invasive reduce the risk of acute urinary retention and when age and comorbidities are taken into surgery on sexual function have been few, but the need for surgery in men with BPH [39]. account [1]. This was the finding from the have assessed outcomes over periods of Similar sexual side-effects to those with Multinational Survey of the Aging Male 1–4 years [33–35]. There have been some finasteride are expected with dutasteride, [1], which evaluated >12 000 men aged reports suggesting possible pain or given that these effects are directly related to 50–80 years, in six European countries discomfort with ejaculation [35] but also the drug's therapeutic mechanism of action and the USA. In this survey, 83% of men emergence of retrograde ejaculation (18%) [39]. In a review of safety and tolerability data reported frequent sexual activity, although [33], decreases in ejaculate volume, and from several 2-year blinded trials and safety the frequency decreased with age and was reduced erectile strength [34]. studies of dutasteride, sexual adverse events inversely associated with age and the severity (including decreased libido, abnormal of LUTS. Of the patients evaluated, 49% 5a-REDUCTASE INHIBITOR (5-ARI) ejaculation, gynaecomastia and impotence, reported ED, 48% had EjD, and 7% had pain which occurred more often with dutasteride during sex. Both ED and EjD were reported as Originally medical treatment for BPH was than with placebo) were those most bothersome by most men who experienced focused on androgen blockade, either by frequently reported [40]. them. Problems in each domain of sexual surgical castration or with medication such as function were strongly associated with the the androgen-receptor blocker flutamide. a-BLOCKERS severity of LUTS, independent of age and Inhibition of androgens can reduce the size of other comorbidities. Overall, LUTS were the prostate but can also cause ED and With the identification of a1-adrenoceptors present in 90% of the men, but only 11% were reduced libido. The focus of pharmacotherapy as the predominant mediators of contraction being treated medically. shifted to with the discovery that men who of prostate smooth muscle, a-blockers have were deficient in 5ARI due to a homozygous become first-line treatment for BPH. The first- These data raise two significant issues that mutation had feminized urogenital structures and second-generation drugs include affect clinical practice: (i) the possible and prostates only 10% of the normal size. prazosin, doxazosin and terazosin. More underestimation of the effects of LUTS on recently, two agents claimed to be selective patients and therefore of a corresponding Conversion of testosterone to DHT by 5a- for one or more a1-adrenoceptor subtypes, need for therapy; and (ii) the need for more reductase increases the potency of androgens tamsulosin and alfuzosin, were introduced. thorough assessment of patients with LUTS, in target tissues, including the prostate. DHT Both of these have been claimed to show including evaluation of sexual function, via has a role in the normal differentiation and clinical uroselectivity (i.e. eliciting desired the use of validated scales that assess all growth of the prostate, as men with enlarged effects on obstruction and LUTS relative to sexual domains. prostates have higher levels of DHT. Two 5ARIs adverse events) and better tolerability than are used in the treatment of BPH, i.e. the traditional a-blockers [27,41–44]. finasteride and dutasteride. BPH THERAPIES: IMPACT ON NON-SUBTYPE SELECTIVE AGENTS: SEXUAL FUNCTION FINASTERIDE TERAZOSIN AND DOXAZOSIN
While the nonsexual side-effects of medical Treatment with finasteride, a competitive Terazosin and doxazosin are non-subtype treatments for BPH, especially the 5ARI acting on one isozyme that does not selective and were originally developed for vasodilatation-related symptoms of dizziness, bind to the androgen receptor, effectively their antihypertensive properties. Both agents asthenia and postural hypotension are well- reduces prostate size, by 19% after 1 year [36] are effective in relieving the symptoms documented [26–29], the effects of BPH and by 27% after 3 years [37]. The greatest of BPH, but can be associated with
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TABLE 1 Clinical characteristics of 5ARIs and a1-adrenoceptor antagonists in the treatment of BPH
Adverse events Drug Effect on prostate size Vasodilatory Sexual Titration required Reference Finasteride Decrease ª27% over 1 year N/A EjD, ED, decreased libido N/A [37] Dutasteride Decrease 20–25% over 1 year N/A EjD, ED, decreased libido N/A [62] Terazosin No effect Yes ED Yes [61] Doxazosin No effect Yes None* Yes [61] Tamsulosin No effect No EjD† No [61] Alfuzosin No effect No EjD‡ No [61]
*A long-term study on sexual function in hypertensive patients [45] suggests that ED may occur with doxazosin, although the difference with placebo was not statistically significant (11.6% vs 16.7%; P = 0.32); †EjD rates were 4–26% [27,48,49]; ‡EjD rates were <1% [29,50]; N/A, not applicable.
cardiovascular or vasodilatory side-effects, increased with alfuzosin treatment; in the 3- of the clinical characteristics of a-blockers e.g. dizziness, asthenia and postural month ALFORTI study, no EjD was reported in and 5ARIs is shown in Table 1 [37,61,62]. hypotension. In a 48-month study evaluating any of the three treatment groups [50]. In a the long-term effects of antihypertensive 12-month extension of the same study, agents, including doxazosin, on sexual alfuzosin once daily produced sustained COMBINED a-BLOCKADE AND 5-ARI function, rates of ED at study endpoint were improvements in symptoms and urinary flow 11.6% with doxazosin and 16.7% with rates [50,51]. In the placebo-controlled 3- In contrast to a-blockers, the 5ARIs do not act placebo, although the difference was not month ALFUS study [29] treatment with rapidly and often take 0.5–1 year to be statistically significant (P = 0.32) [45]. In alfuzosin 10 mg once daily induced a 3.6- effective. Because the 5ARIs and a-blockers addition, a 1.6% incidence of ED was reported point mean reduction in the IPSS from have different modes and onset of action, with terazosin [46]. baseline in the absence of any deleterious studies have examined combinations of these effect on sexual function. Temporary EjD was agents. Studies of up to 1 year in duration In a more recent prospective study, the new reported in one patient (0.6%) in each failed to show that combined therapy was extended-release formulation of doxazosin treatment group, with the cases being more effective in treating symptoms than a- was shown, using the International Index of considered not related to the study drug, as blocker therapy alone [63,64]. However, a Erectile Function, to produce a substantial there was spontaneous resolution with no recent long-term study of combined therapy improvement in sexual function in patients need to discontinue therapy. with doxazosin and finasteride showed that with BPH and comorbid ED [47]. during an average of 4.5 years of treatment, Unlike the non-subtype selective a-blockers combined therapy reduced the risk of acute (e.g. prazosin, terazosin and doxazosin), urinary retention by 81%, the need for ‘UROSELECTIVE’ AGENTS: TAMSULOSIN tamsulosin and alfuzosin are associated with invasive therapy by 67%, and symptom AND ALFUZOSIN a low incidence of postural symptoms, similar progression by 66% compared with observed to that seen with placebo [26,27,52]. disease progression in the placebo group [65]. Tamsulosin and alfuzosin are a-blockers that Although alfuzosin shows no subtype These changes were significantly better than are claimed to be uroselective or act specificity on in vitro tests, it does appear to those seen with either drug alone. preferentially on the lower urinary tract, i.e. be clinically uroselective [44,53–56]. they are clinically and physiologically Safety data reporting the effects on sexual uroselective agents. Both effectively improve Alfuzosin is associated with a much lower function are available from several trials that urinary flow rates and the symptoms of BPH incidence of EjD than is tamsulosin [57]. EjD have evaluated the use of an a-blocker (e.g. without affecting blood pressure at the doses has occurred in 10–11% of subjects taking doxazosin, terazosin, alfuzosin) combined used. Although tamsulosin has shown little tamsulosin 0.4 mg/day and 18–26% of those with the 5ARI, finasteride, in the treatment of effect on blood pressure, findings from taking 0.8 mg/day [48,58]. In a 1-year BPH [63,64,66]. In the 1-year Veterans Affairs several clinical trials indicate that use of this extension study, 30% of patients had EjD Cooperative Study, the combination of drug may be associated with EjD in some during treatment with tamsulosin, causing terazosin and finasteride was associated with patients; in these studies, EjD was reported in 2% to discontinue treatment; 6% had ED [59]. the highest reported rates of ED (combination, 4–26% of patients treated with tamsulosin In contrast, the incidence of EjD was <1% in 9%; terazosin, 6%; finasteride, 9%; placebo, [27,48,49]. clinical studies of alfuzosin once-daily, and 5%; P = 0.05) and EjD (combination, 7%; other sexual adverse events did not occur at terazosin, 0.3%; finasteride, 2%; placebo, 1%; Alfuzosin is used extensively in Europe as a incidences significantly greater than those P < 0.001). In another 1-year study, again the treatment for BPH and was recently approved reported with placebo [29,50]. These findings combined therapy was associated with the by the USA Food and Drug Administration. are supported by long-term trials with other highest rates of ED (combination, 10.5%; Sexual dysfunction does not appear to be formulations of alfuzosin [54,60]. A summary doxazosin, 5.8%; finasteride, 4.9%; placebo,
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3.3%; P < 0.01) and EjD (combination, 2.4%; results of the ‘Cologne Male Survey’. Int J 15 McVary KT. Sexual dysfunction in men doxazosin, 0.4%; finasteride, 2.3%; placebo, Impot Res 2000; 12: 305–11 with lower urinary tract symptoms and 1.5%; P = 0.16) [64]. 4 Helgason AR, Adolfsson J, Dickman P benign prostatic hyperplasia: an emerging et al. Sexual desire, erection, orgasm link. BJU Int 2003; 91: 770–1 The 6-month ALFIN study evaluated the and ejaculatory functions and their 16 NIH Consensus Development Panel on sustained-release formulation of alfuzosin importance to elderly Swedish men: Impotence. NIH, Consensus Conference. 5 mg twice daily with finasteride 5 mg once a population-based study. Age Ageing Impotence. JAMA 1993; 270: 83–90 daily and the combination of the two in the 1996; 25: 285–91 17 Peters TJ. The relationship between treatment of BPH [66]. Here too, combined 5 Calais Da Silva F, Marquis P, LUTS and sexual function. 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57 Schulman CC, Cortvriend J, Jonas U 61 Roehrborn CG, Schwinn DA. a- European Doxazosin and Combination et al. Tamsulosin, the first prostate- Adrenergic receptors and their inhibitors Therapy (PREDICT) trial. Urology 2003; 61: selective a1A-adrenoceptor antagonist. in lower urinary tract symptoms and 119–26 Analysis of a multinational, multicentre, benign prostatic hyperplasia. J Urol 2004; 65 McConnell JD, Roehrborn CG, Bautista open-label study assessing the long-term 171: 1029–35 OM et al. The long-term effect of efficacy and safety in patients with benign 62 Roehrborn CG, Boyle P, Nickel JC, doxazosin, finasteride, and combination prostatic obstruction (symptomatic BPH). Hoefner K, Andriole G. The ARIA3001, therapy on the clinical progression of Eur Urol 1996; 29: 145–54 ARIA3002, and ARIA3003 Study benign prostatic hyperplasia. N Engl J Med 58 Narayan P, Tewari A and members of Investigators. Efficacy and safety of a dual 2003; 349: 2387–98 the United States 94a–01 Study Group. inhibitor of 5-alphareductase types 1 and 66 Debruyne FMJ, Jardin A, Colloi D A second phase III multicenter placebo 2 (dutasteride) in men with benign et al. on behalf of the European controlled study of 2 dosages of modified prostatic hyperplasia. Urology 2002; 60: ALFIN Study Group. Sustained-release release tamsulosin in patients with 434–41 alfuzosin, finasteride and the combination symptoms of benign prostatic 63 Lepor H, Williford WO, Barry MJ et al. of both in the treatment of benign hyperplasia. J Urol 1998; 160: 1701–6 for the Veterans Affairs Cooperative prostatic hyperplasia. Eur Urol 1998; 34: 59 Narayan P, Lepor H. Long-term, open- Studies Benign Prostatic Hyperplasia 169–75 label, phase III multicenter study of Study Group. The efficacy of terazosin, tamsulosin in benign prostatic finasteride, or both in benign prostatic Correspondence: Ajay Nehra, Department of hyperplasia. Urology 2001; 57: 466–70 hyperplasia. N Engl J Med 1996; 335: Urology, Mayo Clinic, 200 First St. SW, 60 Lukacs B, Grange JC, Comet D, 533–9 Rochester, MN 55905, USA. McCarthy C. History of 7,093 patients 64 Kirby RS, Roehrborn C, Boyle P et al. e-mail: [email protected] with lower urinary tract symptoms for the PREDICT study investigators. related to benign prostatic hyperplasia Efficacy and tolerability of doxazosin and Abbreviations: ED, erectile dysfunction; EjD, treated with alfuzosin in general practice finasteride, alone or in combination, in ejaculatory disorder; QoL, quality of life; up to 3 years. Eur Urol 2000; 37: 183– treatment of symptomatic benign 5ARI, 5a-reductase inhibitor; DHT, 90 prostatic hyperplasia: the Prospective dihydrotestosterone.
© 2005 BJU INTERNATIONAL 243 Mini Rev Article ROBOTIC RENAL AND ADRENAL SURGERY KUMAR et al.
Robotic renal and adrenal surgery: present and future
RAJEEV KUMAR, ASHOK K. HEMAL* and MANI MENON* Urology, All India Institute of Medical Sciences, New Delhi, India, and *Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA Accepted for publication 7 January 2005
KEYWORDS complex, highly integrated and controlled technically successful in all the pigs, with interaction of visual and tactile feedback. longer operative times than conventional robotic, laparoscopy, kidney, adrenal, However, in laparoscopic urological surgery laparoscopy. Sung and Gill [12] went on to pyeloplasty, nephrectomy this fundamental coordinated feedback is compare the two available robot systems for significantly minimized or lost. In addition, nephrectomy in 11 procedures and concluded the surgeon’s actions are further that the da Vinci system (Intuitive Surgical, INTRODUCTION compromised by limitations in the movement Sunnyvale, CA) was more intuitive and of the instruments, known as degrees of allowed shorter operating times than the Zeus From its initial use in cardiac surgery, freedom. Furthermore, the two-dimensional system. robotically assisted surgery has progressively vision present in standard laparoscopy results moved to urology such that at present, over in loss of the perception of depth, as well In July 2001, Guillonneau et al. [13] reported half its application is for urological surgery. requiring a human assistant to control the the first telerobotic nephrectomy in a human. One of the principal reasons for this is the camera [2]. The impediment to the widespread They used a Zeus robotic surgical system with advancement of pure laparoscopy in urology. use of laparoscopy in urology has been the two arms for surgical manipulation and an Urological surgery, e.g. radical prostatectomy, complexity and technical demands of AESOP robotic arm to control the camera. The cystectomy and adrenalectomy, seem to be urological procedures, which is why it is robotic instruments were used to complete ideal indications for laparoscopy because the limited to relatively few experts and centres the dissection of the hilum and the kidney, open incision is usually greater than the worldwide [3]. However, with laparoscopic while the patient-side assistant applied target organ, which is deep-seated and nephrectomy becoming the standard of care laparoscopic clips using a standard 12 mm difficult to visualize. Several of these for benign nonfunctioning kidneys, port. They noted technical problems in procedures involve extensive reconstruction, laparoscopically inexperienced surgeons will instrument availability for the robot and relied a technique difficult to master feel the need to offer this to their patients and heavily on the patient-side assistant. The laparoscopically and that requires extensive may benefit from the more rapid learning surgery was successfully completed in experience. The robot provides an excellent afforded by the robot. We review published 200 min with no morbidity. Marella et al. [14] solution to these issues, allowing relatively reports on the use of robotic assistance for presented a series of 18 robot-assisted less experienced laparoscopists the ability to renal and adrenal surgery and discuss its laparoscopic nephrectomies at the annual offer minimally invasive surgery to their potential benefits. meeting of the AUA in 2004 and compared patients which is learned more rapidly than their results with 23 cases of hand-assisted pure laparoscopy, with improved technical laparoscopic nephrectomy. The operative performance [1–5]. duration was longer with the robot, with no RENAL SURGERY immediate advantage to its use. Hubert et al. In urology, the main use for the robot has [15] also presented data on 16 nephrectomies been in radical prostatectomy for prostate Patient positioning and port placement for in 10 patients (six bilateral simple, two radical cancer [6–9]. The reasons for this include the renal and adrenal surgery have been described and two donor nephrectomies) using the da small and deep working space, need for previously [10]. For simple and radical Vinci robot. They had one conversion to open precise dissection of apex of the urethra, nephrectomy, Table 1 [11–17] lists relevant surgery with a mean operative time of division of the bladder neck, preservation of reports. Kavoussi et al. [18] described the 110 min and no significant blood loss. They the neurovascular bundle, reconstruction of initial use of a robot for nephrectomy in a considered that robotics helped their team the urethrovesical junction, and often simply laboratory model where an experienced with moderate experience in laparoscopy to the sheer numbers of prostatectomies. surgeon controlled the camera through a expand the possibilities of minimally invasive robot, while the surgery was performed surgery. The use of the robot for renal and adrenal laparoscopically by another surgeon. Partin surgery is less well explored, possibly because et al. [19] expanded this use, with the surgeon Moore et al. [20] assessed the feasibility of a simple nephrectomy is a standardized controlling up to two robotic arms that held telementored radical nephrectomy and procedure requiring no reconstruction and the laparoscope and a retractor, in four reported failure caused by poorly positioned can be performed well with pure laparoscopy. patients undergoing nephrectomy. Gill et al. robotic arms. A successful telementored However, radical nephrectomy, radical [11] described the first completely robotic, radical nephrectomy between the USA and nephroureterectomy, reconstructive renal and telepresent nephrectomy in a porcine model Singapore was subsequently reported in ureteric surgery are difficult for inexperienced using an AESOP arm to control the camera 2000 by Lee et al. [21], who concluded that laparoscopic surgeons. In open surgery, the and two Zeus robotic arms to perform the these systems may help less experienced surgeon’s actions are coordinated through a surgery on five kidneys in pigs. They were laparoscopic surgeons perform complex tasks
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TABLE 1 Robot-assisted nephrectomy
Reference Subjects N cases Type Technical success Remarks Gill et al. [11] Swine 5 Simple All Technical feasibility of telerobotics Long operative time; learning curve Sung and Gill [12] Swine 11 Simple All Comparison of Zeus and da Vinci systems Guillonneau et al. [13] Human 1 Simple All Zeus and AESOP systems Marella et al. [14] Human 18 Simple Compared with hand assisted laparoscopy Hubert et al. [15] Human 12 Simple 11/12 Moderate laparoscopy experience 2 Radical 2 Donor Pedraza et al. [16] Human 1 Nephroureterectomy All Horgan et al. [17] Human 12 Donor All Longer vessels retrieved, shorter hospitalization
with the help of remote experienced duplicated ureters and nonfunctional upper particularly useful in dissecting the upper surgeons. poles. The robot was used for hilar dissection pole of the kidney and hilar vessels. There was and isolation of the renal pole, while the no donor morbidity and all kidneys functioned Apart from these sporadic reports, there have remaining procedure was completed through immediately. In comparison with laparoscopic been no consistent series of cases reported. pure laparoscopy. During the Third donor nephrectomy, they noted a shorter One of the principal reasons for this is International Robotic Urology Symposium hospital stay and lower blood loss in the probably the absence of benefit perceived (IRUS 2004) at Detroit in October 2004, robotic group. They also reported relatively with purely ablative procedures, which have surgeons from Guy’s Hospital, London, longer vessels retrieved in the robot-assisted become standardized in pure laparoscopy. presented a case of nonfunctioning kidney group than in the pure laparoscopy group. with megaureter that was operated through Robot-assisted surgery could be especially NEPHROURETERECTOMY AND an extraperitoneoscopic approach. useful in harvesting right-sided kidneys, PARTIAL NEPHRECTOMY Nephroureterectomy was performed using where because the renal vein is shorter it four ports in 3 h with an entirely sometimes needs to be divided as it enters the Nephroureterectomy, particularly with retroperitoneal approach, and the patient was vena cava. This necessitates suture closure of removal of a cuff of bladder in cases of TCC of discharged 4 days after surgery. This case the caval defect, which could be more the bladder, provides a more likely application showed the feasibility of robot-assisted dextrously accomplished with robotic for the reconstructive skills of the robot- surgery through an entirely retroperitoneal assistance. Indeed, Sung and Gill [12] reported assisted technique. Dissection of the lower approach, similar to that in pure laparoscopy. one such repair of the vena cava during an end of the ureter also requires greater adrenalectomy in a swine model. precision to avoid injury to the pelvic viscera. DONOR NEPHRECTOMY Currently used techniques for managing the PYELOPLASTY lower end of the ureter during laparoscopic Donor nephrectomy for renal transplantation radical nephroureterectomy include requires more meticulous dissection than Laparoscopic pyeloplasty (Table 2) endoscopic resection, pluck removal, stapling simple nephrectomy. The procedure also [1–3,5,12,28–30] for PUJ obstruction has and freehand suturing [22]. Established requires that patient morbidity is minimised, become a standardized procedure with oncological principles and replication of the particularly because it is being performed on success rates equivalent to open pyeloplasty, open surgical techniques can be achieved an otherwise healthy individual. Laparoscopic and minimal morbidity because it is less through a two-layered suture closure of donor nephrectomy was the first step in invasive [31–33]. The technique is versatile, the bladder wall. Similarly, significant achieving this goal and has now become allowing the management of patients with reconstruction is required in managing an established in over a 100 centres worldwide, all types of pathology, including crossing open pelvicalyceal system and bleeding with minimal morbidity [24–26]. The vessels, high ureteric insertion and redundant parenchyma after a partial nephrectomy. establishment of this technique has also pelvis. Laparoscopic pyeloplasty requires a Laparoscopy has become an established contributed to an increase in the number of significant amount of surgical dexterity option for partial nephrectomy, with minimal donor nephrectomies, thus helping to because of the precise suturing. This technical morbidity and with results similar to those for minimize the gap between donors and difficulty has been cited as the main reason open surgery [23]. recipients [24]. Horgan et al. [17,27] reported for its limited widespread application [34]. the largest experience in robot-assisted donor Robotic technology is ideally suited to While this seems to be a potentially useful nephrectomy. In their 12 cases reported in decrease the technical difficulty in such cases. area for robotic application, the only reported 2002, they used the da Vinci robotic system to It permits a greater degree of freedom at the nephroureterectomy using a robot was by procure the left kidney, in all cases using four wristed instruments, with three-dimensional Pedraza et al. [16] who performed a hemi- ports and a pre-placed hand-port for vision, allowing precise placement of fine nephroureterectomy bilaterally in a girl with specimen retrieval [17]. They found the robot sutures.
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TABLE 2 Robot assisted pyeloplasty
Reference Subjects N cases Technical success Complications Remarks Sung et al. [28] Swine 6 All 0 Technical feasibility of robotic pyeloplasty Sung and Gill [12] Swine 12 All 0 Comparison of Zeus and da Vinci systems Guillonneau et al. [29] Swine 10 All 0 Chronic porcine model Gettman et al. [30] Human 9 All 11% (late) 138 min operative duration Gettman et al. [3] Human 49 All 2% (late) 43 min suturing time Bentas et al. [1] Human 11 All 0 No laparoscopic pyeloplasty experience Hubert et al. [2] Swine 14 All 0 Limited laparoscopy experience Lower surgeon fatigue Yohannes and Burjonrappa [5] Human 1 All 0
TABLE 3 Robot assisted adrenalectomy
Reference Subjects N cases Technical success Remarks Sung and Gill [12] Porcine 10 All Compared Zeus and da Vinci systems Intraoperative vascular repair Young et al. [36] Human 1 All Incidentaloma Bentas et al. [37] Human 4 All Desai et al. [38] Human 2 All Phaeochromocytoma Beninca et al. [39] Human 9 5 High conversion rate due to technical difficulties Brunaud et al. [40] Human 14 All Compared with standard laparoscopy, similar outcomes Undre et al. [41] Human 2 All 119 min No intraoperative complication D’Annibale et al. [42] Human 1 All Five ports
Sung et al. [28] showed the technical times with the robot [3]. In a recent update of complex surgery easily and quickly. They also feasibility of robot-assisted pyeloplasty in a their series of 49 patients, including 10 with considered that robot assistance could study on pigs, where they performed six failed previous endopyelotomies, 40 had a provide faster training for reconstructive robotic and four conventional laparoscopic robot-assisted dismembered Anderson-Hynes laparoscopy, with less fatigue for the surgeon. pyeloplasties, the robotic procedures being pyeloplasty with a mean suturing time of Peschel et al. [3] also reported a subjective conducted using a Zeus operating system. 43 min. There were no intraoperative decrease in operative difficulty and surgeon They also reported similar results when complications or conversion to open surgery. fatigue with the use of a robot in their series comparing the Zeus and da Vinci robotic At a mean follow-up of 7.4 months, they of 49 cases. The more rapid learning after systems, with faster surgery using the latter reported complete success in all their using robotic assistance has been confirmed [12]. Guillonneau et al. [29] confirmed the procedures [35]. by others [4,5]. technical feasibility and safety of the robotic approach in a study on 10 farm pigs. These The major impact of robotic assistance in this studies suggested the technical superiority of otherwise complex laparoscopic procedure ADRENALECTOMY the da Vinci system in achieving successful has been that surgeons claiming lower outcomes, and the initial human cases were laparoscopy skills have also produced similar The adrenal gland is another organ which reported in 2002 by Gettman et al. [30]. They results. Bentas et al. [1] performed 11 robot- seems particularly well suited for the reported their experience of robot-assisted assisted pyeloplasties for PUJ obstruction laparoscopic approach (Table 3) [12,36–42]. dismembered Anderson-Hynes pyeloplasty with a mean operative time of 197 min; they Most tumours are small and require a in nine patients, with no intraoperative had complete success at the 1-year follow-up. large incision for open surgical access. complications or conversion. Their mean They had no experience with laparoscopic Sung et al. [12] reported the initial porcine operative duration was 138 min and one pyeloplasty before this series and affirm the study comparing the Zeus and da Vinci patient required a re-operative closure usefulness of robotic assistance for surgeons robotic systems for adrenalectomy. They of a renal pelvis defect, away from the with limited or no laparoscopic experience. found more rapid operations with the da Vinci anastomotic site. The same authors went on Hubert et al. [2] reported robot-assisted (da system but also had two intraoperative to compare their results with conventional Vinci) laparoscopic pyeloplasties in 14 swine, injuries. This included an inferior vena cava laparoscopic dismembered pyeloplasty and and reaffirmed that surgeons with limited tear that was repaired with intracorporeal reported shorter operative and anastomotic experience in laparoscopy could learn suturing.
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Horgan et al. [43] reported the first human system. The following year, the same authors Lich-Gregoir technique of creating a detrusor adrenalectomy using the robot in 2001. While described their robotic system, ‘PAKY’, which tunnel for the ureter. A three-port approach they do not describe their technique, they also permitted the insertion of a needle in both an with incision on the detrusor followed by re- performed 32 other surgical procedures using in-vitro porcine model and patients, using approximation over the inlaid ureter is used. this device. Young et al. [36] performed a fluoroscopic guidance [45]. The device was Peters [48] used this technique in 19 cases, robot-assisted adrenalectomy for an successful in each of its attempts within a including three with bilateral surgery, with a incidental left adrenal mass in a patient being mean access time of 8.2 min. While this satisfactory outcome and progressively evaluated for mediastinal widening. approach appears promising, there are no shorter operations. Pathology showed a rare adrenal oncocytoma. reports of its incorporation into a regular Later that year, Bentas et al. [37] reported four clinical programme. Olsen et al. [49] described an experimental adrenalectomies by a transperitoneal model of intravesical repair of bilateral reflux approach with no complications or Robots are also being used in conjunction using the Cohen technique of reimplantation. conversions, and Desai et al. [38] reported two with advanced imaging methods to develop The robotic ports are placed into the bladder adrenalectomies, including one for a virtual models that may help to enhance through the abdomen after saline distension. phaeochromocytoma. Their two patients had surgical skills. Hoznek et al. [46] describe the The bladder is kept distended with gas a mean hospital stay of 2.5 days and no development of a surgical model that can insufflation while the surgery is completed. complications during or after surgery. assist the surgeon in choosing the best Peters [48] mentions the use of this technique possible port position for the robot to reach in some of his patients but the outcomes and Beninca et al. [39] reported their experience of the target organ. It also considers data such details were not described. nine robot-assisted adrenalectomies (six for as optimal tissue handling, ergonomics, an adenoma, two for phaeochromocytoma visibility and instrument manoeuvrability. and one for an incidentaloma) and compared Such models are also being used for training CONCLUSIONS them with nine laparoscopic adrenalectomies. surgeons. Surgery was significantly longer in the robotic As with every new technology, robot-assisted surgery group (mean 133 vs 82 min) but there In 2002, Hoznek et al. [47] described a surgery has to pass through various stages of were no intraoperative complications. cadaveric renal transplantation with the evaluation before it can be accepted as a However, they had to convert to traditional entire vascular and uretero-vesical standard option of therapy. Currently, it often laparoscopy because of technical difficulties anastomosis being performed by a remote seems to be a procedure looking for an in four robotic cases. In another comparative surgeon using a robot. The authors consider indication. However, this was also the case study, Brunaud et al. [40] evaluated their that such telerobotic surgery may help to with laparoscopy before it became accepted results of 14 robotic- (da Vinci) assisted prevent transmission of infection between as the standard of care for several procedures. adrenalectomies with another 14 patients patient and recipient, apart from providing The initial reports cited here attest more to its undergoing standard laparoscopic greater dexterity during the fine vascular safe applicability in surgery that is otherwise adrenalectomy. They reported longer anastomosis, an argument similar to that for feasible through pure laparoscopy. The main operations for robotic surgery but a its use in microsurgical vasectomy reversal. proposed advantages for this technology are progressive decrease with increasing its enhanced dexterity, precision and experience. They found no significant ergonomics. These issues are undoubtedly still advantage of robotics but noted that unlike PAEDIATRIC APPLICATIONS present with laparoscopy, which is difficult to standard laparoscopy, there was no effect of learn, with often suboptimal results by body mass index on the technical outcome The principal application of robotic surgery surgeons not dextrous enough in suturing. with robotic surgery, suggesting a possible in children is for correcting congenital benefit of this technique. abnormalities. Most cases of PUJ obstruction The widespread common knowledge about are diagnosed in early infancy or childhood, the advantages of laparoscopy has made it and are repaired in the first few years of life. imperative for most practising urologists to PERCUTANEOUS ACCESS AND Peters [48] described the safety and efficacy offer the option to their patients. However, RENAL TRANSPLANTATION of robotic assistance in this age group. Among the lack of significant experience and training 18 evaluable cases of 22 who underwent opportunities makes it imperative that Percutaneous renal surgery for managing pyeloplasty, he reported a good outcome in easier learning tools are made available to calculi, PUJ anomalies or upper tract tumours 17. One patient had ileus caused by a urinary these physicians. Robot-assisted surgery requires the placing of a carefully positioned leak and required a temporary nephrostomy has opened these options for several needle into the pelvi-calyceal system. This is tube drainage, while another required a laparoscopically naïve or minimally qualified usually done by the surgeon or radiologist repeat robot-assisted pyeloplasty because a surgeons. under ultrasonographic or fluoroscopic crossing vessel was missed during the initial guidance, and can be difficult in patients with surgery. The major problem with robot-assisted minimal dilatation. The possibility of surgery is the cost of equipment and surgery. stereotactic-robotic assistance using an Another application in this age group is in The argument brings a sense of deja vu of interface was first reported in 1997 [44]. The treating VUR; two common techniques have similar problems faced by laparoscopy when it authors successfully punctured the desired been used with robotic assistance [48]. The was initially introduced. While there is no calyx in 10 of 12 procedures using a robotic first involves an extravesical repair using the doubt that it may be difficult to envision a
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robotic revolution if the costs remain as they surgical skills to a laparoscopic and Singapore. Ann Acad Med Singapore currently are, the expansion of indications environment using a robotic interface: 2000; 29: 665–8 coupled with lowering of equipment costs as initial experience with laparoscopic 22 Steinberg JR, Matin SF. Laparoscopic more machines are sold will undoubtedly help radical prostatectomy. J Urol 2003; 170: radical nephroureterectomy. dilemma of to balance the books. 1738–41 the distal ureter. Curr Opin Urol 2004; 14: 10 Hemal AK, Eun D, Tewari A, Menon M. 61–5 Nuances in the optimum placement of 23 Bhayani SB, Rha KH, Pinto PA et al. CONFLICT OF INTEREST ports in pelvic and upper urinary tract Laparoscopic partial nephrectomy. effect surgery using the da Vinci robot. Urol Clin of warm ischemia on serum creatinine. None declared. North Am 2004; 31: 683–92 J Urol 2004; 172: 1264–6 11 Gill IS, Sung GT, Hsu TH, Meraney 24 Ratner LE, Buell JF, Kuo PC. AM. 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Transplantation 32 Klingler HC, Remzi M, Janetschek G, Vattikuti Institute prostatectomy, 2002; 73: 1474–9 Kratzik C, Marberger MJ. Comparison of a technique of robotic radical 18 Kavoussi LR, Moore RG, Partin AW, open versus laparoscopic pyeloplasty prostatectomy for management of Bender JS, Zenilman ME, Satava RM. techniques in treatment of uretero-pelvic localized carcinoma of the prostate: Telerobotic assisted laparoscopic surgery. junction obstruction. Eur Urol 2003; 44: experience of over 1100 cases. Urol Clin initial laboratory and clinical experience. 340–5 North Am 2004; 31: 701–17 Urology 1994; 44: 15–9 33 Baldwin DD, Dunbar JA, Wells N, 7 Cathelineau X, Rozet F, Vallancien G. 19 Partin AW, Adams JB, Moore RG, McDougall EM. Single-center Robotic radical prostatectomy: the Kavoussi LR. Complete robot-assisted comparison of laparoscopic pyeloplasty, European experience. 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© 2005 BJU INTERNATIONAL 249 Mini Rev Article TARGETING BOO VIA THE NITRIC OXIDE/cGMP PATHWAY REITZ et al.
Targeting bladder outlet obstruction from benign prostatic enlargement via the nitric oxide/cGMP pathway?
ANDRÉ REITZ*‡, MICHAEL MÜNTENER†, AXEL HAFERKAMP‡, MARKUS HOHENFELLNER‡ and BRIGITTE SCHURCH* *Neuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, and †Department of Urology, University Hospital, Zurich, Switzerland, and ‡Department of Urology, University of Heidelberg, Germany Accepted for publication 15 January 2005
KEYWORDS relaxation of cavernosal smooth muscle uniform distribution within the gland; NOS cells in the penis, have been reported [5,6]. activity was higher in the peripheral than in nitric oxide, cyclic GMP, phosphodiesterase, Sildenafil, an inhibitor of phosphodiesterase the transitional zone. In both zones NOS was BPH (PDE) type 5, revolutionized the treatment of localized to nerve fibres and ganglia within erectile dysfunction and highlighted the NO/ the smooth muscles of the prostatic stroma cGMP pathway as a focus of attention for the and the subepithelial plexus, as well as in the INTRODUCTION urological community to further understand glandular epithelium [8]. the role of NO in the genitourinary system. The high age-related incidence of benign Thus, NO-based processes have also been Another morphological study on human prostatic enlargement (BPE) often associated implicated elsewhere in the genitourinary prostatic tissue could not confirm these with BOO and LUTS is of considerable system, e.g. within the detrusor, the urethra results and found no difference in nitrinergic significance for public health. Although rarely and the striated external urethral sphincter. innervation density among different parts life-threatening, BPE has a severe impact Currently there is growing evidence that the of the prostate [9]. Using histochemical on the quality of life of patients. Surgical NO/cGMP pathway is involved in regulating NADPH-diaphorase staining, NOS therapy has been considered the the prostatic smooth muscle tone. This review immunohistochemistry and ultrastructural reference standard for treating BPE, but considers the available knowledge about the NADPH examination, there was a dense pharmacological therapy is increasingly significance of the NO/cGMP pathway for nitrinergic innervation of the glandular common, as reflected in the fewer surgical treating BOO and concomitant LUTS related to epithelium, fibromuscular stroma and blood interventions for BPE over the last 20 years. BPE. A hypothesis is developed and possible vessels [9]. Current medical therapies rely basically strategies to prove or disprove the suggested on three approaches: (i) a-adrenoceptor approach discussed. In both studies NOS-containing nerves were antagonists reduce prostatic smooth muscle found in close relationship to prostatic tone by blocking the effects of noradrenaline smooth muscle cells and it was speculated released from sympathetic nerve terminals; NEUROANATOMY that NO promotes prostatic smooth muscle (ii) 5a-reductase inhibitors reduce prostate relaxation [8,9]. Furthermore, the rich volume by blocking the conversion of The human prostate receives autonomic nitrinergic innervation around the prostatic testosterone to dihydrotestosterone; and (iii) innervation from the pelvic plexus travelling glands found in both morphological studies phytotherapeutic drugs seem to be able to through the cavernosal nerves. Basically, generated the assumption that NO is also improve LUTS by a more or less unknown parasympathetic fibres innervate the involved in regulating prostatic secretion mechanism. glandular structures and control prostatic [8,9]. secretion via a cholinergic mechanism; During the last 25 years nitric oxide (NO) has sympathetic nerves innervate the capsule and been recognized as a unique biological stroma of the prostate, and control the NO NEUROPHARMACOLOGY signalling molecule involved in numerous smooth muscle tone via adrenergic receptors. physiological processes and body functions. Nerves containing NOS have the capacity NO was originally known as ‘endothelium- In both noradrenergic and non-noradrenergic to synthesise NO that can serve as a derived relaxing factor’, which if released by nerves innervating the human prostate neurotransmitter. NOS catalyses the reaction endothelium cells can induce the relaxation of the enzyme NO synthase (NOS) has been of the amino acid L-arginine to NO and vascular smooth muscle [1]. Furthermore, NO found [7]. In a morphological study using L-citrulline in the presence of oxygen and is also involved in immunological responses immunohistochemistry, NOS activity was NADPH. Currently, three isoforms of the [2] and acts as an important noncholinergic, found in both the transition and the NOS are known, neuronal (first detected in nonadrenergic neurotransmitter in both the peripheral zone of the human prostate [8]. neuronal tissues), endothelial (first found in central and peripheral nervous systems [3,4]. NO-containing neurones appeared to vascular endothelium) and so-called inducible originate in the neurovascular bundles NOS (first detected in macrophages). After Also within the genitourinary system, NO later penetrating the prostate capsule and being released from the site of synthesis appears to be an important messenger. Both dispersing in the glandular tissue. The level the NO diffuses freely to the target tissue NO-based mechanisms, the endothelium- of NOS activity differs in both zones of where the molecule is thought to act as derived and the neurogenically mediated the prostate, indicating that there is not a a neurotransmitter on nonadrenergic,
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noncholinergic nerves. Throughout the lower normal prostates [9]. Thus, a NO donor had an In vitro the NO donor sodium nitroprusside urinary tract a nitrinergic innervation has antiproliferative effect on human hyperplastic relaxed prostatic smooth muscle strips been identified at different densities; almost prostatic smooth muscle cells [20]. Gradini et isolated from the transition zone of the all NO-induced effects are inhibitory. The NO- al. [21] studied prostatic tissue from men with prostate [24]. Currently, oral NO donors are mediated responses are thought to act and with no hyperplasia for different isoforms widely used for treating coronary artery through an intracellular increase in the of NOS. While neuronal and endothelial disease. Several advantages of NO donors second messenger cGMP via stimulation of NOS were expressed in both normal and make the further evaluation of their effect on the enzyme guanylate cyclase [10–12]. NO- hyperplastic glands, inducible NOS was infravesical resistance worthwhile. Many NO dependent relaxation of urethral smooth expressed only in hyperplastic glands. The donors are well known drugs with good muscle was reported in various species, appearance of inducible NOS has been linked tolerability and a long established safety including rabbit [13] and men [14]. While the to the influence of sex hormones, which have record, and their variable pharmacokinetic nitrinergic innervation and NOS enzyme been considered to be involved in the properties could be an advantage. Especially activity is rich in the urethra, it seems to be development of prostatic hyperplasia. From the fast-acting formulations with an onset of sparse within the detrusor muscle. A NO- this study it was concluded that NO might action within minutes could allow new mediated detrusor smooth muscle relaxation have a potential role in the pathogenesis of treatment strategies with intermittent drug is still controversial, although recent results BPE. use alone or combined with a classical suggest that detrusor relaxation and medical BPE therapy. contractility might be modulated by NO levels These finding may implicate a possible and that NO released from the urothelium involvement of NO in the pathogenesis BPE and coronary artery disease occur in the may be a mediator of detrusor relaxation of BPE, because a reduced nitrinergic same age groups and the coincidence of both during the storage phase of bladder function innervation or a relative NO deficiency may problems in elderly people is supposedly high. [15]. increase the tone of the prostatic smooth Klotz et al. [25] studied 32 patients who had a muscle, which potentially leads to the BOO urological evaluation before starting nitrate associated with clinical BPE. medication for cardiovascular disease. All NO AND PROSTATIC PHYSIOLOGY patients underwent uroflowmetry with a determination of the postvoid residual urine Prostatic specimens from various species TREATING BPE VIA THE volume, TRUS and PSA screening. According including humans have been studied in vitro. NO/cGMP PATHWAY to prostatic symptom scores the authors Takeda et al. [16] were the first to find that NO found that 15 patients had obstructive is involved in the control of prostatic smooth From currently available knowledge there is voiding symptoms, while 17 reported no muscle function. In their study, NO donors evidence that drugs acting on the NO/cGMP subjective voiding complaints. At 2 weeks and caused a relaxation of human and canine pathway might have a potential role in 3 months after starting nitrate medication prostatic tissue, with the relaxing effect being treating subvesical obstruction caused by BPE. the patients were re-evaluated; those who significantly greater in the human than in the The hypothesis relies on the relaxing effect of had reported obstructive symptoms before canine prostate. Heglund et al. [17] confirmed NO on prostatic smooth muscle cells that nitrate medication improved significantly as these observations in human prostatic tissue potentially decrease subvesical obstruction assessed by peak urinary flow rates, symptom and reported a relaxing effect of NO on and improve both voiding and bothersome scores and postvoid residual urine volume, noradrenaline-contracted prostatic LUTS. Considering the pathophysiology of while asymptomatic patients did not change. preparations, while the inhibition of NOS LUTS, the focus has shifted from the prostate PSA values and prostate volumes remained effectively counteracted the relaxing effects. to the bladder [22], and recent results suggest unchanged in both groups. The authors Morphological and functional results in that that detrusor relaxation and contractility concluded that NO medication influence study suggested that neuronally derived NO may be modulated by NO levels [15]. NO voiding variables in patients with obstructive contributes to the inhibitory control of augmented or released from the urothelium BPE and explained this by a potential smooth tension in the prostatic stroma. may be a mediator of detrusor relaxation muscle relaxation within the prostate. during the storage phase of micturition and Another important issue is the effect of age therefore may have favourable effects on PDEs have been identified in different regions and prostatic volume on the nitrinergic LUTS. of the human prostate [24,26,27]. In vitro, the innervation of the prostatic gland. Aikawa functional relevance is supported in that the et al. [18] studied the effect of age on the Basically, two classes of drugs might be adrenergically induced tension of prostatic endogenous NO-mediated prostatic smooth relevant for the suggested approach; first, smooth muscle strips could be relaxed by muscle relaxation and the nitrinergic oral NO donors, and second PDE-inhibiting inhibitors of PDE-4 and -5 [24]. Furthermore, innervation in the rabbit prostate, and found drugs. As heavy bleeding is often reported sildenafil inhibited the proliferation of that both are reduced with ageing. In canine during prostatic surgery, the gland is prostatic hyperplastic tissue [28]. As sildenafil hyperplastic prostates the level of neuronal considered to have a rich blood supply. After has revolutionized the treatment of erectile NO was reduced, suggesting that neuronal oral intake of sildenafil there was a relevant dysfunction, many men worldwide take PDE- NOS expression is down-regulated in the increase in periurethral blood flow, using inhibiting drugs regularly. The prevalence of prostate with benign cellular proliferation colour Doppler TRUS measurements [23], both erectile dysfunction and LUTS increases [19]. In human hyperplastic prostate tissue suggesting that oral administration is a with age, and a close relationship of sexual the nitrinergic innervation was lower than in feasible approach. function and voiding function has been
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recognized in several studies [29–31]. Medical compared in the absence and presence of NO physiologic mediator of penile erection. treatment of lower urinary tract dysfunction using standardized nomograms. Science 1992; 257: 401–3 is known to influence a patient’s sexual 7 Jen PY, Dixon JS, Gearhart JP, Gosling function [32] but almost nothing is known The safety and efficacy of the suggested JA. Nitric oxide synthase and tyrosine of how treating erectile dysfunction with approach need to be assessed in clinical trials. hydroxylase are colocalized in nerves PDE-inhibiting drugs influences voiding For clinical long-term trials NO donors or supplying the postnatal human male dysfunction from BPE. Sairam et al. [33] PDE-inhibiting drugs with long half-lives genitourinary organs. J Urol 1996; 155: assessed the effect of sildenafil on lower are preferred, to maintain a sufficient 1117–21 urinary tract function; the coincidence of drug level over several hours and to 8 Burnett AL, Maguire MP, Chamness SL erectile dysfunction and voiding difficulties offer the opportunity to use a once-daily et al. Characterization and localization of associated with BPE in older men is well administration scheme. As BPE in older men nitric oxide synthase in the human known, and indeed treatment with sildenafil causes obstruction and bothersome LUTS, prostate. Urology 1995; 45: 435–9 appeared to improve urinary symptom scores clinical studies must address both changes in 9 Bloch W, Klotz T, Loch C, Schmidt G, in that study, suggesting a possible role of obstruction and LUTS, which can be assessed Engelmann U, Addicks K. Distribution of PDE-inhibiting drugs in treating BPE in the by frequency-volume charts, voiding diaries nitric oxide synthase implies a regulation future. and the standardized IPSS questionnaire. of circulation, smooth muscle tone, and secretory function in the human prostate Functional studies in vivo assessing the direct by nitric oxide. Prostate 1997; 33: 1–8 effect of NO on the human lower urinary tract ACKNOWLEDGEMENTS 10 Persson K, Alm P, Johansson K, Larsson are rare. However, after oral administration B, Andersson KE. Co-existence of in healthy humans, a NO donor had a The authors are grateful to Prof Karl Erik nitrergic, peptidergic and acetylcholine functionally relevant effect on the resting Andersson, University of Lund, Sweden for his esterase- positive nerves in the pig lower tone and contractile behaviour of the human excellent comments on the manuscript which urinary tract. J Auton Nerv Syst 1995; 52: external urethral sphincter in vivo [34]. In improved its quality and understanding. 225–36 a functional study in humans with spinal 11 Dokita S, Smith SD, Nishimoto T, cord injury, subvesical obstruction caused Wheeler MA, Weiss RM. Involvement by detrusor-sphincter dyssynergia was CONFLICT OF INTEREST of nitric oxide and cyclic GMP in rabbit successfully reduced by oral administration of urethral relaxation. Eur J Pharmacol 1994; a NO donor [35]. Recently, the immediate None declared. 266: 269–75 influence of systemic NO augmentation on 12 Morita T, Tsujii T, Dokita S. Regional bladder outlet resistance was investigated difference in functional roles of cAMP and in healthy men using pressure-flow studies. REFERENCES cGMP in lower urinary tract smooth Relative to the mean average flow rate, muscle contractility. Urol Int 1992; 49: the average intravesical pressure during 1 Furchgott RF, Zawadzki JV. 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18 Aikawa K, Yokota T, Okamura H, influence of nitrates on micturition in 32 Clifford GM, Farmer RD. Medical Yamaguchi O. Endogenous nitric oxide- patients with benign prostatic therapy for benign prostatic hyperplasia. mediated relaxation and nitrinergic hyperplasia. Int Urol Nephrol 1999; 31: A review of the literature. Eur Urol 2000; innervation in the rabbit prostate: the 335–41 38: 2–19 changes with aging. Prostate 2001; 48: 26 Stacey P, Rulten S, Dapling A, Phillips 33 Sairam K, Kulinskaya E, McNicholas TA, 40–6 SC. Molecular cloning and expression of Boustead GB, Hanbury DC. Sildenafil 19 Crone JK, Burnett AL, Chamness SL, human cGMP-binding cGMP-specific influences lower urinary tract symptoms. Strandberg JD, Chang TS. Neuronal phosphodiesterase (PDE5). Biochem BJU Int 2002; 90: 836–9 nitric oxide synthase in the canine Biophys Res Commun 1998; 247: 34 Reitz A, Bretscher S, Knapp PA, prostate. aging, sex steroid, and pathology 249–54 Muntener M, Wefer B, Schurch B. The correlations. J Androl 1998; 19: 358–64 27 Fawcett L, Baxendale R, Stacey P et al. effect of nitric oxide on the resting tone 20 Guh JH, Hwang TL, Ko FN, Chueh SC, Molecular cloning and characterization of and the contractile behaviour of the Lai MK, Teng CM. Antiproliferative effect a distinct human phosphodiesterase gene external urethral sphincter: a functional in human prostatic smooth muscle cells family PDE11a. Proc Natl Acad Sci USA urodynamic study in healthy humans. by nitric oxide donor. Mol Pharmacol 2000; 97: 3702–7 Eur Urol 2004; 45: 367–73 1998; 53: 467–74 28 Adolfsson PI, Ahlstrand C, Varenhorst 35 Reitz A, Knapp PA, Muntener M, 21 Gradini R, Realacci M, Ginepri A et al. E, Svensson SP. Lysophosphatidic acid Schurch B. Oral nitric oxide donors: a Nitric oxide synthases in normal and stimulates proliferation of cultured new pharmacological approach to benign hyperplastic human prostate: smooth muscle cells from human BPH detrusor-sphincter dyssynergia in spinal immunohistochemistry and molecular tissue: sildenafil and papaverin generate cord injured patients? Eur Urol 2004; 45: biology. J Pathol 1999; 189: 224–9 inhibition. Prostate 2002; 51: 50–8 516–20 22 Siroky MB. Lower urinary tract 29 Rosen R, Altwein J, Boyle P et al. Lower 36 Muntener M, Schurch B, Wefer B, symptoms: shifting our focus from the urinary tract symptoms and male sexual Hauri D, Reitz A. Systemic nitric oxide prostate to the bladder. J Urol 2004; 172: dysfunction: the multinational survey of augmentation leads to a rapid decrease of 1237–8 the aging male (MSAM-7). Eur Urol 2003; the bladder outlet resistance in healthy 23 Pinggera A, Schuster F, Frauscher G, 44: 637–49 men. Eur Urol 2005; 45 (Suppl): Abstract Bartsch H. Sildenafil citrate causes a 3 30 Schou J, Holm NR, Meyhoff HH. Sexual fold increase in periurethral prostatic function in patients with symptomatic Correspondence: André Reitz, Neuro-Urology, blood flow. J Urol 2004; 171: A1348 benign prostatic hyperplasia. Scand J Urol Swiss Paraplegic Center, Balgrist University 24 Uckert S, Kuthe A, Jonas U, Stief CG. Nephrol Suppl 1996; 179: 119–22 Hospital, Forchstrasse 340, 8008 Zurich, Characterization and functional relevance 31 Namasivayam S, Minhas S, Brooke J, Switzerland. of cyclic nucleotide phosphodiesterase Joyce AD, Prescott S, Eardley I. The e-mail: [email protected] isoenzymes of the human prostate. J Urol evaluation of sexual function in men 2001; 166: 2484–90 presenting with symptomatic benign Abbreviations: BPE, benign prostatic 25 Klotz T, Mathers MJ, Bloch W, Nayal W, prostatic hyperplasia. Br J Urol 1998; 82: enlargement; NO(S), nitric oxide (synthase); Engelmann U. Nitric oxide based 842–6 PDE, phosphodiesterase.
© 2005 BJU INTERNATIONAL 253 Mini rev Article CREATIVITY IN ACADEMIC DEPARTMENTS HEATON
The vital role of creativity in academic departments
JEREMY P.W. HEATON Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada Accepted for publication 26 January 2005
KEYWORDS arises as a result of human thinking and can only support a concept once it has been be seen as a particular form of knowledge or created and reaffirmed many times, making creativity, organization, surgery, academic understanding that makes a transition from the major creative contribution a relatively department being internal, or tacit, to being revealed or distant historical footnote. Nevertheless, explicit [3]. Without communication in some iterative medical advance remains a necessary form it remains unrecognized. Individuals goal in an academic department. The creative INTRODUCTION working in an organization contribute contribution of a better way of doing surgery their individual aliquots of creativity to the or medicine probably occurs in small measure Organizations such as academic departments benefit of themselves as individuals and the almost daily, is very difficult to communicate and universities have long had a tacit organization. However, it is clear that only an except to trainees, is very difficult to evaluate understanding of the need for creativity. individual can truly be said to be creative [4] and would rarely rise to the level of However, the practice of creativity has usually and organizational creativity flows from that. influencing a department or its environment. been allowed to develop through individual So Fig. 1a might be redrawn as Fig. 1b, where The adoption of creative steps pioneered efforts and nurturing environments, with no the sum of creativity in an organization elsewhere becomes a proxy for innovation formal encouragement or realisation of the comes from contributions from individuals and may be encouraged. Keeping up with a true benefits. Creativity has been an implicit while the total creative impact may be standard of care is a necessary informal and expectation of the new appointment as well organizational. The recognition and unrecognized manifestation of creativity. The as a criterion for advancement in a somewhat measurement of creativity and innovation development and implementation of new stylised form (university promotion criteria). in an academic department is most clearly therapies and procedures help patients, may However, the disciplined recognition and embodied in the criteria for promotion, and bring financial reward and may also bring implementation of original, untried and comes from peer recognition in scholarly kudos to a department, faculty and university, potentially risky new thought has the publications, research grants or innovative boosting academic standing and improving potential to confer significant competitive educational programmes. Enlightened the quality of the incoming students. advantage [1]. Particularly in chaotic universities have recently recognized environments, where there is little to patenting as evidence of scholarly creative differentiate competitors, creativity may activity. Publication count, impact factor, CREATIVITY IN AN ACADEMIC provide the flexibility of output, process or grant duration, grant value and standing of MEDICAL DEPARTMENT structure that enables survival and growth. the granting agency are the common metrics A university department with creativity of merit in academia. Usually administrative It is easily seen that, within this framework of potentially improves its capacity to compete effort and administrative or financial creativity, an increase in publication quantity for funding, people, reputation and, innovation are defined as service and, unless and quality should further the career of the eventually, postgraduate students. they extend into the realm of scholarly individuals and enhance the standing of the publication, would not be considered for department. Publications and creative the individual in terms of promotion or research planning underlie applications for CREATIVITY AND THE DEPARTMENT merit, although the organization may benefit research funding, which is commonly the and change as a result. Thus creativity in second major measure of creative output. If creativity is recognisable on an individual managing the placement of sick elderly Patenting activity, often in tandem with level without much difficulty it is a small step patients through an 11-day power cut technology transfer units, has become better to grasping the concept of organizational (January 1998) was not recognized for the established and recognized in universities. creativity: ‘the creation of a valuable, useful physicians involved (they did not publish); Increased patent and intellectual property new product, service, idea, procedure or nonetheless, their creative management of activity is now more commonly recognized as process by individuals working together the crisis changed the organizations a valid contribution. That patenting is a in a complex social system’ [2]. Individual (department, hospital and faculty-adopted measure central to increased national creativity, innovation and organizational crisis planning processes). The narrow competitiveness is not widely appreciated. change and creativity are closely linked and university measures of academic achievement Patenting is incorporated in global measures hierarchically related, as shown in Fig. 1a. can overlook real organizational change. of national competitiveness and universities are integral to that measure [6]. All creativity, innovation and organizational Creativity is vital to the development of change can be traced ultimately to human new therapies, and evidence-based medicine It has been indicated that motivation, beings, most often aided by the environment, [5] is at the pinnacle of quality care. Yet expertise and creative thinking underpin other humans and technology [2]. Creativity intrinsically, evidence-based medicine can organizational creativity [7]. Improvements in
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FIG. 1. Creativity as: a, a subset of innovation and (promotion, recognition, grants, consulting, MAKING CREATIVITY WORK FOR AN change, and b, as a product of individual effort. etc.) for their creativity. ACADEMIC DEPARTMENT a CREATIVITY BLOCKS It has been said that ‘Creativity is as much about believing in new ideas and bringing Organizational change The potentially ‘dyscreative’ forces in a them into form, as it is about generating the department can be paralleled to those ideas in the first place’ [12]. Several factors identified in business organizations, even have been identified that encourage creativity: though the product is different, i.e. time challenge, freedom, resources, intellectual Innovation pressure, administrative pressures, culture, working environment, encouragement, and leadership, short-term thinking, resources organizational support [7]. (money, time and skilled personnel), unclear goals, poor communication, fear of change In revitalizing an organization the Creativity and a failure to initiate it [9]. organization should be viewed as a whole and not as a series of disconnected problems. There are some common errors that Think of an organization as a homeostatic contribute to creative dullness: Defining the system; the changes have to be system-wide problem incorrectly (a time and perspective to gain lasting effect, embody feedback and issue); judging ideas too quickly (common); be internal (not external consultant-based). stopping with the first good idea (often b relates to time pressure); and failing to get the In shaping a creative department, attributes politics right [10]. The potential barriers to (human traits) that favour innovation can Organizational change innovation are: be better selected than made; so when recruiting, select a creative ‘right-brained’ • Culture: the fixed mindset; the established surgeon. Conceptual skills, with the emphasis Innovation assumptions, beliefs and values (‘nothing fails on cognition and the ability to reassemble old like success’). learning in new ways, are more amenable to • Technological or structural: inertia based improvement by training; seminars and on technology that has been committed to; retreats may usefully be directed to this. rules, regulations and procedures that are Behaviours can be influenced by leadership Creativity self-justifying and punitive of failure. and culture (especially in academia) [13]. • Management: styles that kill ideas, Processes can be reshaped and simplified to discourage risk-taking and inhibit feedback. emphasize the creative areas and limit the • People: resistance to change, complacency, dulling of people who should flourish. A Individuals as conflicts and incompetence categorized table of revitalizing steps is: creative units In an academic medical department the • Culture: redesign duties and responsibilities assumption that creativity is given free rein and reward ideas, reward learning even if it these areas carry with them benefits that will and is self-sufficient is not necessarily does not progress to creativity. permeate organizational culture and ensure justified. The lack of infrastructure funding in • Technological or structural: improve that tomorrow’s answers are not just echoes medicine and surgery is common; it is the rare communications, reward technical creativity, of today’s. The ‘spin-off’ from increases in department with the present generation of discourage inactivity, mitigate the effects of creativity has been described in terms of four surgical robot and it is even rarer to have two time pressure. subsystems of an organization: culture, generations of surgical robots. Physicians are • Management: introduce formal training in techno-structural, management and people notoriously resistant to even inspired organizational theory, creativity and lateral [8]. Important links between these subsystems leadership, and the culture of independence thinking, use of protected time. and creativity have been identified. Creativity in medicine decreases the likelihood of team • People: avoid unhelpful reactions to will increase the knowledge capital of a activity. Teams incorporate a redundancy of change, (cursory evaluation and rejection department and bring cultural and structural thinking that favours new ideas and creative of ideas, evaluations biased by status or benefits. Techno-structural aspects would be solutions [4]. Furthermore, in medicine and insecurity), admit imperfections and mistakes. visible as improvements in treatment, either surgery the overarching need for safety often truly innovative or to new standards. quenches progress in the name of caution These are some of the elements that will Management in an environment of increased (‘It’s too risky’, ‘better to be a fast follower, support an increase in creativity. The design creativity can look forward to improved than a first mover’) [11]. In addition, of an action plan will vary significantly student intake and the possibility of new managerial practices have a greater capacity with the departmental context, but includes spin-off research interests or institutes. The to stifle creativity when there are many identifying the need for change, establishing staff in a creatively enhanced department streams of management, as is the case in current views, agreeing a course of action should experience internal rewards (job many academic medical departments and a timeline, setting some measurable satisfaction) and external rewards (hospital, departmental, faculty, university). outcomes and planning for review and
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feedback. A department can reinforce this CONFLICT OF INTEREST Harvard Business Rev 1998; 76: 76– internally by guaranteeing participatory 87 safety, encouraging the challenging of None declared. 8 Tan G. Creativity in organizations: a total assumptions, overtly deciding to target system approach. Creativity Innovation excellence, incorporating people who ‘don’t Management 1998; 7: 23–31 fit’, supporting ‘favourite’ projects and 9 Gardner D. Barriers to the encouraging fun [14]. Individuals should REFERENCES implementation of management systems: be prepared to give ideas away, challenge lessons from the past. Qual Assurance others to act on their ideas, and be creative 1 Cook P. The creativity advantage – is your 2000; 8: 3–10 connectors (critical but not corrosive). organization the leader of the pack? 10 Gundry LK, Kickul JR, Prather C. Indust Commercial Training 1998; 30: Building the creative organization. In a department the criteria for success and 179–84 Organizational Dynamics 1994; 22: 22– contribution should be lowered (to less than 2 Woodman RW, Sawyer JE, Griffin RW. 37 those required for promotion), there should Toward a theory of organizational 11 Anderson JV. Creativity and play: A be broader support for other dimensions of creativity. Acad Management Rev 1993; systematic approach to managing creativity (administration, consulting) and 18: 293–321 innovation. Business Horizons 1994; 37: some concepts relating to quality (not just 3 Nonaka I. The knowledge-creating 80–5 quantity) should be introduced. Resources company. Harvard Business Rev 1991; 69: 12 Kilroy D. Creating the future; how should be directed to where they will increase 96–104 creativity and innovation drive creativity (e.g. grant and report writing, in the 4 Nonaka I, Toyama R, Konno N. SECI, shareholder wealth. Management short term, and new staff and new types of Ba and leadership. A unified model of Decision 1999; 37: 363–71 staff in the long term). A department should dynamic knowledge creation. Long Range 13 Rowley DJ, Sherman H. The special increase its willingness to recognize and Planning 2000; 33: 5–34 challenges of academic leadership. harness success in a wider scope of activities; 5 Sackett DL, Rosenberg WM. On the need Management Decision 2003; 41: and then it should nudge its environment in a for evidence-based medicine. J Public 1056–63 similar direction. Health Med 1995; 17: 330–4 14 McFadzean ES. Enhancing creative 6 World Bank. World Economic Forum. thinking within organisations. Global Competitiveness Report 2004. Management Decision 1998; 36: http://www.Weforum.Org/Site/ 309–15 ACKNOWLEDGEMENT Homepublic.Nsf/Content/ Global+Competitiveness+Programme%5c Correspondence: Jeremy Heaton, Department The author would like to acknowledge the global+Competitiveness+Report. of Urology, Kingston General Hospital, stimulus from Dr Tony Gibbs and colleagues Accessed January 2005 Kingston, Canada. at Oxford Brookes Business School. 7 Amabile TM. How to kill creativity. e-mail: [email protected]
256 © 2005 BJU INTERNATIONAL Rev Article PHOSPHODIESTERASE TYPE 5 INHIBITORS FOR ERECTILE DYSFUNCTION CARSON and LUE
This is our first presentation Phosphodiesterase type 5 inhibitors of Great Drug Classes, and we start with a description of for erectile dysfunction phosphodiesterase type 5 inhibitors CULLEY C. CARSON and TOM F. LUE* and their use in erectile Department of Surgery, Division of Urology, School of Medicine, University of North Carolina at dysfunction. This is an in-depth Chapel Hill, Chapel Hill, NC and *Department of Urology, University of California San Francisco, review of this class of drugs, San Francisco, CA, USA offering the reader a description of Accepted for publication 30 March 2005 how they work, in which conditions they may be particularly beneficial, and a comparison of the three different drugs. It is of necessity The cyclic nucleotide signalling pathway KEYWORDS longer than the usual manuscript mediates the smooth-muscle relaxing accepted for the BJU International, effects of nitric oxide necessary for normal cGMP, efficacy, erectile dysfunction, erectile function. Down-regulation of this pharmacokinetics, phosphodiesterase type 5, with a full list of references. pathway is central to the pathophysiology safety, sildenafil, vardenafil, tadalafil of many forms of erectile dysfunction (ED), which is often associated with other chronic diseases (e.g. hypertension, type INTRODUCTION 2 diabetes mellitus) and treatments (e.g. certain drugs, radical prostatectomy). The diagnosis and treatment of erectile Conversely, selective inhibition of the dysfunction (ED) provide opportunities to enzyme that catalyses the degradation of enhance patient health and well-being. This cGMP (phosphodiesterase type 5, PDE-5) condition affects >150 million men across the promotes erectile responses to sexual world [1], including ª17% of Europeans [2]. stimulation. The successful launch and Despite effective ED therapies, 70–90% of commercialization of the selective PDE5 men with ED do not receive treatment. ED inhibitor (PDE5I) sildenafil transformed erodes the quality of life for many patients the treatment of ED, not only by providing and their partners, and often signals the an effective, well tolerated oral ED therapy, presence of other treatable diseases, including but also by fostering greater candour about hypertension and type 2 diabetes mellitus the problem among men. Sildenafil is highly (DM2). In this article we survey the aetiology effective in promoting erectile responses and pathophysiology of ED, and consider across a wide spectrum of severity and at greater length the treatment of this causes of ED, including patients with ED condition using selective inhibitors of that is often refractory to treatment. The phosphodiesterase type 5 (PDE5Is). recent advent of vardenafil, which has the highest in vitro potency of all available PDE5Is, and tadalafil, which has HISTORICAL PERSPECTIVE a prolonged half-life that may enable couples to have sexual activity with less CYCLIC NUCLEOTIDE SIGNALLING PATHWAY planning, represent further advances. Other PDE5Is offering further potential Although the availability of oral medications improvements are under active that inhibit PDE5 dates only to 1998, the basic investigation. science underlying their development can be
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TABLE 1 Overview of the PDEs
Isoenzyme family Substrate specificity Tissue distribution Inhibitor PDE1 cAMP Brain, lung, heart Vinpocetine PDE2 cAMP/cGMP Brain, adrenal cortex, liver, goblet cells, olfactory neurones PDE3 cAMP Smooth muscle, platelets, cardiac muscle, liver Milrinone PDE4 cAMP Very wide tissue distribution Rolipram PDE5 cGMP Very wide tissue distribution: PDE5A1/A2: brain, lung, heart, Papaverine, sildenafil, kidney, bladder, prostate, urethra, penis, uterus, skeletal muscle vardenafil, tadalafil, PDE5A3: heart, bladder, prostate, urethra, penis, uterus zaprinast PDE6 cGMP Retina (rods and cones) PDE7 cAMP Skeletal muscle, T-lymphocytes PDE8 cAMP Testis, ovary, gastrointestinal tract PDE9 cGMP Spleen, gastrointestinal tract, brain PDE10 cAMP/cGMP Brain, testis, thyroid PDE11 cAMP/cGMP Smooth muscle; cardiac muscle; prostate, pituitary, and salivary glands; testis; liver; kidney; skeletal muscle
traced back 50 years. In 1958, Sutherland and cell NOS (eNOS) and neural NOS (nNOS). family have >65% amino-acid homology [8] Rall [3] discovered an enzyme (PDE) that NO traverses the smooth muscle cell (SMC) and substrate (e.g. cAMP, cGMP) specificity. abolished the biological actions of the second membrane and binds with soluble guanylate Conservation of the catalytic domain messenger cAMP in mammalian tissue cyclase (sGC) in the cytoplasm. suggests that PDEs pre-date the evolutionary extracts. This magnesium-dependent PDE divergence of eumetazoans from fresh-water cleaved the 3¢,5¢-cyclic phosphate moiety, Binding of NO to sGC activates this enzyme, sponges. A conserved catalytic domain hydrolysing the phosphodiester bond to with increased formation of cGMP; cGMP consisting of ª300 amino acids shows form the inactive linear 5¢-AMP. Further then triggers a biochemical cascade 20–45% amino-acid sequence homology investigation also showed that this PDE was culminating in penile vasodilatation, across PDE family members, suggesting inhibited by methylxanthines and stimulated increased blood flow, expansion of erectile that the three-dimensional structures of by imidazole [3,4]. tissues, and trapping of blood through the catalytic domains are similar. compression of emissary veins. Physiological functions are highly sensitive to PDE5 is widely distributed, with animal intracellular levels of cyclic nucleotides, Because PDE5 is the predominant PDE in studies having located the enzyme in vascular, including cAMP and cGMP. These cyclic the penis [6], selective inhibition of this pulmonary and visceral smooth muscle, as nucleotides are tightly regulated, such that isoenzyme increases intracellular cGMP levels well as kidney, platelets and the cerebellum maximum physiological responses are in vascular and corporal SMCs and thus (Table 1). Based largely on mammalian in vivo produced by transient, two- to three-fold potentiates the NO-mediated vasorelaxant studies, PDEs are considered putative increases in intracellular concentrations [5]. (erectile) response to sexual arousal. The first regulators or modulators of olfaction (by Cyclic nucleotide levels are determined by: (i) in vivo demonstration of this effect was PDE1), visual transduction (PDE6) and other synthesis through the activities of adenylate reported in 1992 at the AUA meeting and neural activities; insulin action (PDE3); and cyclase and guanylate cyclase on ATP and GTP, published in 1994 [7]. The researchers platelet aggregation, vascular tone and other respectively; and (ii) enzymatic degradation reported that cavernosal nerve-stimulated cardiovascular effects (PDE3, PDE5). (inactivation) through the activity of PDEs. penile erections were markedly enhanced when monkeys were given the PDE5 inhibitor Agents that inhibit PDEs have been evaluated cGMP is a second messenger for the smooth- zaprinast [7]. In 1998, Louis Ignarro, Robert as treatments for a wide range of diseases. muscle relaxing effects of nitric oxide (NO; Furchgott and Ferid Murad were awarded the Among the earliest recognized PDE inhibitors endothelium-derived relaxing factor) within Nobel Prize in Physiology/Medicine for their were caffeine and theophylline [4]. The PDE3 the penis. The cascade of events linking NO work on NO-cyclic nucleotide signal- inhibitors milrinone and amrinone were with smooth-muscle relaxation in the transduction mechanisms, which supported investigated in the 1980s as positive inotropic penile vasculature and erectile tissues begins the development of PDE5Is. agents for patients with heart failure. with on-demand synthesis of NO by NO synthase (NOS) from L-arginine and oxygen, PDEs The PDE4 inhibitor cilostazol was used as on sexual arousal. NO is generated by both a treatment for intermittent claudication. nonadrenergic, noncholinergic nitrergic Enzymes that regulate diverse physiological Another PDE4 inhibitor, rolipram, was neurones and endothelial cells. This functions in a wide range of organs and investigated for treating depression, and compound is a highly unstable, transient, tissues, PDEs are divided into 11 families to reduce coronary artery smooth-muscle gaseous mediator synthesized by endothelial- encoded by distinct genes. Members of each proliferation, thus preventing re-stenosis
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after percutaneous intervention. Another among pharmacy beneficiaries increased by spongiosum, which houses the urethra and is PDE4 inhibitor, roflumilast, is under late-stage 84% from 1998 to 2002, but this still only more involved in ejaculation than erection. clinical investigation as a treatment for represented 1.4% (15 246/1 077 318) of Each corpus (or body) is a longitudinal chronic obstructive pulmonary disease. The pharmacy beneficiaries at the end of this cylindrical structure containing a mass or antiplatelet treatment dipyridamole blocks interval [10]. bundle (trabecula) of smooth muscle. PDE8 and PDE9 as well as PDE5. BASIC SCIENCE Within this meshwork of smooth muscle/ OVERVIEW OF THE PDE5I CLASS connective tissues are endothelial-lined PHYSIOLOGY OF ERECTION vessels and spaces (also termed sinusoids or The first PDEI developed for treating ED was lacunae). Vascular supply is from the papaverine; this opium poppy alkaloid is a The erectile response to sexual arousal pudendal-cavernous-helicine arterial tree. relatively nonselective PDEI, promoting depends on a complex series of neural and Each corpus is encapsulated by a fibrous cavernosal smooth-muscle relaxation by vascular events that transform the penile sheath, the tunica albuginea, which also inhibiting both PDE5 and PDE3, and thus vasculature and erectile tissues from a confers structural support. increasing intracellular levels of cGMP and contracted, minimally perfused state to a cAMP, respectively. Treatment with relaxed, blood-engorged state. The urogenital The smooth-muscle tone of the corpora papaverine may further promote smooth- reflex underlying erection consists of sensory cavernosa determines the erectile state of the muscle relaxation through blockade of afferents from the penis and autonomic penis. Vascular tone is maintained in a voltage-dependent Ca2+ channels. Papaverine efferents from parasympathetic neurones dynamic equilibrium consisting of contractile is administered via injection into the corpora with cell bodies in the sacral spine. This reflex (anti-erectile) and relaxant (pro-erectile) cavernosa of the penis, either alone or is influenced by supraspinal structures, factors. In the absence of sexual arousal, both together with other vasoactive substances including the medial preoptic area (MPOA) trabecular and vascular smooth muscle is (e.g. alprostadil). and paraventricular nucleus of the tonically contracted through sympathetic hypothalamus, which assimilate sexual neural input. Release of endothelin-1 and
The first oral PDE5I approved for treating ED, sensations (images, smells, touch, tastes) with prostaglandin F2a (PGF2a) from endothelial sildenafil citrate, was initially investigated as a cognitions, fantasies, memories and other cells, as well as other mediators (e.g. treatment for angina pectoris. Before input. angiotensin II, neuropeptide Y), exerts sildenafil, oral ED therapy was confined to vasoconstrictor effects, further limiting blood largely ineffective treatments, including off- Various neurotransmitters, including central flow into the penis (Fig. 1) [12]. label trazodone and the natural remedy NO, oxytocin and dopamine, are recognized as yohimbine. Zaprinast is also a selective PDE5I pro-erectile neurotransmitters [11]. The The contractile effects of noradrenaline that has been evaluated in studies of sexual observation that dopamine exerted central and endothelin-1 are partly mediated by dysfunction. Sildenafil transformed the pro-erectile effects helped to trigger the the RhoA/Rho-kinase signalling pathway treatment of ED; the success of this ED development of a sublingual dopamine (Fig. 2) [13,14]. When noradrenaline or therapy and attendant public awareness agonist (Uprima®, IxenseTM). Although Ixense endothelin-1 binds to SMC receptors, RhoA is helped to usher in a new era of candour about is available in Western Europe for treating ED, converted from an inactive, cytosolic GDP sexual dysfunction. In the USA, presentation Uprima has not been approved by the USA complex into an active, membrane-bound GTP rates for ED more than doubled after the Food and Drug Administration. complex. regulatory approval of sildenafil. The sacrospinal ‘sex centre’ also receives RhoA-GTP in turn activates Rho-kinase, which There are now three oral medications descending inhibitory input from phosphorylates the myosin-binding subunit (sildenafil, vardenafil and tadalafil) that serotonergic centres within the brain. of the regulatory enzyme myosin light-chain inhibit PDE5 and are indicated for treating In vivo work suggested that serotonin (MLC) phosphatase, thus inhibiting this ED. Each of the three PDE5I registration (5-hydroxytryptamine) receptors inhibit enzyme. With MLC phosphatase inactive, programmes involved >2000 patients. In the certain sexual activities or processes and MLCs remain phosphorylated, are sensitized USA, sildenafil was approved in 1998 and facilitate others. In animals, selective agonists to intracellular Ca2+, and bind to actin both vardenafil and tadalafil in 2003. As of of 5-hydroxytryptamine-2 receptors inhibit filaments, thus promoting smooth-muscle 2001, sildenafil had been approved for use in erectile responses but facilitate ejaculation contraction. >110 countries; as of this writing, >20 million [11]. Other central mediators with inhibitory patients across the world have received effects on sexual behaviours and/or erectile Release of NO from nonadrenergic, sildenafil and >4 million have received function (EF) include enkephalins, prolactin, noncholinergic neurones in response to tadalafil for ED. and g-aminobutyric acid [11]. sexual arousal triggers the shift toward vascular and smooth-muscle relaxation Although the PDE5Is offer effective therapy During the erectile response, the penis acts as (Fig. 3) [12]. This shift is amplified by for ED, the recent Men’s Attitudes to Life a capacitor, filling with and retaining blood. enhanced parasympathetic input, with Events and Sexuality study showed that only The major anatomical structures involved in increased acetylcholine release and further 16% of men with ED were receiving a PDE5I male sexual function are the three corpora: a NO output from endothelial cells lining [9]. Among commercially insured adult pair of dorsally located corpora cavernosa, helicine arterioles. Although several Americans, the prevalence of sildenafil use and a more ventrally situated corpus vasodilators have been implicated in the
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FIG. 1. Molecular mechanisms of penile smooth-muscle contraction. Noradrenaline from sympathetic nerve endings, and endothelins and PGF2a from the endothelium, activate receptors on SMCs to initiate the cascade of reactions that results in elevation of intracellular calcium concentrations and smooth-muscle contraction. Protein kinase is a regulatory component of the calcium-independent, sustained phase of agonist-induced contractile responses. From [12]. © Copyright 2000 Massachusetts Medical Society. All rights reserved.
erectile response, including vasoactive kinase, with reduced influx of Ca2+ forces ascribed to this increased blood flow intestinal peptide and PGs, as well as across the plasma membrane; membrane activate eNOS within sinusoidal endothelial acetylcholine, NO is considered the pivotal hyperpolarization through increased Na+/K+- cells, amplifying NO release and potentiating physiological stimulus for cavernosal ATPase activity, with further reduced influx of smooth-muscle relaxation and the erectile vasorelaxation. Ca2+ and Ca2+ sequestration by cellular response. organelles, including the sarcoplasmic cGMP is a second messenger for the reticulum. Expansion of trabecular erectile tissues leads vasorelaxant effects of NO (Fig. 3) [12]. to compression by the noncompliant tunica Through several downstream mediators, Under conditions of low cytosolic Ca2+, albuginea of thin-walled subtunical veins including protein kinase G, cGMP triggers myosin heads detach from actin filaments draining the penis, restricting venous outflow. a cascade of events leading to reduced and smooth muscles relax. With As blood is retained within the penis by this intracellular availability of Ca2+ ions. These vasodilatation of helicine arterioles, there is a veno-occlusive mechanism, intracorporal events include phosphorylation of Ca2+ rapid, ª10-fold rise in penile perfusion with pressure approaches mean arterial pressure channels by a cGMP-dependent protein engorgement of the corporal sinuses. Shear (full erection phase). Contraction of
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FIG. 2. RhoA/Rho-kinase pathway. Through phosphorylation of several downstream intermediates, Rho-kinase mediates the vasoconstrictor (i.e. anti-erectile) effects of noradrenaline and endothelin-1. There is potential cross-talk between this signalling pathway and the NO-cyclic nucleotide pathway during sexual arousal. NE, norepinephrine; SM, smooth muscle.
VASOCONSTRICTORS VASORELAXANTS (NANC nerves) NE ET-1 NO (Symp. nerves) (Endothelial cells) (Endothelial cells) PKG cGMP sCG
RhoA RhoA-GTP Inactive Active Downstream Rho-Kinase substrates (cytosolic) (membrane-bound) CPI-17 (inhibits MLC phosphatase)
Rho-Kinase Calponin (inhibits actomyosin interactions) Adducin (stimulates Na+/K+-ATPase-mediated ? hyperpolarization and SM relaxation)
MLC Phosphatase MLC Phosphatase Active Inactive
MLC MLC-P (myosin light chains (myosin light chains phosphorylated with not phosphorylated; actomyosin bridge formation) actomyosin bridge formation)
KEY VASORELAXATION TONIC Activates ERECTION CONTRACTION FLACCIDITY Inhibits
©2005 Rete Biomedical Communications Corp.
perineal skeletal muscles (ischiocavernosus, Although the NOS-NO-sGC-cGMP and Rho- with maximal effects at 10–15 min [16]. bulbocavernosus) is necessary to achieve the kinase signalling pathways are largely These beneficial effects were accompanied by rigid erection phase, which produces supra- independent, in vivo studies [15] suggest that only marginal changes in mean arterial systolic pressure within the corpora there is cross-talk between them. Protein pressure. cavernosa. kinase G, a downstream mediator in the cyclic-nucleotide signalling pathway, inhibits Enzymatic degradation of cGMP by PDE5 RhoA activation, biasing the Rho-kinase CAUSES OF ED is the key event terminating the above pathway toward vasorelaxation and penile cascade. Consequently, selective inhibition erection. ED has many causes (Fig. 4) [17], with most of PDE5 by sildenafil, vardenafil or tadalafil (75–80%) cases being attributed to vascular potentiates the erectile response. Because Rho-kinase inhibition represents a promising or neural disorders. Other causes include this response depends on NO synthesis and pharmacological approach to treating ED. endocrine imbalances, anatomical disorders release upon sexual stimulation, PDE5Is are Topical administration of the Rho-kinase (Peyronie’s disease) and psychological contingent agonists of the sexual response; inhibitor Y-27632 to the tunica albuginea conditions (and/or their treatments). In many they are effective only with sufficient sexual induced penile erection in rats, elevating cases, more than one of these factors arousal. intracorporal pressure within a few minutes, contribute to ED.
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Vascular FIG. 3. Molecular mechanisms of penile smooth-muscle relaxation. cAMP and cGMP, the intracellular second-messengers mediating smooth-muscle relaxation, activate their specific protein kinases, which Blood flow into the penis is a vascular process phosphorylate certain proteins to cause opening of potassium channels, closing of calcium channels, and dependent on a functioning endothelium. sequestration of intracellular calcium by the sarcoplasmic reticulum and other cellular organelles. The Thus, endothelial pathology often leads to ED. resulting fall in intracellular calcium leads to smooth-muscle relaxation. Sildenafil, vardenafil and tadalafil The degree of ED varies directly with the inhibit the action of PDE5, thus increasing the intracellular concentration of cGMP. From [12]. Copyright 2000 number of arterial risk factors, including Massachusetts Medical Society. All rights reserved. hypertension, hyperlipidaemia, DM2 and smoking [18]. Several factors, including atherosclerosis, DM2 and ageing itself, are construed as NO-deficient processes.
According to the basic science, DM2 and advanced age are associated with down- regulation of the NO–cGMP signal- transduction mechanism, partly via increased formation of advanced glycation end products. These compounds, such as pentosidine, can glycate or inactivate (‘quench’) NO and/or inhibit eNOS [19]. In addition, corporal smooth-muscle strips from men with ED and DM undergoing penile implantation showed impaired endothelium- dependent and autonomically mediated smooth-muscle relaxation [20]. This impaired smooth-muscle relaxation was significantly correlated with the duration of DM.
In vivo work in senescent rats showed that the presence of advanced age and/or vascular risk factors (e.g. hypertension) may be associated with decreases in: (i) NOS activity per gram of tissue; and/or (ii) NO-stimulated sGC levels, as well as increases in inducible NOS (iNOS) activity with elevated SMC apoptosis [21–24]. Apoptosis, with fewer SMCs in human corporal tissues, may also contribute to ED by compromising the veno-occlusive mechanism [25].
Hypertension is also a well-documented risk factor for ED [26]. In the human microvasculature, hypertension attenuates endothelium-dependent NO-mediated SMC relaxation. Hypertension also represents a broader dysregulation of vascular relaxant and contractile factors. In the presence of hypertension, NO may be unable to offset the anti-erectile influences of increased peripheral sympathetic neural activity disorder. The estimated prevalence of ED is Peripheral nervous system disorders and other pro-contractile mediators (e.g. 70% in men with multiple sclerosis, 60% in contributing to the development of ED endothelin-1, prostanoids, neuropeptide Y, those with Parkinson’s disease and 30% in include autonomic insufficiency and diabetic angiotensin II) [13]. those with stroke [17]. Given sacrospinal (somatic and autonomic) neuropathy. involvement in the urogenital reflex, it is not Peripheral neuropathies may also be Neural surprising that ED occurs in up to 80% of men secondary to vitamin B deficiencies, chronic with sacrospinal-cord lesions, compared with alcoholism, scleroderma, systemic lupus CNS disorders associated with ED include 10% with suprasacral lesions. Other central erythematosus, amyloidosis or AIDS. Sensory Parkinson’s disease, Alzheimer’s disease, causes of ED include head trauma, tumour penile thresholds often increase significantly stroke, multiple sclerosis and major depressive and temporal-lobe epilepsy [17]. as a result of peripheral nervous system
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FIG. 4. The multifactorial causes of ED. From [17]. Copyright 1999 Handbooks in Health Care Co. All rights nitrosative stresses, increased iNOS reserved. expression with formation of toxic peroxynitrites may also reduce both MPOA neurones needed for central processing of sexual input and neurones generating GnRH.
Prolactin levels are elevated in ª5% of men complaining of ED [30]. Hyperprolactinaemia is often characterized by low libido and other forms of sexual dysfunction, gynaecomastia, galactorrhoea, and/or exceedingly low testosterone levels (<150 ng/dL). Hyperprolactinaemia can occur in association with DM, chronic renal failure and cirrhosis of the liver, among other conditions.
Obesity and/or DM can also negatively affect circulating androgens by raising sex hormone-binding globulin [31]. Both hyperthyroidism and hypothyroidism have also been cited as contributors to the development of ED [17]. Chronic alcoholism can reduce EF in part through effects on the androgen/oestrogen balance [17,31].
DM can compromise erectile responses via all four mechanisms (i.e. vascular, neural, local- tissue, endocrine). This fact may help to explain why: (i) the prevalence of ED is up to 75% in men with DM2; and (ii) men with ED and DM2 often present with a worse quality disorders. These thresholds are critical to the Endocrine of life and ED that is refractory to therapy. ability of men to achieve and maintain erections. Because of elevated sensory Apart from DM, endocrine abnormalities are Many medical and surgical treatments can thresholds in elderly men with ED and/or DM, considered to be less frequent precipitants of also cause ED. Treatment with certain increased tactile stimulation is often ED than either neural, vascular or anatomical vasodilators, antihypertensives, and diuretics necessary to ensure an adequate erectile factors. However, a large endocrine screening (e.g. thiazides, spironolactone) increase the response with or without PDE5Is. programme conducted by Buvat and Lemaire risk of ED. For instance, a-adrenergic blockers [27] showed that 9% of men with ED and (e.g. propranolol) can impair EF by enhancing Local-tissue/anatomical. The erectile aged >50 years met diagnostic criteria for a-adrenoceptor activity and/or suppressing response to sexual stimulation is critically hypogonadism. In the First International libido [11,17]. dependent on: (i) adequate compliance of the Consultation on Erectile Dysfunction, the corpora cavernosa, which enables erectile WHO recommended that testosterone be Other iatrogenic causes of ED include tissues to expand during the ‘filling’ phase; assayed in men with low sexual desire and treatment with psychotropic agents and (ii) the structural integrity of the tunica atrophic testes (£19 mL) because ED and medications associated with albuginea, which supports the corpora as they secondary to hypogonadism is potentially hyperprolactinaemia. These include become engorged with blood and mediate the reversible using testosterone-replacement medications with effects on central veno-occlusive mechanism during the therapy [28]. dopamine, such as a-methyldopa and ‘storage’ phase. reserpine, which deplete central dopamine Animal studies indicate that androgens stores; dopamine-receptor blockers, such as Causes of veno-occlusive dysfunction (i.e. may promote EF by suppressing the chlorpromazine, butyrophenones (e.g. ‘venous leak’) include DM, Peyronie’s disease responsiveness of cavernous vascular SMCs to haloperidol), and benzamides (e.g. and atherosclerosis, which can lead to the pro-contractile (i.e. anti-erectile) effects metoclopramide); and agents that block the degeneration of the tunica albuginea and/or of a-adrenergic input [29]. In vivo work also effects of endogenous dopamine, such as alter endothelial function or gap junctions; suggests that reductions in testosterone may amoxapine, cimetidine and verapamil. chronic ischaemia, which can alter collagen accompany, as well as cause, ED; increased Cocaine abuse can also elicit ED through content (i.e. corporal fibrosis); and NOS activity in the corpora cavernosa occurs effects on endogenous dopamine, as well as psychogenic inhibition, which can result in with normalization of testosterone in through increased a-adrenergic activity and inadequate neurotransmitter release. castrated animals. Under oxidative and endothelial dysfunction.
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FIG. 5. Molecular structures of the PDE5Is and the biological PDE5 substrate cGMP. Adapted with permission from [34]. Copyright 2004 Elsevier Science Inc. All rights reserved.
Several pelvic, perineal and other surgical to Gln-817 of the catalytic site. Slight PDE5 is a homodimeric, cytosolic enzyme procedures can induce ED through adverse differences in the core ring system of consisting of two identical ª99-kDa subunits. effects on neural and/or vascular structures. vardenafil may enable stronger interactions Each subunit is a chimeric protein comprising The prevalence of ED is estimated at 40–70% with one or more amino acids that are both a carboxy-terminal metal-binding in men after radical prostatectomy (RP, nerve- important for binding to the PDE5 catalytic catalytic domain and an amino-terminal sparing), 20–60% after abdominoperineal site, including Gln-817, Tyr-612, Val-782, Phe- regulatory (allosteric) domain (Fig. 6) [37]. resection, 30% after aorto-iliac vascular 820, and Leu-785. Tadalafil is one of a series Within the regulatory domain are two bypass, and 4% after TURP [17]. Pelvic of a-carboline–based PDE5Is and has a identical tandem homologous sequences irradiation may also contribute to the piperazinedione ring rather than the of 110 amino acids (GAF a and b domains). development of ED. hydantoin ring found in sildenafil. PDE5 is a zinc-dependent enzyme with high
substrate specificity for cGMP (Km 1–5 mmol)
In addition to spinal-cord injury, other forms THREE-DIMENSIONAL STRUCTURE OF PDE5 over cAMP (Km 300 mmol). The three PDE5Is of trauma, such as pelvic fractures, may give AND BINDING INTERACTIONS BY INHIBITORS bind exclusively to the catalytic domain, not rise to ED through injury to vascular and/or the regulatory domain. Binding of either a neural structures. Habitual bicycling for long Three isoforms (splice variants) of PDE5 PDE5I or cGMP to one catalytic domain does distances can impair EF, possibly via perineal (PDE5A1-A3) have been identified in animal not appear to kinetically influence the activity nerve entrapment or penile arterial injury and/or human tissues [35]; the predominant of the catalytic domain on the other [32,33]. isoform is PDE5A2. These isoforms differ in monomer. their N-terminal regions, which correspond to different 5¢ regions of mRNA. The human A Korean group elucidated the three- BIOCHEMISTRY AND PHARMACOLOGY PDE5 gene is located on chromosome 4q26 dimensional structure of the PDE5 catalytic and comprises 23 exons encompassing site (residues 537–860) using X-ray STRUCTURES >100 kb. A PDE5A promoter preceding these crystallographic analyses (Fig. 7) [38]. The exons includes a 139-bp core, as well as a PDE5 catalytic site comprises three helical The molecular structures of sildenafil, 156-bp downstream enhancer and a 308-bp subdomains: a C-terminal helical bundle vardenafil, tadalafil and the natural substrate upstream enhancer. The PDE5A promoter is (residues 726–860), a linker region (residues cGMP are depicted in Fig. 5 [34]. Although inducible by cGMP, such that increased cGMP 679–725), and an N-terminal cyclin-fold the structure of tadalafil differs from the levels lead to increased PDE5 gene expression domain (residues 537–678). The PDE5Is structures of sildenafil and vardenafil, all in a negative-feedback loop [36]. bind to the catalytic site (Fig. 7) with a three PDE5Is share a heterocyclic nitrogen- stoichiometry of ª1 mole of PDE5I per PDE5 containing double-ring system. This core ring All three PDE5 isoforms share similar subunit, according to tritiated-substrate structure mimics the purine base of cGMP and substrate specificity and cGMP catalytic binding studies [34]. The PDE5 active site is interacts with the same PDE5 catalytic site. activity. PDE5A3 expression in males is limited accessed via a narrow (1 nm) cleft housed to smooth muscle in the penis, bladder, within a larger 33 nm substrate pocket The chief structural difference between urethra, prostate gland and aorta, whereas containing four subdomains. These include a sildenafil and vardenafil is in these core ring both PDE5A1 and PDE5A2 are more widely metal-binding region (M site), a core pocket systems; N-1 of the purine ring in cGMP binds distributed. (Q pocket) and two other regions less
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FIG. 6. Schematic representation of PDE5, Reproduced with permission from [37]. Copyright 2004 Nature (chromatopsia), increased sensitivity to light Publishing Group. All rights reserved. or blurred vision in £3% of patients, or vardenafil (e.g. blurred vision, chromatopsia in <2% of patients) at therapeutic doses [40–42]. Imbalances in cGMP levels can interfere with visual signalling and culminate in photoreceptor cell death and retinal degeneration. Insufficient numbers of patients with retinitis pigmentosa have been studied to safely recommend administration of any PDE5Is to patients with this condition [40–42].
Sildenafil and vardenafil are one to two orders of magnitude more selective for PDE5 than PDE11 compared with tadalafil. Tadalafil has been shown to inhibit human recombinant PDE11A1 activity at therapeutic concentrations [41]. However, the function of PDE11, as well as the roles of other PDEs (PDEs 7–10), have not been completely elucidated. PDE7 has been located in skeletal muscle and T lymphocytes; PDE8 in the small and large intestines, testis and ovary; PDE9 in the brain, intestine and spleen; PDE10 in the brain, testis and thyroid gland; and PDE11/PDE11A in the prostate, pituitary and salivary glands, as well as the kidney, liver, testis and skeletal muscle. Although PDE11 is expressed in the testis and intimately involved in PDE5 binding by BINDING POTENCY pituitary gland as well as in smooth muscle sildenafil and vardenafil: a hydrophobic [43], daily tadalafil treatment did not alter pocket (H pocket) and a lid (L region). Possibly The concentration of each agent needed spermatogenesis or reproductive-hormone because PDE5Is are large molecules with more to inhibit PDE5 activity by 50% (IC50) is secretion in healthy men with mild or no ED extensive interactions with Q-pocket amino 3.7 nmol/L for sildenafil, 0.091 nmol/L for [44]. acids, they bind ª1000 times more avidly to vardenafil, and 1.8 nmol/L for tadalafil; thus, the catalytic site than does cGMP [37]. the sildenafil : vardenafil : tadalafil in vitro potency ratio is ª1 : 41 : 2 [34]. PDE5I- CLINICAL DATA
An ethyloxyphenyl structure in sildenafil and specific dissociation constant (KD) values, vardenafil fits into the H pocket, which which are more direct indices of enzyme PHARMACOKINETICS includes the amino acids Phe-786, Ala-783 binding, indicate similar potency relations and Leu-804. The L region then forms a lid among the PDE5Is [34]. All three PDE5Is are rapidly absorbed over sildenafil and vardenafil through after oral administration; the absolute residues 662–664, narrowing the passage and PDE SELECTIVITY bioavailability is 40% for sildenafil and 15% sterically limiting access to the PDE5 active for vardenafil. The median time to maximum site [38]. As shown in Table 2 [39], all three PDE5Is are concentration (tmax) is 1 h for sildenafil and
highly selective for PDE5 over other PDEs, vardenafil, and 2 h for tadalafil. Median tmax Tadalafil does not interact with the L region although there are differences among the values as low as ª40 min have been reported and forms a single hydrogen bond to Gln-817, agents. The PDE5 : PDE6 selectivity ratio is with vardenafil at the 20 mg dose and a rather than the bidentate hydrogen bond 6.8 : 1 for sildenafil, 2.9 : 1 for vardenafil, and supra-therapeutic dose of 40 mg [45,46]. between this amino acid and sildenafil, within 780 : 1 for tadalafil. PDE6 is localized to the Q pocket. On the other hand, the cyclic photoreceptor cells in the rods and cones, High-fat meal intake influences the methylenedioxyphenyl substituent of tadalafil and is activated following photoexcitation absorption profiles of both sildenafil and undergoes more extensive interactions with of rhodopsin with binding of the G-protein vardenafil. Sildenafil’s maximum plasma the H pocket than does either sildenafil or visual pigment transducin to PDE6. The concentration (Cmax) is reduced by 29% and vardenafil. These more extensive hydrophobic difference in the selectivity ratio of tadalafil tmax delayed by 1 h when the agent is interactions may help to explain how compared with sildenafil or vardenafil may administered with a high-fat meal. When tadalafil maintains high affinity to the account for the lower frequency of visual vardenafil was administered with a high-fat catalytic site without binding to the L side-effects with tadalafil (<0.1%) compared breakfast including 910 calories, with 57% of region [38]. with sildenafil, i.e. colour tinge to vision total calories derived from fat (58 g), the Cmax
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FIG. 7. Interactions between sildenafil and the catalytic site of PDE5. Panel A: Stereo view of the active site of the PDE5-sildenafil complex. Sildenafil is shown as a stick model with carbon atoms in yellow. Metal- and inhibitor-binding residues of PDE5 are shown as stick models with carbon atoms in white. Zinc (the larger model) and magnesium ions are shown in orange and green, respectively. The amide moiety of the pyrazolopyrimidinone group of sildenafil forms a bidentate hydrogen bond with the a-amide group of Gln-817, which is well ordered by a hydrogen-bond relay involving Gln-817 to Gln-775, Gln-775 to Ala-767, and Gln-775 to Trp-853. Panel B: Detail of panel A. Reproduced with permission from [38]. Copyright 2003 Nature Publishing Group. All rights reserved.
A
Y664 E682 Y664 E682
H685 H685 D764 D764 H653 H653 F820 F820 D654 D654
M816 H557 M816 H657 H613 H613 Q817 F786 Q817 F786 H617 A76 H617 A767 Y612 Y612
W863 Q775 W853 Q775
B Met816 Tyr664
N O Gly819 N S O His613 Mg Phe820
Leu804 OH Asp654 N 2
Phe786 N OH2 OH2 Zn His653 O HN N O Asp764 His617 Ala783 O Tyr612
NH2 Ala767 Gln817 Val782 was reduced by ª18% compared with the under the concentration : time curve (AUC) The three PDE5Is are distributed value after an overnight fast [47]. In addition, was essentially unaltered. On the other hand, widely throughout tissues and the tmax was delayed from 1 to 2 h, whereas meal intake has no effect on the absorption of extensively (≥ 94%) protein bound. the extent of absorption, as indicated by area tadalafil. Volumes of distributions (VD) are 105 L for
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Based on these studies, an American Heart Selectivity ratio vs PDE5 TABLE 2 Association/American College of Cardiology Family/gene Sildenafil Vardenafil Tadalafil Relative selectivity profiles consensus panel recommended that nitrates of PDE5Is PDE1 not be administered within 24 h after PDE1a 290 630 20 000 sildenafil dosing [50]. PDE1b 1 100 5 000 21 000 PDE1c 110 460 11 000 Vardenafil 20 mg potentiated increases in PDE2a 19 000 72 000 49 000 heart rate and hypotensive effects of PDE3 sublingual nitrates (0.4 mg) when PDE3a 12 000 7 700 38 000 administered 1–8 h (but not 24 h) before PDE3b 17 000 15 000 18 000 nitrates [42]. Tadalafil 20 mg potentiated PDE4 – – – the hypotensive effects of sublingual PDE4a 6 000 46 000 30 000 nitroglycerine for 2–24 h (but not 48–96 h) PDE4b 5 800 33 000 22 000 after tadalafil 20 mg dosing in a randomized, PDE4c 5 200 34 000 23 000 placebo-controlled, double-blind crossover PDE4d 3 600 16 000 13 000 study of 150 men (mean age 57 years) [54]. PDE5 1 1 1 PDE6 6.8 2.9 780 Acute postural hypotension symptoms have PDE7a 22 000 200 000 47 000 also been reported when sildenafil is PDE8a 19 000 310 000 30 000 administered together with the a-adrenergic PDE9a 540 3 600 19 000 blocker doxazosin, used for treating BPH and PDE10a 3 100 12 000 9 000 hypertension. According to USA prescribing PDE11a 1 500 640 14 information, sildenafil at doses of >25 mg should not be administered within 4 h after a Selectivity ratios are based on IC50 values for each enzyme relative to patient takes an a-blocker [40]. For vardenafil the IC50 for PDE5. IC50 denotes the concentration of substrate (PDE5I) and tadalafil, coadministration of a-blockers needed to inhibit half the enzymatic activity; lower values denote is listed as a precaution in the USA label more potent enzymatic inhibition, e.g. the PDE5 : PDE2 selectivity ratio [41,42]. However, concomitant administration of 19 000 for sildenafil indicates that the concentration of sildenafil of either tadalafil or sildenafil with other needed to inhibit half the PDE2 enzymatic activity is 19 000 times antihypertensive agents (e.g. calcium-channel higher than the concentration needed to inhibit half that of PDE5. blockers) is well tolerated and did not result in From [39]. significant declines in blood pressure or increased occurrence of hypotension, syncope or other adverse cardiovascular events compared with placebo [52,55]. sildenafil, 208 L for vardenafil and 63 L for PDE5Is is principally as fecal metabolites Alcohol is a mild vasodilator with effects on tadalafil. [40–42]. eNOS activity and NO output by endothelial cells [56]. In a recent placebo-controlled The cytochrome P450 system is the chief In men aged ≥65 years, the AUC (i.e. systemic crossover trial involving eight healthy non- metabolic pathway for sildenafil, vardenafil exposure) of sildenafil increases by 40% [40]. smoking men, there were no untoward and tadalafil. All three agents are cytochrome The AUC and Cmax of vardenafil are increased haemodynamic interactions between P3A4 substrates. Sildenafil has a desmethyl by 52% and 34%, respectively, in elderly sildenafil 100 mg and red wine (750 mL; metabolite that accounts for ª20% of its men [42]. Hence, lower starting doses are 13.5% v/v) consumed 60 min after sildenafil overall pharmacological activity [40]. recommended for older men, i.e. 25 mg for dosing (i.e. the tmax for sildenafil) [57]. Red Vardenafil is metabolized to a desethyl- sildenafil and 5 mg for vardenafil. No such wine intake significantly elevated the cardiac piperazine derivative that accounts for ª7% adjustments are necessary for elderly men index and heart rate, and sildenafil alone of overall vardenafil pharmacological activity taking tadalafil [41]. significantly lowered mean arterial pressure [42]. Tadalafil is metabolized to a catechol by up to 7% and peripheral vascular derivative that is methylated and resistance by up to 8%. However, the glucuronidated; however, metabolites are DRUG INTERACTIONS combination had no effect on any of these unlikely to contribute to the pharmacological variables compared with red wine alone. activity of tadalafil [41]. Because PDE5Is potentiate the vasodilator/ Vardenafil did not potentiate the hypotensive hypotensive effects of NO donors, treatment effects of ethanol within 4 h in healthy Both sildenafil and vardenafil have terminal with any PDE5I is contraindicated in patients subjects drinking alcohol (0.5 g/kg) [42]. half-life (t1/2) values of 4–5 h [40,45,46]. taking any form of NO donor, including Similarly, tadalafil did not potentiate the
Tadalafil has a t1/2 of 17.5 h, which is organic nitrates [40–42,50–52]. Studies hypotensive effects of ethanol at a dose of consistent with a broad window of clinical have shown that sildenafil potentiates the 0.6 g/kg, with no orthostatic hypotension or responsiveness [48,49]. Excretion of all three hypotensive effects of nitrates [52,53]. increased frequency of dizziness compared
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with alcohol alone. Only at a higher alcohol FIG. 8. Therapeutic effectiveness: the emerging conceptual framework for evaluating and predicting dose (0.7 g/kg) equivalent to 180 mL of vodka outcomes of therapies for ED. Based on data from [59]. (40% alcohol) did tadalafil significantly lower blood pressure and/or induce postural effects Treatment effectiveness [41]. None of the PDE5I USA package labels recommends co-administration with alcohol. Treatment response Complete Treatment satisfaction Potent inhibitors of cytochrome P3A4, Partial including HIV protease inhibitors (e.g. Non-response indinavir, ritonavir), azole antifungals, and Efficacy erythromycin, can increase systemic exposure Patient Partner Objective (Rigiscan) (AUC) of the PDE5Is by 2- to 16-fold. For Complete Complete Subjective Safety/tolerability example, the protease inhibitor ritonavir Partial Partial IIEF, IIEF-5 (SHIM), Dissatisfied Dissatisfied increases the systemic exposure (AUC) SEP, GAQ of sildenafil 11-fold, and caution should be exercised when prescribing the two medications concurrently [40]. Vardenafil therapy should not exceed a single 2.5 mg when either evaluating or predicting On the other hand, the ability to engage dose per 24 h in patients taking indinavir, treatment outcomes. As shown in Fig. 8 [59], in and complete intercourse is a more ketoconazole 400 mg, or itraconazole the concept of therapeutic effectiveness conservative outcome measure. These 400 mg, or per 72 h in those taking ritonavir integrates the treatment response of the variables are typically reported by the patient [42]. Tadalafil treatment should not exceed a patient with the treatment satisfaction of and/or partner and are thus subjective single 10 mg dose, and should not be taken both the patient and his partner. endpoints. Assessments using event logs or more than once per 72 h, in patients taking diaries include the Sexual Encounter Profile potent cytochrome P3A4 inhibitors [41]. As the gatekeeper to consensual sexual (SEP), which helps to delineate the proportion Cytochrome P3A4 inducers such as rifampin intercourse, the partner needs to be of responders at specific drug doses. The can reduce circulating PDE5I levels. considered when planning, assessing third question of the SEP (SEP-Q3) diary is, expectations and motivations, and evaluating ‘Did your erection last long enough for Grapefruit juice inhibits first-pass cytochrome the outcomes of treatment. A recent you to have successful intercourse?’ The P450 metabolism in the gastrointestinal tract European survey [60] showed that lack of International Index of Erectile Function and may thus increase oral bioavailability of sexual interest on the part of the partner (IIEF) developed by Rosen et al. [62] is a the PDE5Is. A randomized crossover trial [58] contributed to the 31% rate of patient validated multidimensional (15-item) evaluated the effects of taking a single noncompliance with effective sildenafil questionnaire that has been translated into sildenafil 50 mg dose 1 h before, or at the treatment. several languages (and cross-validated). The same time as, 250 mL of grapefruit juice in 24 EF domain is a highly sensitive and reliable healthy male volunteers. Compared with Treatment response is further subdivided into barometer of treatment efficacy. On the basis water (reference period), grapefruit juice efficacy and safety/tolerability; the last two of an analysis of 1151 subjects, IIEF EF domain consumption increased the AUC values for need to be factored under treatment scores of ≥26 are correlated with ‘no ED’ [63]. sildenafil and N-desmethylsildenafil by response, in part because adverse events (AEs)
23–24% and slightly prolonged the tmax (by or concerns about long-term health may Abridged versions of the IIEF, including the ª15 min). Grapefruit juice also rendered compromise adherence to the regimen and IIEF-5 (containing only five items) or Sexual sildenafil pharmacokinetics more variable, thus reduce treatment response. Efficacy Health Inventory for Men, are also available. and the authors concluded that the outcome measures with potential utility in Although of limited value to characterize combination should be avoided, especially in randomized controlled trials (RCTs) and efficacy, global (overall) assessments, such as patients who might be prone to more marked clinical practice are further subdivided into the Global Assessment Question (GAQ; ‘Did haemodynamic effects [58]. objective and subjective measures. the treatment improve your erections?’), play a role in many RCTs. The use of these and Penile plethysmography using the RigiScan® other overlapping efficacy measures enables device (Timm Medical, Eden Prairie, MN) highly reliable and consistent evaluations of EFFICACY enables objective evaluations of penile rigidity treatment efficacy. based on changes in circumference at BACKGROUND ON OUTCOME MEASURES different anatomical loci of the penis. The To capture data from the other chief domain two major assessment paradigms include of therapeutic effectiveness (treatment The PDE5Is are effective across a wide range responses to visual sexual stimulation and satisfaction), the Erectile Dysfunction of outcomes in promoting erectile responses nocturnal penile tumescence testing, the Inventory of Treatment Satisfaction (EDITS) to sexual stimulation. However, as articulated latter of which is physiologically sound in part developed by Althof et al. [64] is useful. The by a recent multidisciplinary expert panel [59], because the rigidity of nocturnal erections EDITS enables the investigator to reliably the efficacy of ED treatments should not be correlates significantly with corporal SMC assess both patient and partner satisfaction equated with their therapeutic effectiveness content [61]. with therapy, and probe the effects of
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FIG. 9. The percentage of patients returning to an EF domain score (≥26) associated with ‘no ED’, stratified by IIEF EF domain score of ≥26 after 12 weeks of baseline ED severity (intent-to-treat population, last observation carried forward). Reproduced with treatment with vardenafil 20 mg, as did half permission from [75]. Copyright 2003 American Society of Andrology. All rights reserved. of those with moderate ED and ª79% of those with mild ED at baseline (Fig. 9). The 100 vardenafil pivotal trials excluded sildenafil Placebo nonresponders [75]. 90 Vardenafil 5 mg Vardenafil 10 mg 80 Similarly, integrated phase III tadalafil studies 26, % Vardenafil 20 mg ≥ [48] involving 1112 patients showed that the
in 70 a IIEF EF domain score at the end of 12 weeks of om
d 60 treatment (or greater) was ª24 in men receiving tadalafil 20 mg, compared with ª15 50 in men receiving placebo (P < 0.001). Patients 40 were ª59 years old, 61% had organic ED, and rning to EF u 90% had ED for >1 year. Treatment with 30 tadalafil 20 mg also significantly enhanced 20 the intercourse satisfaction and overall tients ret a
P satisfaction domains of the IIEF. A total of 10 81% of responses to the GAQ indicated 0 improved erections in the tadalafil 20 mg Mild Mild-to-Moderate Moderate Severe group, in contrast to 35% in the placebo (22-25) (17-21) (11-16) (£10) group (P < 0.001) [48]. More than 70% of Baeline ED severity intercourse attempts were successfully completed with tadalafil 20 mg from >30 min to 36 h after dosing (Fig. 10) [48]. satisfaction on treatment continuation. A phase III trials were reported in 1998 [74]. In a DIFFICULT-TO-TREAT ED score of ≥50 (on a scale of 0–100) is indicative dose-escalation (50–100 mg) study involving of treatment satisfaction. 329 men (mean age 59 years) with ED for Men with DM are at greater risk of ED; in a ª5 years (organic ED in ≥55%), the mean European survey [76] involving 1460 patients SHARED EFFECTS/OUTCOMES score for the IIEF EF domain at the end of with DM (34% with severe ED), DM was 12 weeks of treatment was 22.1 in the responsible for a 3- to 4-fold increase in Sildenafil, vardenafil and tadalafil are highly sildenafil group and 12.2 in the placebo group the risk of ED, particularly in men with effective in enhancing EF across a wide range (P < 0.001). neuropathy, severe depressive symptoms, of outcome measures, causes of ED, patient and/or current or former nicotine use. Men subgroups and regional populations [65–69]. Scores on the orgasmic function, intercourse with both ED and DM also report significantly Because of differences in trial designs, satisfaction, and overall satisfaction domains worse disease-specific health-related quality comparisons among the three PDE5Is across (but not the sexual desire domain) also of life [77]. studies are not feasible. Therefore, the clinical significantly improved. Pivotal RCTs with each data below cannot be presented in an entirely of the PDE5Is have shown no significant The Sildenafil Diabetes Study Group [78] parallel manner. improvement in libido among patients showed that 56% of men with ED and DM receiving active treatment compared with who received sildenafil (25–100 mg) The effects of sildenafil, vardenafil and placebo [48,74,75]. treatment for 12 weeks reported improved tadalafil have been evaluated with penile erections, in contrast to 10% of patients plethysmography in individual studies The efficacy of vardenafil was evaluated in receiving placebo (P < 0.001). In that study, [45,70–73]. Sildenafil improved nocturnal 805 men (age 57 years) with a duration of ED 61% of men randomized to sildenafil reported penile erections in men with and without of ≥2.9 years [75]. At least 54% of men in at least one successful attempt at sexual ED, and increased nocturnal penile erection each treatment group had organic ED. The intercourse, compared with 22% of controls frequency in healthy volunteers [71]. In mean IIEF EF score increased (improved) from (P < 0.001). Similarly, 452 men with ED and men with ED, vardenafil 20 mg significantly 12.8 at baseline to 21 at week 12 of vardenafil DM treated with vardenafil for 12 weeks had improved penile rigidity compared with 20 mg treatment compared with an increase significant increases in the EF domain score of placebo [45]. Similarly, in a study involving from 13.6 to only 15.0 in the placebo 5.9 for vardenafil 10 mg and 7.8 for vardenafil men with ED, tadalafil significantly improved group [75]. In addition, ª73% of patients 20 mg compared with 1.4 for placebo penile rigidity compared with placebo, and randomized to vardenafil 10 mg and 81% of (P < 0.001 for each comparison) [79]. Based this effect persisted 24 h after dosing [72]. those randomized to the 20 mg dose reported on positive responses to the GAQ after 12 that treatment improved their erections, in weeks of treatment, 54% and 72% of patients RCTs show similar efficacy and tolerability of contrast to 39% of placebo-treated patients receiving vardenafil 10 mg and 20 mg, sildenafil, vardenafil and tadalafil in men with (P < 0.001 for each comparison vs placebo). respectively, reported that their erections ED of varying severity and aetiology. Sildenafil About 40% of patients with severe ED had an were improved, in contrast to 13% of placebo
© 2005 BJU INTERNATIONAL 269 CARSON and LUE
controls (P < 0.001 for each comparison vs FIG. 10. Effects of tadalafil on successful intercourse completion with time after dosing. More than 70% of placebo) [79]. At the endpoint, 54% of attempts were successful from >30 min to 36 h after dosing. Reproduced with permission from [48]. intercourse attempts were successful in men Copyright 2002. Lippincott Williams & Willkins. All rights reserved. receiving vardenafil 20 mg and 49% in those receiving vardenafil 10 mg, compared with 100 23% in placebo controls (P < 0.001 for each 90 comparison vs placebo). Among men with 80% 80% 79% severe ED, the intercourse success rate was 80 73%
40% in patients receiving vardenafil 20 mg * compared with 11% in placebo controls g 70 (P < 0.001). 59% 60
In the study of men with ED and DM reported 50 by Sáenz de Tejada et al. [80] tadalafil 10 mg or 20 mg significantly improved the IIEF EF 40 e of successful intercourse domain score by 6.4 and 7.3, respectively, g compared with 0.1 for placebo (P < 0.001 for 30 each comparison). The EF domain scores were attempts with tadalafil 20 m
Percenta 20 similar to those reported in a retrospective analysis of 12 RCTs involving 637 men with 10 ED and DM [81]. 0 £ > -£ > -£ > -£ > -£ Sildenafil, vardenafil and tadalafil have all 30 Min 30 Min 4 h 4 h 12 h 12 h 24 h 24 h 36 h been shown to be effective therapies for men *SEP Question 3: Did your erection last long enough to have successful intercourse? with ED and DM. In addition, tadalafil was an effective treatment for ED in men with a history of microvascular complications associated with their DM; ª22% of patients of the PDE5Is results in significant A double-blind RCT involving 303 men (mean randomized had a history of diabetic improvements in EF. In an open-label age 60 years) with ED seen 12–48 months retinopathy, laser treatment for diabetic eye study of sildenafil involving 84 men (mean (mean ª25 months) after bilateral nerve- disease, or a urine microalbumin : creatinine age 62 years) with ED 2.1 years after RP, 53% sparing RP showed that treatment with ratio >3.0 [80]. On the other hand, sildenafil receiving sildenafil at 50–100 mg reported tadalafil 20 mg for 12 weeks significantly and vardenafil RCTs excluded patients with improved erections and 40% reported an enhanced EF [84]. Among all tadalafil patients, proliferative diabetic neuropathy or enhanced ability to achieve and maintain 62% reported improved erections at the autonomic neuropathy [78,79]. erections [82]. EF was directly related to the completion of study compared with 23% degree of nerve sparing, with men after of controls (P < 0.001). About 54% of Despite the favourable data for PDE5I therapy bilateral nerve-sparing tending to respond intercourse attempts resulted in successful in patients with DM, longer-term RCTs are better than those receiving unilateral or non- penetration among men randomized to needed. In the longitudinal Exploratory nerve-sparing RP. A lower pathological stage tadalafil, compared with 32% in controls Comprehensive Evaluation of Erectile and greater age were also predictive of (P < 0.001); ª41% of intercourse attempts Dysfunction study [77], men in an improved outcomes. were successfully completed among patients observational disease registry showed on tadalafil compared with 19% among substantial improvements in the EF and Therapy with vardenafil 10 and 20 mg for controls (P < 0.001) [84]. intercourse satisfaction domains of the IIEF 12 weeks also significantly enhanced EF in after 6 months of treatment, followed by 440 men with ED associated with either Treatment benefits were significant and more relapse to nearly pre-treatment levels at 12 bilateral or unilateral nerve-sparing RP [83]. pronounced in the about two-thirds of months. There was a similar relapsing trend Patients were ª60 years old and ª2 years patients capable of penile tumescence after in the Emotional Life domain of the (20 months) after RP at randomization. On RP; 71% of men on tadalafil 20 mg with Psychological Impact of Erectile Dysfunction the basis of responses to the GAQ, ª65% of tumescence after RP reported improved scale. patients who completed treatment with erections at the endpoint, compared with vardenafil 20 mg reported improved 24% of controls (P < 0.001). In these same PROSTATE CANCER erections, in contrast to 13% of placebo groups, ª69% of intercourse attempts controls (P < 0.001). At study completion, resulted in successful penetration, and 52% Because intact innervation of the penis is successful penetration was reported in 48% of attempts resulted in successful intercourse, necessary for physiological erectile responses, of attempts with vardenafil 20 mg compared at endpoint (P < 0.001 for each comparison vs substantial proportions of patients with with 22% with placebo (P < 0.001), and placebo) [84]. prostate cancer have ED after either nerve- successful intercourse in 34% of attempts sparing retropubic RP or radiation therapy. with vardenafil 20 mg (vs 10% with placebo; Based on data presented at the AUA Among such patients, treatment with each P < 0.001). meeting in 2003, early or prophylactic
270 © 2005 BJU INTERNATIONAL PHOSPHODIESTERASE TYPE 5 INHIBITORS FOR ERECTILE DYSFUNCTION
treatment of ED may promote normalization study [87], there were 21 successes from 100 ‘therapeutic probe’ for other sources of of EF after nerve-sparing RP; 67% of patients attempts with vardenafil 10 mg within 10 min discord. having bilateral nerve-sparing RP randomized of dosing, compared with 14 for placebo. to intracavernosal alprostadil injections Dividing the numerator and denominator by From the physiological standpoint, genetic (three times weekly for 6 months) recovered 4, the difference between vardenafil and polymorphisms may influence the response erections sufficient for sexual intercourse, placebo at this sample time is once again to sildenafil therapy [91,92]. Recent work compared with 20% in those with no such about two successes per 100. Because only a by a German group [91] suggested that treatment. Further, treatment of patients few more intercourse attempts are successful therapeutic responses to this PDE5I were after RP with sildenafil was associated within 1 h after PDE5I administration affected by polymorphisms in genes for with a significant increase in the return compared with placebo, it is prudent to angiotensin-converting enzyme and NOS. Lin of spontaneous erections compared recommend PDE5I dosing ª1 h or more [35] also suggested that increased cGMP with placebo. This improvement may be before attempted intercourse. levels from PDE5I treatment may increase the attributable to neuronal regeneration expression of PDE5. As this feedback loop secondary to enhanced nocturnal erection EFFICACY OF PDE5IS: POSSIBLE ensues, increasing dosages of PDE5 inhibitors oxygenation, although further studies are WITHIN-CLASS DIFFERENCES may be required to produce the desired required to test this hypothesis [85]. therapeutic effect over the long-term. Sildenafil has confirmed efficacy across a However, clinical experience does not support wide spectrum of causes of ED (particularly this concept because studies show that PDE5I ONSET OF ACTION organic) and patient nationality (Fig. 11). As efficacy is maintained during long-term reviewed by Sadovsky et al. [65], sildenafil is therapy [88,93,94]. Considerable attention has turned to the effective in patients with: cardiovascular onset of treatment effects in men with ED disease; prostate cancer (including men For men with low testosterone levels who receiving PDE5Is, even though all three receiving radiation or androgen deprivation did not respond to sildenafil, adjunctive medications have an onset of activity within therapy); spinal-cord injury; end-stage renal testosterone ‘rescue’ therapy (testosterone 20 min. The time of onset of activity is 14 min failure; major depressive disorder and gel) has been used successfully. In a RCT, 75 with sildenafil, 10 min with vardenafil and iatrogenic (selective serotonin reuptake hypogonadal men with ED and testosterone 16 min with tadalafil, using similar methods inhibitor-induced) ED; multiple sclerosis; levels of <4 mg/L who had not responded to [72,73,86]. Under the study design, patients Parkinson’s disease; and spina bifida. sildenafil therapy alone received placebo or a receive four doses of a PDE5I or placebo for Treatment with tadalafil or vardenafil is also 1% testosterone gel 5 mg daily together with at-home use as needed over a 4-week effective in men with ED with a broad sildenafil 100 mg [95]. After 12 weeks, men interval. Patients use a stopwatch and record spectrum of causes and patients from diverse receiving testosterone and sildenafil 100 mg the earliest time to an erection judged cultures [48,67–69,88]. had superior increases (improvements) in the adequate for vaginal penetration, using the EF domain of the IIEF (4.4 units) compared SEP diary. Patient and partner satisfaction, two critical with sildenafil-placebo (2.1 units; P = 0.029). components of therapeutic effectiveness, Adjunctive testosterone-sildenafil regimens In the Onset Time of Vardenafil in Men With have also been well documented with also significantly improved overall ED trial [87], 21% of intercourse attempts sildenafil. In a recent meta-analysis of 14 satisfaction and orgasmic satisfaction using vardenafil 10 mg were successfully RCTs, Montorsi and Althof [89] reported that domains, as well as other efficacy outcome completed at 10 min, compared with 14% for 74% of female partners of men aged measures, compared with sildenafil alone [95]. placebo (P < 0.025). Setting aside the <65 years who were receiving sildenafil were somewhat artificial design involving couples satisfied with treatment (i.e. EDITS score 50) in Sexual stimulation is vital because PDE5Is using stopwatches before intercourse, the contrast to 35% of partners of men receiving potentiate NO-mediated vasorelaxation only meaning of these studies is open to question, placebo (P < 0.001). Similar findings were in the presence of adequate sexual arousal. especially their use to differentiate PDE5Is. reported among partners of elderly men. Patients should also be counselled to use a For instance, in an RCT involving tadalafil Correlations between patient and partner PDE5 inhibitor several times before declaring treatment, 15.7% of intercourse attempts EDITS scores were significant (P < 0.001) in it ‘ineffective’; for instance, the cumulative were successful within 16 min after tadalafil both placebo (r = 0.80) and sildenafil probability of success with sildenafil increases 20 mg, compared with 7.7% after placebo, or treatment (r = 0.86) groups. up to 9–10 attempts, after which it stabilises ª16 successes with tadalafil and eight with [96]. placebo from 100 attempts [72]. In a review of sildenafil data [90], Seftel reported that some patients (14–47%) have The long-term efficacy and tolerability of However, by conservative estimates the true suboptimal acceptance or lack of long-term vardenafil have been reported in recent frequency per number of total doses is four adherence to therapy with sildenafil. These clinical trials ranging from 26 weeks in a USA (16/4) with tadalafil and two (8/4) with findings reflect the fact that drug adherence multicentre study [97], to 2 years in a placebo, because patients qualified with a is a complex matter, with potential European multicentre trial [88]. In the latter, single successful attempt from four doses. psychosocial and physiological 566 men age >18 years (mean ª55; range Thus, the difference between tadalafil and underpinnings. From the psychosocial 22–89) who had ED for ≥6 months in a placebo at 16 min is only two successes per perspective, restoration of EF can reveal other stable heterosexual relationship were 100 attempts. Similarly, based on the reported difficulties in a relationship, acting as a eligible, provided that they had no history
© 2005 BJU INTERNATIONAL 271 CARSON and LUE
of treatment with vardenafil or either poor FIG. 11. Efficacy of sildenafil treatment in patients participating in double-blind placebo-controlled trials. responsiveness or intolerance to sildenafil Panel A: percentage of patients responding yes to the question, ‘Did treatment improve your erections?’ Panel therapy [88]. The mean IIEF EF domain score B: patient-reported percentage of attempts at sexual intercourse that were successful during the last 4 weeks in patients randomized to vardenafil 20 mg of treatment. *P < 0.001; †P < 0.0001. Reproduced with permission from [65]. Copyright 2001. International increased from 13.8 at baseline, which is Journal of Clinical Practice. All rights reserved. consistent with moderate ED, to 25.7 at up to 2 years. The latter score approaches the Placebo Sildenafil A threshold of 26, an EF domain score defined 90 † † † as ‘no ED’ [63]. † * † 80 * † Treatment with vardenafil 20 mg more than 70 doubled the proportion of sexual intercourse 60 attempts resulting in vaginal penetration ing yes, % (SEP-Q2) or successful intercourse (SEP-Q3), d 50 to 90–94% after 2 years of treatment (Fig. 12) 40 [88]. Interestingly, 65% of patients’ sexual 30 partners reported that erections were tients respon
a 20 maintained after penetration when the P patient took vardenafil 20 mg, and 53% 10 reported that intercourse was either always or 0 almost always satisfactory. On the other hand, US UK Latin America Africa Malaysia Hong Kong Taiwan China patients reported no substantial changes in Philippines Indonesia either the ‘partnership relation’ or ‘general Singapore Thailand satisfaction’ items of the checklist [88]. This finding underscores the fact that the effects B 80 † of ED treatments on erectile responses do not † * † necessarily confer benefits to patient-partner 70 * † † relationships. † 60
Tadalafil therapy has a broader window of 50
clinical responsiveness than either sildenafil ttempts, %
a 40 or vardenafil because of its longer half-life l u (17.5 vs 4–5 h for sildenafil or vardenafil) 30
[40–42]. Tadalafil enhances EF in men with ccessf u 20 ED for up to 36 h. Thus, tadalafil may be S associated with less planning or pressure 10 to have sexual intercourse after dosing. 0 Dissociation of the sexual encounter from US UK Latin Africa Malaysia Hong Kong Taiwan China the time of taking the medication may be America Philippines Indonesia associated with greater patient and/or partner Singapore Thailand convenience.
Active comparator (crossover) trials evaluating preferences for one PDE5I over tadalafil against sildenafil cannot readily headache, dyspepsia, flushing, myalgia/back another among patients with ED receiving control for the relative novelty of the newer pain and rhinitis. In RCTs, flushing was more sildenafil or tadalafil have been conducted. In agents. Moreover, it is intrinsically difficult to common in patients receiving sildenafil or prospective randomized crossover studies compare the treatment effects of tadalafil, vardenafil, and back pain/myalgia was more involving ª600 men with ED, patients which is designed for use at a dose of either common in those receiving tadalafil. However, preferred tadalafil over sildenafil by 10 or 20 mg, with those of sildenafil, whose these events were typically mild and transient, statistically significant margins of three dose levels are more conducive to abated with time, and prompted treatment ª7 : 3 to 9 : 1, including two European titration. discontinuation in small proportions (£3%) populations [98–100]. These ratios were stable of patients [48,69,74,97]. and statistically significant irrespective of comorbidity or previous sildenafil use (Fig. 13) TOLERABILITY AND SAFETY Based on USA prescribing information for [98]. sildenafil [40], AEs occurring in ≥3% of Most AEs associated with PDE5I therapy can patients comprise headache in 16% of Despite patient preference for tadalafil over be ascribed to inhibition of PDE5 in nonpenile patients taking sildenafil compared with 4% sildenafil in these prospective clinical trials, tissues. Untoward events observed with of men receiving placebo, flushing (10% vs comparing the efficacy of either vardenafil or sildenafil, vardenafil and tadalafil include 1%), dyspepsia (7% vs 2%), and nasal
272 © 2005 BJU INTERNATIONAL PHOSPHODIESTERASE TYPE 5 INHIBITORS FOR ERECTILE DYSFUNCTION
FIG. 12. Mean per-patient response to SEP questions at baseline and after 2 years of treatment with FIG. 13. Patient preference for sildenafil vs tadalafil vardenafil 10 mg or 20 mg (last observation carried forward). Reproduced with permission from [88]. overall (A) and by comorbidities (B) and previous Copyright 2004. Blackwell Publishing Ltd. All rights reserved. sildenafil use (C). *P < 0.001. Reproduced with permission from [98]. Copyright 2003 Elsevier B.V. Vardenafil 10 mg All rights reserved. Vardenafil 20 mg 100 A 92.0 94.2 89.3 100 86.5 80 73%* 80 60
40 27% 20 60 0 47.7 Preferred sildenafil Preferred tadalafil 43.4 treatment (n = 49) treatment (n = 132) 40 B 100
n per-ptient respnse, % ‘yes’ 87%*
a 79%* 80 Me 20 15.9 17.4 60 40 21% 0 20 13% n: 252 274 252 274 251 273 251 273 0 Baseline LOCF Baseline LOCF Diabetes (n = 23) Hypertension (n = 43) SEP 2: Were you able to insert SEP 3: Did your erection last C your penis into your partner’s vagina? long enought for successful intercourse? 100 76%* 80 71%* congestion (4% vs 2%). Discontinuations due In the long-term study by Stief et al. [88], the 60 to AEs were infrequent, occurring in 2.5% of incidence of treatment-emergent AEs was 40 29% 24% patients receiving sildenafil, compared with highest within the first few weeks of 20 2.3% of patients receiving placebo [40]. vardenafil treatment, then rapidly declined 0 with further use up to 2 years. Previous sildenafil No previous Based on USA prescribing information for use (n = 118) sildenafil use (n = 63) vardenafil [42], AEs reported by ≥3% of Similar findings were recorded in an analysis patients consisted of headache in 15% of 4348 patients (age ª55 years) with mostly compared with 4% of men receiving placebo, moderate-severe ED in 17 double-blind flushing (11% vs 1%), rhinitis (9% vs 3%) and flexible-dose (25–100 mg) sildenafil RCTs DM, they excluded patients with unstable dyspepsia (4% vs 1%). ranging from 8 to 26 weeks in duration. cardiovascular disease [40–42]. Accordingly, Treatment-related AEs, including headache, PDE5Is are either not recommended or are to According to USA prescribing information for dizziness, dyspepsia, rhinitis and abnormal be used with caution in men with unstable tadalafil [41], AEs occurring in ≥3% of vision, peaked at ª15% during the first angina, recent myocardial infarction (MI), patients comprised headache in 11–15% of 2 weeks of treatment and declined to ª4% at cardiac failure, life-threatening/uncontrolled patients taking tadalafil at as-needed doses of treatment weeks 6–8. The AE rate ¥ time plots arrhythmia, poorly controlled blood pressure 5, 10 or 20 mg, compared with 5% of men showed a bimodal distribution, with a second (resting blood pressure <90/50 mmHg or receiving placebo; dyspepsia (4–10% vs 1%); peak (AE rate ª8%) at treatment weeks 8–10. >170/100–110 mmHg) and/or heart failure back pain (3–6% vs 3%); and myalgia (1–4% Maximum AE rates with sildenafil were 1.2% [40–42]. In addition, patients with left- vs 1%). for abnormal vision and 1.8% for dyspepsia ventricular outflow obstruction secondary to over treatment weeks 0–2, 0.8–1.0% at weeks aortic stenosis or idiopathic hypertrophic Long-term studies of sildenafil [101], 8–10, and <1% at weeks 12–14. In all, 1.4% of subaortic stenosis, as well as men with vardenafil [88], and tadalafil [94] found patients discontinued sildenafil or placebo severe autonomic insufficiency, may be similar AE profiles compared with those because of AEs [102]. especially sensitive to the vasodilator effects described above. Because tadalafil and of PDE5Is. vardenafil have been available for a shorter SAFETY time than sildenafil, these agents may not Consensus guidelines have been issued for have been on the market long enough to Although clinical trials of sildenafil, risk-stratifying and counselling patients with discern differences (vs sildenafil) in their vardenafil, and tadalafil included many concomitant sexual dysfunction and safety profiles, particularly for infrequent AEs. patients with cardiovascular disease and cardiovascular disease [103]. Men with ED,
© 2005 BJU INTERNATIONAL 273 CARSON and LUE
particularly those with concomitant Even at supra-therapeutic doses consistent enlargement or other abnormalities; and cardiovascular disorders, need to be with concomitant treatment using signs or symptoms indicative of counselled that there is a transient increase in cytochrome P450 inhibitors or the presence hypogonadism. In such cases, further the relative risk of cardiovascular events of renal impairment, none of the PDE5Is diagnostic evaluation should be undertaken. during and within ª2 h after sexual increases the QTc interval in a clinically intercourse. However, the absolute risk of significant manner [41,109,110]. Neither Whether to screen all patients with ED for having a MI within each hour after sexual sildenafil 50–400 mg nor vardenafil hypogonadism, as well as the threshold activity is considered to be low in otherwise 10–80 mg increased the absolute QT interval, testosterone level below which exogenous healthy men with ED. Patients experiencing and each agent modestly prolonged the QTcF testosterone should be administered, are cardiac symptoms when initiating sexual (Fridericia-corrected) interval 1 h after dosing complex and controversial matters. Certain activity should be counselled to seek medical in healthy men aged 45–60 years (mean 53) investigators contend that circulating attention immediately and abstain from [109]. At 1 h after a 50-mg dose of sildenafil, testosterone should be determined in all men further sexual activity. the uncorrected QT interval changed by a aged > 50 years, but only in the presence of mean of -2 ms, the linear QT interval (QTci) by low libido or abnormal physical examinations Exercise echocardiographic studies show that 4 ms, and the QTcF interval by 6 ms compared (e.g. atrophic testes <19 mL) in younger men. treatment with sildenafil 50–100 mg, with placebo; corresponding values for a The presence of low testosterone (<300 ng/ vardenafil 10 mg or tadalafil 10 mg did not supra-therapeutic 400 mg dose were -1, 6 dL) may warrant further endocrine adversely affect haemodynamic variables, and 9 ms. At 1 h after a 10-mg dose of assessments, including prolactin and LH exercise capacity (treadmill time), and/or time vardenafil, the uncorrected QT interval levels, and other testing. to cardiac ischaemia (or first awareness of changed by -2 ms, the QTci interval by 4 ms angina) in patients with stable coronary artery and the QTcF interval by 8 ms compared with Investigators have voiced concerns that long- disease [41,104,105]. placebo; corresponding values for a supra- term testosterone replacement may unmask therapeutic 80 mg dose were -2, 6 and 10 ms occult neoplasms, particularly prostate In sildenafil and tadalafil clinical trials [109]. In a separate study of tadalafil at a carcinomas. Cancer of the prostate or breast reported to date, the incidence rates of MI single oral dose of 100 mg, the mean change contraindicates testosterone replacement were low and similar to those with placebo, in QTcF for tadalafil relative to placebo therapy, and both baseline and on-treatment i.e. 0.53/100 patient-years for patients taking was 3.5 ms, and the mean change in the monitoring of haemoglobin, haematocrit, and sildenafil in open-label studies and 0.80/100 individually corrected QT interval was 2.8 ms prostate changes by a DRE, PSA assay, voiding patient-years for those receiving sildenafil in relative to placebo. In addition, torsade de changes and/or prostate biopsy, are RCTs (P = 0.88 vs 0.84/100 patient-years with pointes has not been reported in studies of recommended. placebo) [106]. The overall incidence rate of sildenafil, vardenafil or tadalafil [41,109,110]. MI across 43 clinical trials in tadalafil-treated The clinician should attempt to involve both patients was 0.33/100 patient-years: 0.36/100 The systemic exposures of PDE5Is may be the patient and his partner (if available) in patient-years in open-label studies and increased in patients with renal insufficiency treatment planning. When considering the 0.26/100 patient-years in RCTs (vs 0.41/100 and/or hepatic impairment. Starting or other range of treatment options (Fig. 14B) [111], it patient-years for placebo controls) [107]. The doses of PDE5Is may need to be limited to is important to assess the couple’s treatment slight disparities between MI incidence rates sildenafil 25 mg, vardenafil 5 mg or tadalafil goals, expectations, and preferences. across sildenafil and tadalafil trials may 5–10 mg in certain patients with these reflect differences in age or other patient conditions [40–42]. Focus-group research shows that patients opt characteristics at baseline. for different ED treatments based on a wide range of lifestyle considerations that are not There is a first-dose haemodynamic effect in DIAGNOSIS AND TREATMENT OPTIONS strictly medical. These include the relative patients taking vardenafil 10 mg; in a FOR MEN WITH ED costs, reversibility, discretion, simplicity randomized crossover multiple-dose of the regimen, long-term risk and partner comparison, 35 men with ED also received The first step in evaluating and treating ED is acceptability of treatment. The assessment three doses of sildenafil 50 mg weekly [108]. to conduct a thorough history and focused and treatment planning phases offer Changes in blood pressure and heart rate physical examination (Fig. 14A) [111]; the opportunities for patient and partner after the first dose of vardenafil were greater latter should be used in every patient with ED, counselling, including the necessity for than those after the first dose of sildenafil. and should include an assessment of body adequate sexual stimulation to promote Heart rate increased by 3.1 beats/min, habitus (secondary sexual characteristics) and PDE5I efficacy. Counselling should be while systolic blood pressure decreased by an evaluation of the cardiovascular, tailored to the individual cultural, religious 8.02 mmHg and diastolic blood pressure by neurological and genitourinary systems, and lifestyle patterns and needs of each 6.6 mmHg. Syncope was reported in three focusing on penile, testicular and rectal couple. (8.6%) patients after the first dose of examinations. Blood pressure and heart rate vardenafil [108]. However, two of these three should be measured if not assessed in the Lifestyle modification may be advised for patients received concomitant therapy with previous 3–6 months. In conducting the patients who smoke, abuse alcohol, or lead doxazosin for BPH. In the USA, vardenafil physical examination, special attention sedentary lifestyles. However, in large-scale treatment is contraindicated in patients should be given to signs of penile abnormality longitudinal epidemiological studies involving treated with a-adrenergic blockers [42]. (e.g. Peyronie’s disease); prostatic men in middle age at baseline, only increased
274 © 2005 BJU INTERNATIONAL PHOSPHODIESTERASE TYPE 5 INHIBITORS FOR ERECTILE DYSFUNCTION
FIG. 14. Algorithms for assessing (A) and treating (B) ED, from the Second International Consultation on Erectile Dysfunction of the WHO. From [111]. Copyright 2004 Journal of Sexual Medicine. All rights reserved.
A
physical activity has been associated with the surgery or implantation of a penile prosthesis over PDE6 compared with sildenafil, and UK- reversal of ED. In a recent clinical study, is a potential option. 357903, which has been well tolerated in weight loss improved EF in about a third of human studies [114]; Bristol-Myers Squibb’s obese patients [112]. On multivariate analysis, FUTURE PROSPECTS BMS-341400; FR229934, which has been in- increased physical activity and reduced body licensed from Fujisawa Pharmaceutical by TAP mass index were significant independent Other PDE5Is with potentially enhanced Pharmaceuticals (Abbott Laboratories and predictors of increases (improvements) in the pharmacological properties are under Takeda Chemical Industries Ltd); and E-8010, IIEF EF domain. clinical and experimental investigation for which is under late-stage clinical treating ED. Successful introduction and development by Eisai. Patients or partners who are dissatisfied with commercialization of these agents may assist the outcome of PDE5I treatment, or in whom in further bridging the gap in treating ED. Oral and transurethral TA-1790, an such therapy is contraindicated, are typically Enhanced therapeutic options will probably experimental PDE5I, is also under referred to a urologist. Such specialists may bring more patients to their physician’s investigation by Vivus. Oral TA-1790, recommend the use of a vacuum erection or offices, while enhanced supportive care which is in phase II development, has high constriction device, or more invasive medical will probably remain important to facilitate PDE5 : PDE6 selectivity and less pronounced therapies such as cavernosal injections or couples’ transitions from avoidance and/or declines in systemic blood pressure (vs transurethral suppositories of vasoactive abstinence to greater intimacy [113]. sildenafil) when co-administered with organic agents (e.g. PGE1, alprostadil). For the small nitrates in preclinical studies. Vivus also minority of patients with ED that is refractory Investigational PDE5Is for ED include Pfizer’s manufactures the Medicated Urethral System to the foregoing treatments, penile vascular UK-343664, which is more selective for PDE5 for Erection (MUSE®) for transurethral
© 2005 BJU INTERNATIONAL 275 CARSON and LUE
FIG. 14. Continued electrical field stimulation [15]. Also promising are potentially ‘curative’ B treatments, such as gene or growth factor therapies, including vascular endothelial growth factor for vasculogenic ED, brain- derived neurotrophic factor for neurogenic ED, as well as eNOS, calcitonin-gene related peptide, and intracavernosal potassium- channel openers for general ED.
CONCLUSIONS
The assessment and treatment of ED confer unique clinical opportunities to enhance health and well-being. Because a dysregulated NO-cyclic nucleotide signalling pathway is a pivotal pathophysiological factor in many forms of ED, treatments that up- regulate this pathway represent promising pharmacological avenues. Of all therapies, none has met with greater clinical success, or transformed the treatment landscape in more fundamental ways, than the PDE5I sildenafil. However, patient acceptance of and adherence to even the most effective and well-tolerated therapies for ED are largely influenced by other than medical (lifestyle) factors. The recent advent of the highly effective and well-tolerated PDE5Is vardenafil and tadalafil, and potential agents now in clinical development, may assist clinicians in tailoring treatment regimens to the unique needs of each couple.
ACKNOWLEDGEMENTS
This review was solicited by BJU Int and was supported by Lilly ICOS LLC (Indianapolis, IN, and Bothell, WA). Assistance in the preparation of this manuscript was provided by Stephen W. Gutkin, Rete Biomedical Communications Corp., Ridgewood, NJ.
Culley Carson is a paid consultant to Lilly, GSK and Pfizer.
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280 © 2005 BJU INTERNATIONAL Original Article CA IX AND MOLECULAR MARKERS IN RCC LEPPERT et al.
The use of carbonic anhydrase IX as Carbonic anhydrase IX and the future a promising molecular marker in RCC is described by authors from of molecular markers in renal Los Angeles, who discuss the cell carcinoma promise that molecular markers hold to improve diagnosis, staging, JOHN T. LEPPERT, JOHN S. LAM, ALLAN J. PANTUCK, ROBERT A. FIGLIN* and treatment, surveillance and ARIE S. BELLDEGRUN survival of patients with RCC. Departments of Urology and *Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Accepted for publication 21 April 2005 There is a whole range of new treatments being introduced in the management of metastatic renal KEYWORDS of CA IX and discuss the promise that cancer. The use of VEGF–targeted molecular markers hold to revolutionise the therapy has particular importance, kidney cancer, molecular markers, carbonic diagnosis, staging, treatment, surveillance anhydrase IX, staging, targeted therapy and survival of patients with RCC. especially as it has a strong genetically linked rationale for its potential success in this area. INTRODUCTION THE DEVELOPMENT OF STAGING SYSTEMS: FROM MACRO TO MICRO Authors from the USA show that Cancer of the kidney and renal pelvis is TO MOLECULAR substantial clinical activity has estimated to account for 36 160 new cases been reported in initial clinical and 12 660 deaths in the USA in 2005 [1]. RCC RCC staging systems have developed in trials. is a highly aggressive tumour; a third of parallel with the rapid increase in patients will have evidence of metastasis at understanding of the tumour biology of the time of diagnosis [2] and >40% of kidney cancer. The first formal staging In prostate cancer, drugs targeting patients with RCC will die from their disease systems, proposed by Flocks and Kadesky microtubules, such as taxanes, have [3]. Advances in imaging, staging and [6] and later modified by Robson [7], used already been introduced clinically, treatment have resulted in improved survival the anatomical information available to for a selected group of patients and an overall clinicians at the time. Numerous refinements and their success has received change in the natural history of RCC [4]. have led to the current TNM system proposed widespread attention. A new group Future advances will require a deeper by the Union Internationale Contre le of drugs, the epothilones, have understanding of the genetic and protein- Cancer [8]. Integrated staging systems were then developed from numerous non- similar but not identical binding expression profile of each histological type of RCC. A molecular profile of each tumour will anatomical variables that were shown to properties to microtubules, and probably improve treatment and guide be prognostic indicators for RCC. For authors from the USA describe how patient selection for targeted therapies. example, the University of California Los they have shown activity in Carbonic anhydrase IX (CA IX) is the most Angeles (UCLA) Integrated Staging System significant molecular marker for RCC to date. (UISS) supplements the anatomical TNM hormone-refractory prostate CA IX is located downstream of the von staging with the Eastern Cooperative cancer, and are moving to phase III Hippel-Lindau (VHL) tumour-suppressor gene Oncology Group (ECOG) performance status testing. and is activated by the hypoxia-inducible and the Fuhrman grade [9] of the tumour [10]. pathway [5]. The highly specific expression The UISS is a powerful tool for assessing pattern of CA IX has affected the diagnosis, patients with localized and metastatic RCC staging and treatment selection for patients [11]. Inclusion of important genetic and with RCC. We present a comprehensive review protein molecular markers, such as CA IX,
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represents the next advance in RCC staging FIG. 1. The ras/raf and AKT pathways are activated through tyrosine kinase receptors. These pathways up- systems [12]. regulate the expression of HIF-1a. In hypoxia, or through loss of VHL function, HIF-1a can translocate into the nucleus and act as a master transcription regulator, leading to the production of CA IX.
CA IX
The CA family comprises enzymes that catalyse the reversible conversion of carbon dioxide and water to carbonic acid. CA IX is a transmembrane enzyme that is thought to play a role in the adaptation of tumours to hypoxic conditions, by regulating the pH of the intracellular and extracellular compartment [13]. CA IX expression by normal tissues is limited to the gastrointestinal tract, gallbladder and pancreatic ducts [14]. There is over-expression of CA IX in tumours of the kidney, cervix, breast, lung, oesophagus, stomach, biliary tree, colon, bladder and skin [13,14]. Furthermore, it is also over-expressed in RCC specimens [15]. CA IX is not expressed by normal fetal or adult kidney specimens, suggesting that it has no role in organogenesis, but rather is a product of tumour biology [16]. CA IX expression varies among different kidney tumours. There is positive immunohistochemical staining in clear cell, granular, spindle and papillary RCC, but not in chromophobe RCC and oncocytomas [17]. The expression of CA IX is regulated by hypoxia [18] through hypoxia-inducible factor 1-a (HIF-1a) [19]. Loss of function of the VHL tumour suppressor gene, either by mutation or hypermethylation, can also lead to HIF-1a accumulation [20], and up-regulation of CA IX expression (Fig. 1). Restoring VHL function in RCC cell lines down-regulates CA IX expression to normal levels [21]. The clear cell subtype of RCC is genetically linked with the loss of VHL function and is commonly associated with a hypoxic tumour microenvironment. CA IX expression serves as a strong biomarker for kidney cancer and is particularly important for clear cell RCC.
CA IX AND RCC STAGING
The first report of CA IX immunohistochemistry in RCC found positive expression in 46 of 47 primary and seven of eight metastatic lesions [22]. A study at UCLA confirmed the high specificity of CA IX staining, with 94% of clear cell RCC specimens staining positively; CA IX expression was uniformly negative in normal
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FIG. 2. Lack of CA IX expression in a representative tissue core from normal kidney, ¥ 100 (1) and ¥ 400 (2). CA IX AND RESPONSE TO INTERLEUKIN-2 There is intense membranous CA IX staining, representative of >85% expression, in clear cell RCC (3, 4). CA IX expression also predicts the response to interleukin-2-based immunotherapy. In a cohort of patients from UCLA, all patients with a complete response to interleukin-2- based regimens had high CA IX expression (>85%) [23]. Using an identical threshold of 85%, Atkins et al. [27] showed that tumour specimens with high CA IX expression were significantly more likely in patients who had a complete or partial response to high-dose interleukin-2-based therapy (odds ratio 3.3). This higher response rate was associated with a significant survival benefit and survival for >5 years was limited to patients with high CA IX-expressing tumours. Importantly, the association between CA IX expression and patient response to interleukin-2-based therapy is maintained across the various histological subtypes of RCC, e.g. papillary and chromophobe subtypes respond poorly to interleukin-2 and have little to no CA IX expression. Response to interleukin-2-based therapy is modest and treatment with interleukin-2 is associated with significant morbidity [28]. The ability to select a patient kidney tissue [23]. Recursive partitioning incorporating a host of markers associated group with higher response rates to survival-tree analysis [24] defined a threshold with the development of malignancies. interleukin-2 will decrease unnecessary of 85% expression as the optimum to Immunohistochemical analysis of Ki-67, p53, exposure of patients to treatment toxicity. differentiate disease-free survival (Fig. 2). gelsolin, CA IX, CA XII, PTEN, EpCAM [26], and This approach will also maximize the benefit Patients with metastatic RCC and <85% CA IX vimentin was performed on a custom tissue of interleukin-2-based immunotherapy, expression had a significantly worse disease- microarray using clear cell RCC specimens increasing response rates among patients free survival (hazard ratio 3.1, 95% CI 1.99– from 318 patients [12]. Increased staining for selected for treatment. Molecular markers 4.83) in a multivariate analysis controlling for Ki-67, p53, vimentin and gelsolin correlated will play a significant role in selecting patients tumour T stage, Fuhrman grade, nodal with worse survival, while the inverse was for interleukin-2-based immunotherapy and involvement and performance status. Low CA true for CA IX, PTEN, CA XII and EpCAM. In for the numerous emerging targeted IX expression was also associated with a multivariate analysis, CA IX, vimentin and p53 therapies. worse prognosis for patients with clinically were statistically significant predictors of localized high-risk tumours [23]. survival, independent of the tumour T stage, the presence of metastasis, ECOG CA IX AS A POTENTIAL performance status and Fuhrman grade. A THERAPEUTIC TARGET prognostic model was then constructed using MULTIPLE-MARKER STAGING SYSTEMS a combination of clinical variables and marker The highly specific expression of CA IX by INCORPORATING CA IX data. This nomogram was calibrated, using RCC makes it an attractive candidate for bootstrap bias-corrected estimates, to be vaccine development. Being important in High-throughput tissue-array analysis has accurate to within 10% of the actual 2- and RCC tumour biology, CA IX provides a ultimately allowed for the simultaneous study 4-year survival rates. This integrated rationale, beyond functioning merely as a of multiple molecular markers in hundreds of molecular model provides more accurate tumour-associated antigen (TAA), for its tissue specimens. A natural extension of this prognostic information than standard clinical use as a target for immunotherapy [5]. CA technology is the creation of molecular predictors such as TNM stage, histological IX-derived CD8+ and CD4+ T cell epitopes staging systems that integrate multiple grade and ECOG performance status. The have been reported, which are immunogenic markers with traditional prognostic variables. ability to predict survival based entirely on and can induce CA IX-specific T cells in vitro CA IX expression has been combined with protein expression and to improve traditional [29,30]. CA IX-transduced peripheral blood Ki67, a marker of cellular proliferation, to staging systems with protein expression monocytes have generated cytotoxic T further stratify patients into low- (high CA IX/ information are dramatic examples of the cell lymphocytes capable of lysing CA IX low Ki67), intermediate- (high Ki67 or low CA potential of molecular marker technology and expressing cancer cells [31]. To enhance IX) and high-risk (high Ki67/low CA IX) groups its important future role in RCC staging immunogenicity, a granulocyte macrophage [25]. A multimarker model was created, systems. colony-stimulating factor (GM-CSF)-CA IX
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fusion molecule has been created [31–33]. therapy, including markers of angiogenesis, 3 Janzen NK, Kim HL, Figlin RA, This dual-delivery strategy provides the the AKT/mTOR pathway and NFkB [5]. Agents Belldegrun AS. Surveillance after radical TAA with an immunomodulating agent for targeting angiogenesis pathways, vascular or partial nephrectomy for localized renal antigen-presenting cells. The GM-CSF-CA endothelial growth factor (VEGF)-A and the cell carcinoma and management of IX molecule was delivered using plasmid or family of tyrosine kinase receptors are recurrent disease. Urol Clin North Am adenovirus vectors. Interestingly, CA IX was currently undergoing clinical trials. Antibody 2003; 30: 843–52 the only TAA common to all the tumour therapy against VEGF-A has already shown a 4 Pantuck AJ, Zisman A, Belldegrun lysates used to generate antitumour response longer time to progression for patients with AS. The changing natural history of using this fusion-protein strategy [32]. metastatic clear cell RCC [39]. As new renal cell carcinoma. J Urol 2001; 166: Other targeted strategies involve direct therapies are discovered and tested in clinical 1611–23 administration of anti-CA IX antibodies. The trials, it will become increasingly important to 5 Pantuck AJ, Zeng G, Belldegrun AS, first CA IX antibody (G250) was generated understand the protein expression of these Figlin RA. Pathobiology, prognosis, and from the immunisation of mice with drug targets to guide the selection of patients targeted therapy for renal cell carcinoma: human RCC homogenates [22]. WX-G250, or most likely to benefit from these promising exploiting the hypoxia-induced pathway. Rencarex® (Wilex, Germany), is a humanized agents. Clin Cancer Res 2003; 9: 4641–52 chimeric version of this antibody. Early studies 6 Flocks RH, Kadesky MC. Malignant showed WX-G250 treatment to be well neoplasms of the kidney; an analysis of tolerated in 36 patients, resulting in one CONCLUSION 353 patients followed five years or more. complete response, one partial regression J Urol 1958; 79: 196–201 and 11 patients with stable disease [34]. A High-throughput tissue arrays have 7 Robson CJ, Churchill BM, Anderson W. phase III clinical trial, the Adjuvant Rencarex facilitated the rapid analysis of potential The results of radical nephrectomy for (WX-G250) Immunotherapy Phase III trial to molecular markers. CA IX can be used to renal cell carcinoma. J Urol 1969; 101: Study Efficacy in nonmetastatic RCC (ARISER), predict survival in patients with metastatic 297–301 is currently enrolling patients investigating clear cell RCC and response to interleukin-2- 8 Guinan P, Sobin LH, Algaba F et al. this approach in an adjuvant setting. based immunotherapy. Staging systems TNM staging of renal cell carcinoma: incorporating CA IX with Ki67 and other Workgroup, 3. Union International Contre molecular markers are demonstrably better le Cancer (UICC) and the American Joint CA IX TARGETED IMAGING AND than traditional clinical nomograms. Committee on Cancer (AJCC). Cancer RADIOIMMUNOTHERAPY Combining tumour anatomy, pathology, 1997; 80: 992–3 histology and molecular profiling has allowed 9 Fuhrman SA, Lasky LC, Limas C. RCC lesions are also being targeted by for further refinement of staging constructs. Prognostic significance of morphologic coupling radioisotopes to antibodies directed Molecular markers, e.g. CA IX, represent parameters in renal cell carcinoma. Am J against CA IX (131I-mG250) [35]. Early phase attractive targets for directed imaging, Surg Pathol 1982; 6: 655–63 I/II clinical trials confirmed the accurate immunotherapy, and the development of 10 Zisman A, Pantuck AJ, Dorey F et al. imaging of lesions of >2 cm. There were novel vaccines and pharmaceuticals. The Improved prognostication of renal cell several minor tumour responses, with an understanding of tumour biology gleaned carcinoma using an integrated staging apparent improvement in survival compared from molecular marker research will be system. J Clin Oncol 2001; 19: 1649– with historical trials [36]. These trials were critical to the future treatment of patients 57 limited by the development of human with RCC and for the development of a cure 11 Patard JJ, Kim HL, Lam JS et al. Use of antimouse antibodies targeting the murine for kidney cancer. the University of California Los Angeles G250 antibody. A humanized chimeric version integrated staging system to predict of the antibody (cG250) was created to avoid survival in renal cell carcinoma: an this immune response and to increase the CONFLICT OF INTEREST international multicenter study. J Clin maximum tolerated dose of the antibody [37]. Oncol 2004; 22: 3316–22 131I-labelled cG250 also has excellent imaging None declared. Source of funding: supported 12 Kim HL, Seligson D, Liu X et al. Using characteristics with no evidence of host in part by The Richard and Nancy Bloch protein expressions to predict survival in response, and a phase I/II clinical trial is Kidney Cancer Research Fund. clear cell renal carcinoma. Clin Cancer Res currently enrolling patients [38]. The 2004; 10: 5464–71 techniques used to harness the selective 13 Potter C, Harris AL. Hypoxia inducible expression of CA IX for imaging and the REFERENCES carbonic anhydrase IX, marker of tumour delivery of therapeutic agents could also be hypoxia, survival pathway and therapy applied to any emerging molecular marker. 1 Jemal A, Murray T, Ward E et al. Cancer target. Cell Cycle 2004; 3: 164–7 statistics, 2005. 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expression as a potential biomarker in 25 Bui MH, Visapaa H, Seligson D et al. based on the granulocyte-macrophage renal cell carcinoma. BJU Int 1999; 83: Prognostic value of carbonic anhydrase IX colony-stimulating factor and carbonic 743–7 and KI67 as predictors of survival for renal anhydrase IX fusion gene. Clin Cancer Res 16 Pastorekova S, Parkkila S, Parkkila AK clear cell carcinoma. J Urol 2004; 171: 2003; 9: 1906–16 et al. Carbonic anhydrase IX, MN/CA IX. 2461–6 34 Bleumer I, Knuth A, Oosterwijk E et al. A Analysis of stomach complementary DNA 26 Seligson DB, Pantuck AJ, Liu X et al. phase II trial of chimeric monoclonal sequence and expression in human and Epithelial cell adhesion molecule (KSA) antibody G250 for advanced renal cell rat alimentary tracts. Gastroenterology expression. Pathobiology and its role as an carcinoma patients. 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The role of interferon and G250 in metastatic renal cell carcinoma. Res 2000; 60: 7075–83 interleukin-2 in the immunotherapeutic Clin Cancer Res 1998; 4: 2729–39 19 Grabmaier KMC, AdW, Verhaegh GW, approach to renal cell carcinoma. Semin 37 Steffens MG, Boerman OC, Oosterwijk- Schalken JA, Oosterwijk E. Strict Oncol 1991; 18 (Suppl. 7): 102–7 Wakka JC et al. Targeting of renal cell regulation of CAIX (G250/MN) by HIF- 29 Vissers JL, De Vries IJ, Schreurs MW carcinoma with iodine-131-labeled 1alpha in clear cell renal cell carcinoma. et al. The renal cell carcinoma-associated chimeric monoclonal antibody G250. Oncogene 2004; 23: 5624–31 antigen G250 encodes a human leukocyte J Clin Oncol 1997; 15: 1529–37 20 Mandriota SJ, Turner KJ, Davies DR et al. antigen (HLA)-A2.1-restricted epitope 38 Divgi CR, O’Donoghue JA, Welt S et al. HIF activation identifies early lesions in recognized by cytotoxic T lymphocytes. Phase I clinical trial with fractionated VHL kidneys: evidence for site-specific Cancer Res 1999; 59: 5554–9 radioimmunotherapy using 131I-labeled tumor suppressor function in the 30 Vissers JL, De Vries IJ, Engelen LP et al. chimeric G250 in metastatic renal cancer. nephron. Cancer Cell 2002; 1: 459–68 Renal cell carcinoma-associated antigen J Nucl Med 2004; 45: 1412–21 21 Ivanov SV, Kuzmin I, Wei MH et al. G250 encodes a naturally processed 39 Yang JC, Haworth L, Sherry RM et al. Down-regulation of transmembrane epitope presented by human leukocyte A randomized trial of bevacizumab, an carbonic anhydrases in renal cell antigen-DR molecules to CD4(+) T anti-vascular endothelial growth factor carcinoma cell lines by wild-type von lymphocytes. Int J Cancer 2002; 100: antibody, for metastatic renal cancer. Hippel-Lindau transgenes. Proc Natl Acad 441–4 N Engl J Med 2003; 349: 427–34 Sci USA 1998; 95: 12596–601 31 Mukouyama H, Janzen NK, Hernandez 22 Oosterwijk E, Ruiter DJ, Hoedemaeker JM et al. Generation of kidney cancer- Correspondence: Arie S. Belldegrun, PJ et al. Monoclonal antibody G 250 specific antitumor immune responses Department of Urology, David Geffen School recognizes a determinant present in using peripheral blood monocytes of Medicine at UCLA, 10833 Le Conte Avenue, renal-cell carcinoma and absent from transduced with a recombinant 66–118 CHS, Box 951738, Los Angeles, CA normal kidney. Int J Cancer 1986; 38: adenovirus encoding carbonic anhydrase 90095–1738, USA. 489–94 9. Clin Cancer Res 2004; 10: 1421–9 e-mail: [email protected] 23 Bui MH, Seligson D, Han KR et al. 32 Tso CL, Zisman A, Pantuck A et al. Carbonic anhydrase IX is an independent Induction of G250-targeted and Abbreviations: CA IX, carbonic anhydrase IX; predictor of survival in advanced renal T-cell-mediated antitumor activity VHL, von Hippel-Lindau; UCLA, University of clear cell carcinoma: implications for against renal cell carcinoma using a California Los Angeles; UISS, UCLA Integrated prognosis and therapy. Clin Cancer Res chimeric fusion protein consisting of Staging System; ECOG, Eastern Cooperative 2003; 9: 802–11 G250 and granulocyte/monocyte-colony Oncology Group; HIF-1a, hypoxia-inducible 24 Liu X, Minin V, Huang Y, Seligson DB, stimulating factor. Cancer Res 2001; 61: factor 1a; TAA, tumour-associated antigen; Horvath S. Statistical methods for 7925–33 GM-CSF, granulocyte macrophage colony- analyzing tissue microarray data. 33 Hernandez JM, Bui MH, Han KR et al. stimulating factor; VEGF, vascular endothelial J Biopharm Stat 2004; 14: 671–85 Novel kidney cancer immunotherapy growth factor.
© 2005 BJU INTERNATIONAL 285 Original Article VEGF-TARGETED THERAPY IN RCC RINI et al.
Therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: biology, clinical results and future development
BRIAN I. RINI, JEFFREY A. SOSMAN* and ROBERT J. MOTZER† Taussig Cancer Center, Cleveland Clinic Foundation, the *Vanderbilt Ingram Cancer Center and †Memorial Sloan-Kettering Cancer Center, USA Accepted for publication 20 April 2005
KEYWORDS VEGF expression is regulated by several initial target in CCRCC. Examination of RCC factors. Pertinent to RCC, VEGF expression tumours for VEGF (mRNA transcripts and/or RCC, VEGF, VHL, bevacizumab, SU11248, BAY results from inactivation of the von Hippel- VEGF protein) show VEGF overexpression in 43–9006 Lindau (VHL) tumour- suppressor gene the vast majority of samples [9]. observed in most RCC (see below), thus identifying VEGF as a particularly relevant Taken together, these data provide compelling INTRODUCTION therapeutic target in RCC. evidence for VHL inactivation in most CCRCC tumours, leading to VEGF overexpression that A limited subset of patients with metastatic drives tumour angiogenesis. Thus, inhibiting RCC obtain clinically meaningful benefit BIOLOGY OF VEGF EXPRESSION IN RCC VEGF has been pursued as a therapeutic from standard interleukin-2 and/or target in RCC. interferon-a therapy [1]. A growing Patients with an inherited mutation of the understanding of the underlying biology VHL gene often develop clear-cell RCC of RCC has identified vascular endothelial (CCRCC) tumours. VHL syndrome kindreds CLINICAL RESULTS OF VEGF-TARGETED growth factor (VEGF) as a logical therapeutic were subsequently investigated and the VHL THERAPY IN RCC target. Therapy directed against the biological gene mapped to chromosome 3p25–26 [8]. In activity of VEGF has undergone initial clinical sporadic (not inherited) CCRCC, there is also Strategies to inhibit VEGF in RCC, including testing in metastatic RCC, with evidence of a VHL gene inactivation through mutation or binding of the VEGF protein, blockade of the substantial antitumour effect; further methylation in most tumours [9]. Non-clear VEGF receptor, or inhibiting VEGF receptor investigation is ongoing. cell RCC tumours do not have VHL gene signalling through their tyrosine kinases, have abnormalities in structure or expression. recently been tested clinically in metastatic RCC. Table 1 summarizes the clinical data VEGF on selected anti-VEGF agents in RCC. BIOLOGICAL CONSEQUENCES OF VHL GENE Comparison of anti-VEGF agents is not VEGF is a glycoprotein that is critically INACTIVATION IN RCC currently possible because separate studies important in both normal and tumour- have used different patient selection, associated angiogenesis through several The VHL gene encodes a 213 amino acid methods and outcome criteria. Nonetheless, mechanisms: increased microvascular protein (pVHL); in conditions of normoxia and there is significant antitumour activity (both permeability to plasma proteins [2], induction normal VHL gene function, pVHL is the objective responses, and tumour regression of endothelial cell division and migration [3,4], substrate-recognition component of a not meeting criteria for response, recorded as promotion of endothelial cell survival through ubiquitin-ligase complex that targets a stable disease), placing VEGF blockade protection from apoptosis [5] and reversal of protein transcription factor, hypoxia- strategies at the forefront of the clinical endothelial cell senescence [6]. VEGF exerts its inducible factor (HIF), for proteolysis [10–12]. investigation of RCC. biological effect through interaction with In conditions of hypoxia or with defective receptors present on the cell surface. These pVHL function, HIF is constitutively transmembrane tyrosine kinase receptors activated and not broken down through ANTI-VEGF ANTIBODY (BEVACIZUMAB) include VEGFR-1 (Flt-1) and VEGFR-2 (KDR/ the proteosome, leading to increased Flk-1), selectively expressed on vascular transcription of hypoxia-inducible genes A recombinant human monoclonal antibody endothelial cells [7]. Upon binding of VEGF to [13,14]. Several hypoxia-inducible genes are against VEGF (rhuMAb VEGF, bevacizumab; the extracellular domain of its receptor, activated by this process, including VEGF Avastin®, Genentech, South San Francisco, dimerization and autophosphorylation of the [13,14], platelet-derived growth factor (PDGF) CA) binds and neutralises all biologically intracellular receptor tyrosine kinases occurs, [15], TGF, erythropoietin, chemokine receptor active isoforms of VEGF [16]. This humanized and a cascade of downstream proteins are 4 and carbonic anhydrase 9, which could play antibody inhibits bovine capillary endothelial activated. These protein cascades promote the a role in the pathogenesis and clinical cell proliferation in response to VEGF, and has pro-angiogenic endothelial cell effects noted features of CCRCC. Among these VHL- antitumour effects in sarcoma and breast above. mediated genes, VEGF has emerged as an cancer cell lines [16].
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TABLE 1 A summary of clinical results with VEGF-targeting agents in metastatic RCC
Agent Trial design Clinical activity Common toxicity VEGF-binding antibody Bevacizumab Randomized, placebo-controlled 10% response rate (WHO criteria) Hypertension, proteinuria trial; all patients pre-treated Delay of time to progression vs placebo (2.5 vs 4.9 months) Bevacizumab Single-arm phase II 21% response rate (RECIST criteria) Rash, hypertension, proteinuria + erlotinib 32% pre-treated VEGF receptor inhibitors SU11248 Single-arm phase II, all pre-treated 33% response rate (RECIST criteria) Fatigue/asthenia, nausea, diarrhoea, stomatitis BAY 43–9006 Randomized discontinuation design 15% response rate (WHO criteria) Hand–foot syndrome, rash, fatigue, 86% pretreated 4% response rate (RECIST criteria) diarrhoea, hypertension
WHO defines the objective response as a ≥ 50% reduction in the sum of the bidimensional measurement of tumours; RECIST defines objective response as a ≥ 30% reduction in the sum of the unidimensional measurement of tumours.
The clinical utility of bevacizumab in effect [22]. Nonetheless, preclinical SU11248 metastatic RCC was investigated in a investigation in human RCC xenograft models randomized phase II trial in which 116 of bevacizumab and erlotinib, a small SU11248 (Sutent Pfizer, Inc. La Jolla, CA) is an patients with treatment-refractory, molecule EGFR inhibitor, showed the potential orally bioavailable oxindole small-molecule metastatic CCRCC were randomized to receive benefit of combined therapy on tumour tyrosine-kinase inhibitor of VEGFR-2 and placebo, low-dose (3 mg/kg) or high-dose growth inhibition, perhaps because EGFR PDGFR-B. In vitro assays showed inhibition of (10 mg/kg) bevacizumab, given intravenously resistance is mediated through VEGF [23]. VEGF-induced proliferation of endothelial every 2 weeks [17]. All groups were well A clinical trial in metastatic RCC with cells and PDGF-induced proliferation of balanced for established prognostic factors bevacizumab 10 mg/kg i.v. daily for 2 weeks mouse fibroblast cells. Investigation in mouse [18]. There were four partial responses, all combined with erlotinib 150 mg oral every xenograft models showed growth inhibition in the high-dose bevacizumab arm (in 39 day reported a 25% partial response rate [24]. of various implanted solid tumours and patients, 10% objective response rate). A recently completed placebo-controlled, eradication of larger, established tumours An intent-to-treat analysis showed a randomized phase II trial of bevacizumab with [25]. significantly longer time to progression in or without erlotinib in untreated, metastatic the high-dose than the placebo arm (4.8 vs RCC may provide further insight into SU11248 was investigated in a single-arm, 2.5 months; P < 0.001, log-rank test). There potential additive or synergistic clinical effect multi-institutional phase II study in 63 were no life-threatening toxicities or deaths of this combined therapy. To enhance the patients with advanced RCC in whom initial attributable to bevacizumab. In the high-dose blockade of proteins that may play a role in cytokine treatment had failed [26]. Patients bevacizumab arm, hypertension of any grade the pathogenesis of CCRCC downstream of were treated with 50 mg daily of oral occurred in 36% of patients, and grade 3 HIF-1a, imatinib (Gleevec, Novartis), a known SU11248 on a ‘4-weeks on’, ‘2-weeks off’ hypertension (not controlled by one standard PDGF receptor inhibitor, has been added to cycle. Fifteen patients (24%) had a partial medication) in 21%. There was asymptomatic this two-drug regimen for additional response, as defined by the Response proteinuria with no renal insufficiency in 64% horizontal blockade. Results of these phase Evaluation Criteria In Solid Tumours (RECIST) of patients in the high-dose arm. All toxicities I/II studies are pending. criteria. An additional five patients (8%) had a were reversible on stopping therapy. There partial response but await confirmation of was grade 1 or 2 haemoptysis in two patients response status. Of the 15 patients who had a receiving bevacizumab and two receiving SMALL-MOLECULE VEGFR INHIBITORS partial response, one progressed at 5 months placebo. No thromboembolic events were and 14 remain progression-free with a reported in any arm. An alternative approach to VEGF inhibition median duration of response of ≥6 months. involves small molecule tyrosine-kinase Bevacizumab was further investigated inhibitors. These agents inhibit not only Toxicity in the phase II trial, most commonly combined with an anti-epidermal growth VEGFR, but also other receptors in the split grade 1 or 2, included fatigue/asthenia factor receptor (EGFR) strategy. TGF-a is a kinase domain superfamily of receptor (78%), nausea (56%), diarrhoea (51%) and VHL-regulated growth factor for RCC, with a tyrosine kinases, including the PDGFR, which stomatitis (44%). Grade 3/4 toxicities included biological effect through interaction with the is expressed in pericytes, and serve as lymphopenia (30%), elevated lipase (21%) EGFR [19–21]. However, single-agent studies structural supporting cells for endothelial and amylase (8%) with no clinical signs of with small molecules or antibodies directed cells; thus class effects of these drugs on pancreatitis, elevated phosphorus (13%), and against the EGFR showed limited antitumour PDGFR may have therapeutic relevance. fatigue/asthenia (8%). Two patients were
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taken off the study for asymptomatic survival of 23 weeks, with half progression- SU11248 with additional agents that target decreases in left ventricular ejection fraction free at 24 weeks. pathways implicated in RCC carcinogenesis of > 20% compared to baseline. A (e.g. gefitinib, a small molecule EGFR confirmatory single-arm phase II trial in 100 inhibitor). patients with cytokine-refractory metastatic ONGOING CLINICAL TRIALS OF RCC recently completed accrual. VEGF-TARGETED THERAPY IN RCC Further, the clinical cross-resistance of this class of agents is unknown. Given the distinct BAY 43–9006 Given the promising data showing an effect anti-VEGF mechanism of the small molecule of bevacizumab on time to progression in agents such as SU11248 and the extended BAY 43–9006 (Sorafenib Bayer RCC, an Intergroup phase III trial investigating spectrum against VHL-mediated targets Pharmaceuticals, West Haven, CT and Onyx the addition of bevacizumab to initial relevant to RCC (e.g. PDGF), there is a Pharmaceuticals, Richmond, CA) is an orally systemic therapy in RCC is underway [30]. biological rationale for investigating SU11248 bioavailable bi-aryl urea Raf kinase inhibitor, Patients with metastatic CCRCC and no in bevacizumab-refractory patients. A which inhibits Ras-dependent human tumour previous systemic therapy are randomized to multicentre trial of SU11248 in patients with xenograft models [27]. Activated Ras either low-dose interferon-a2b (Intron A, metastatic RCC who have disease progression promotes cell proliferation through the Schering-Plough, Kenilworth, NJ) 9 MU despite previous bevacizumab therapy is Raf/MEK/ERK pathway by binding to and three times weekly, or the same dose and ongoing, with a primary endpoint of overall activating Raf kinase. BAY 43–9006 also schedule of interferon-a2b combined with response rate. directly inhibits VEGFR-2, VEGFR-3 and bevacizumab 10 mg/kg i.v. every 2 weeks. PDGFR-B [28]. Xenograft models treated with Patients are stratified by nephrectomy status A phase III, randomized controlled trial of BAY daily BAY 43–9006 had significant inhibition and established prognostic factors to ensure 43–9006 vs placebo in patients who had of tumour angiogenesis, as measured by anti- balanced randomization [18,31,32]. The received and failed one previous systemic CD31 immunostaining. A major question, still primary endpoint of the trial is overall biological therapy (interferon or interleukin- unanswered, is what, if any, role the Raf survival. A similarly designed phase III trial is 2) has recently completed accrual. The trial kinase inhibitory activity plays in its clinical underway in Europe using interferon-a2a was intended to enrol 884 patients, with activity. Based on its multi-targeted profile (Roferon, Hoffmann-LaRoche, Grenzach- overall survival the primary endpoint and (VEGFR and PDGFR), similar to SU11248, the Wyhlen, Germany) instead of interferon-a2b. progression-free survival the secondary Raf kinase inhibition may not be of clinical endpoint. Other trials are using BAY 43–9006 significance in CCRCC. Clinical trials of another approach to initial combined with additional inhibitors of the therapy in metastatic RCC, high-dose VEGF pathway (bevacizumab), inhibitors of A phase II randomized discontinuation study interleukin-2 combined with bevacizumab, the TGFa-EGFR pathway (gefitinib or with BAY 43–9006 was reported in refractory are also soon to begin. The rationale for this erlotinib) or mTOR inhibitors (tesirolimus, CCI- solid tumours, including the initial 106 combination includes that inhibition of VEGF 779, Wyeth Pharmaceuticals) that may patients with metastatic RCC [29]. All patients may prevent much of the tumour-induced decrease translation of HIF-1a. These trials received oral BAY 43–9006 400 mg twice immunosuppression attributed to VEGF and are in their early phases of dose-finding and daily, and patients with stable disease after thereby enhance the immune-enhancing toxicity at both the National Cancer Institute- 12 weeks of treatment were randomized to effects of interleukin-2 [33,34]. In addition, intramural and an extramural group of continue drug or receive placebo. Patients interleukin-2 toxicity may be reduced by the centres (Vanderbilt-Penn-Harvard). Following with ≥25% tumour shrinkage by the sum of vascular effects of bevacizumab. Bevacizumab these trials will be a large randomized phase II the bidimensional measurement of tumours may decrease the significant vascular leak trial of doublets of bevacizumb, BAY 43–9006, at 12 weeks (defined as ‘responders’) syndrome associated with interleukin-2 and erlotinib and CCI-779 through the Eastern continued open-label BAY 43–9006. Of the allow more doses of interleukin-2 to be Cooperative Oncology Group. There will be six first 89 patients with RCC who had reached administered, with less toxicity. Finally, the arms with 50 patients enrolled per arm, with the initial 12-week assessment, 71% had response subpopulation may be different for time to progression as the primary endpoint. stable disease and 29% progressed, and were the different agents. Bevacizumab 10 mg/kg Finally, a phase I/II trial of BAY 43–9006 with removed from the trial. Using the RECIST i.v. daily for 2 weeks will be integrated with interleukin-2 is planned within the Cytokine criteria for tumour measurements, only ª4% standard high-dose interleukin-2 regimens, Working Group. Because of concerns over of patients had objective responses, but many with both progression-free and overall the effects that a Raf kinase inhibitor (BAY had >25% regression using the WHO survival as primary endpoints. Bevacizumab 43–9006) may have on proliferation of (bidimensional) criteria. More recently, Bayer combined with low-dose interleukin-2 will lymphocytes stimulated by interleukin-2, the released data from the randomized cohort of also be evaluated in a separate trial. two treatments will be given in sequence, 65 patients who received either placebo or with no overlap in their periods (3–6 weeks) continued on BAY 43–9006 after stable The role for SU11248 in the treatment of of administration. disease at 12 weeks. Those randomized to metastatic RCC is being further investigated placebo had a median progression-free in a confirmatory single-arm trial of second- Lastly, a placebo-controlled, randomized survival of only 6 weeks, and after 24 weeks line therapy, and in a randomized phase III study of BAY 43–9006 in the neoadjuvant only 18% of patients were progression-free. trial of first-line therapy compared with setting is planned through the Eastern However, those randomized to continue BAY interferon-a. Future investigations will test Cooperative Oncology Group, with a 43–9006 had a median progression-free the efficacy and tolerability of combining progression-free survival endpoint.
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Comparison of renal biopsy material before 4 Ferrara N, Davis-Smyth T. The biology chain gene in human endothelial cells. treatment and nephrectomy specimens of vascular endothelial growth factor. J Clin Invest 1990; 86: 670–4 afterward will provide further insight into the Endocr Rev 1997; 18: 4–25 16 Presta LG, Chen H, O’Connor SJ et al. molecular mechanisms of this agent. Further, 5 Benjamin LE, Golijanin D, Itin A, Pode Humanization of an anti-vascular the safety of administering this agent before D, Keshet E. Selective ablation of endothelial growth factor monoclonal surgery will be evaluated. Although activity of immature blood vessels in established antibody for the therapy of solid tumors this class of agents was reported in the human tumors follows vascular and other disorders. Cancer Res 1997; 57: metastatic setting, patients with earlier stage endothelial growth factor withdrawal. 4593–9 RCC should be treated in a clinical trial until J Clin Invest 1999; 103: 159–65 17 Yang JC, Haworth L, Sherry RM et al. safety and efficacy in this setting is 6 Watanabe Y, Lee SW, Detmar M, Ajioka A randomized trial of bevacizumab, an confirmed. I, Dvorak HF. Vascular permeability anti-vascular endothelial growth factor factor/vascular endothelial growth factor antibody, for metastatic renal cancer. (VPF/VEGF) delays and induces escape N Engl J Med 2003; 349: 427–34 FUTURE DIRECTIONS from senescence in human dermal 18 Motzer RJ, Bacik J, Murphy BA, Russo microvascular endothelial cells. Oncogene P, Mazumdar M. Interferon-alfa as a The exciting clinical response data with VEGF 1997; 14: 2025–32 comparative treatment for clinical trials inhibition in RCC has provided an opportunity 7 Dvorak HF. Vascular permeability factor/ of new therapies against advanced renal for treatment advances in this historically vascular endothelial growth factor. a cell carcinoma. J Clin Oncol 2002; 20: resistant malignancy. As the clinical activity of critical cytokine in tumor angiogenesis 289–96 existing agents is further defined in ongoing and a potential target for diagnosis and 19 Knebelmann B, Ananth S, Cohen HT, trials, several questions on optimizing their therapy. J Clin Oncol 2002; 20: 4368–80 Sukhatme VP. Transforming growth utility remain. Furthermore enrichment of 8 Latif F, Tory K, Gnarra J et al. factor alpha is a target for the von Hippel- patients susceptible to VEGF blockade, beyond Identification of the von Hippel-Lindau Lindau tumor suppressor. Cancer Res restriction to clear cell histology, is needed. disease tumor suppressor gene. Science 1998; 58: 226–31 Examination of RCC tumour tissue for the 1993; 260: 1317–20 20 Gunaratnam L, Morley M, Franovic A predictive value of VHL mutation status, HIFa, 9 Rini BI, Small EJ. Biology and clinical et al. Hypoxia inducible factor activates VEGF expression or other markers is development of vascular endothelial the transforming growth factor-alpha/ warranted. Investigation of clinical predictive/ growth factor-targeted therapy in renal epidermal growth factor receptor growth prognostic factors, as have been developed cell carcinoma. J Clin Oncol 2005; 23: stimulatory pathway in VHL (-/-) renal cell for patients with RCC undergoing 1028–43 carcinoma cells. J Biol Chem 2003; 278: immunotherapy, is warranted with this class 10 Kibel A, Iliopoulos O, DeCaprio JA, 44966–74 of agents. Kaelin WG Jr. Binding of the von Hippel- 21 de Paulsen N, Brychzy A, Fournier MC Lindau tumor suppressor protein to et al. Role of transforming growth Elongin B and C. Science 1995; 269: factor-alpha in von Hippel–Lindau CONFLICT OF INTEREST 1444–6 (VHL) (-/-) clear cell renal carcinoma 11 Maxwell PH, Wiesener MS, Chang GW cell proliferation: a possible mechanism Brian Rini received research funding from et al. The tumour suppressor protein VHL coupling VHL tumor suppressor Genentech and Pfizer; and is a paid targets hypoxia-inducible factors for inactivation and tumorigenesis. Proc Natl consultant to Bayer. Jeffrey Sosman received oxygen-dependent proteolysis. Nature Acad Sci USA 2001; 98: 1387–92 research funding from Genentech, Chiron, 1999; 399: 271–5 22 Motzer RJ, Amato R, Todd M et al. Phase Pfizer and Wyeth. 12 Cockman ME, Masson N, Mole DR et al. II trial of antiepidermal growth factor Hypoxia inducible factor-alpha binding receptor antibody C225 in patients with and ubiquitylation by the von Hippel- advanced renal cell carcinoma. Invest New REFERENCES Lindau tumor suppressor protein. J Biol Drugs 2003; 21: 99–101 Chem 2000; 275: 25733–41 23 Viloria-Petit A, Crombet T, Jothy S et al. 1 Bukowski RM. Cytokine therapy for 13 Iliopoulos O, Levy AP, Jiang C, Kaelin Acquired resistance to the antitumor metastatic renal cell carcinoma. Semin WG Jr, Goldberg MA. Negative effect of epidermal growth factor Urol Oncol 2001; 19: 148–54 regulation of hypoxia-inducible genes by receptor-blocking antibodies in vivo: a 2 Dvorak HF, Orenstein NS, Carvalho AC the von Hippel-Lindau protein. Proc Natl role for altered tumor angiogenesis. et al. Induction of a fibrin-gel investment: Acad Sci USA 1996; 93: 10595–9 Cancer Res 2001; 61: 5090–101 an early event in line 10 hepatocarcinoma 14 Gnarra JR, Zhou S, Merrill MJ et al. Post- 24 Hainsworth JD, Sosman JA, Spigel DR growth mediated by tumor-secreted transcriptional regulation of vascular et al. Phase II trial of bevacizumab and products. J Immunol 1979; 122: 166–74 endothelial growth factor mRNA by the erlotinib in patients with metastatic renal 3 Dvorak HF, Brown LF, Detmar M, product of the VHL tumor suppressor carcinoma (RCC). ASCO Proceedings. J Clin Dvorak AM. Vascular permeability factor/ gene. Proc Natl Acad Sci USA 1996; 93: Oncol 2004; 23: A4502 vascular endothelial growth factor, 10589–94 25 Mendel DB, Laird AD, Xin X et al. In vivo microvascular hyperpermeability, and 15 Kourembanas S, Hannan RL, Faller DV. antitumor activity of SU11248, a novel angiogenesis. Am J Pathol 1995; 146: Oxygen tension regulates the expression tyrosine kinase inhibitor targeting 1029–39 of the platelet-derived growth factor-B vascular endothelial growth factor and
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platelet-derived growth factor receptors: solid tumors in a phase II randomized 33 Gabrilovich DI, Chen HL, Girgis KR determination of a pharmacokinetic/ discontinuation trial (RDT). ASCO et al. Production of vascular endothelial pharmacodynamic relationship. Clin Proceedings. J Clin Oncol 2004; 23: growth factor by human tumors Cancer Res 2003; 9: 327–37 A4501 inhibits the functional maturation of 26 Motzer RJ, Rini BI, Michaelson MD et al. 30 Rini BI, Halabi S, Taylor J, Small EJ, dendritic cells. Nat Med 1996; 2: 1096– SU 011248, a novel tyrosine kinase Schilsky RL and the Cancer and 103 inhibitor, shows anti-tumor activity in Leukemia Group B 90206. A randomized 34 Gabrilovich DI, Ishida T, Nadaf S, Ohm second-line therapy for patients with phase III trial of interferon-alpha or JE, Carbone DP. Antibodies to vascular metastatic renal cell carcinoma. Results of interferon-alpha plus anti-vascular endothelial growth factor enhance the a phase II trial. ASCO Proceedings. J Clin endothelial growth factor antibody efficacy of cancer immunotherapy by Oncol 2004; 23: A4500 (bevacizumab) in metastatic renal cell improving endogenous dendritic cell 27 Lyons JF, Wilhelm S, Hibner B, Bollag carcinoma. Clin Cancer Res 2004; 10: function. Clin Cancer Res 1999; 5: 2963– G. Discovery of a novel Raf kinase 2584–6 70 inhibitor. Endocr Relat Cancer 2001; 8: 31 Mickisch GH, Garin A, van Poppel H, 219–25 de Prijck L, Sylvester R. Radical Correspondence: Brian I. Rini, 9500 Euclid 28 Wilhelm SM, Carter C, Tang L et al. BAY nephrectomy plus interferon-alfa-based Ave/Desk R35, Cleveland, OH 44195, 43–9006 exhibits broad spectrum oral immunotherapy compared with USA. antitumor activity and targets the RAF/ interferon alfa alone in metastatic e-mail: [email protected] MEK/ERK pathway and receptor tyrosine renal-cell carcinoma: a randomised kinases involved in tumor progression and trial. Lancet 2001; 358: 966–70 Abbreviations: VEGF(R), vascular endothelial angiogenesis. Cancer Res 2004; 64: 7099– 32 Flanigan RC, Salmon SE, Blumenstein growth factor (receptor); VHL, von Hippel- 109 BA et al. Nephrectomy followed by Lindau; CCRCC, clear cell RCC; HIF, hypoxia- 29 Ratain MJ, Flaherty KT, Stadler WM. interferon alfa-2b compared with inducible factor; PDGF, platelet-derived et al. Preliminary antitumor actvity of BAY interferon alfa-2b alone for metastatic growth factor; EGFR, epidermal growth factor 43, 43–9006 in metastatic renal cell renal-cell cancer. N Engl J Med 2001; 345: receptor; RECIST, Response Evaluation carcinomaand other advanced refractory 1655–9 Criteria in Solid Tumours.
290 © 2005 BJU INTERNATIONAL Original Article MULTIDETECTOR CT VS MRI FOR DEFINING TUMOUR THROMBUS IN RCC LAWRENTSCHUK et al.
Multidetector computed tomography vs magnetic resonance imaging for defining the upper limit of tumour thrombus in renal cell carcinoma: a study and review
NATHAN LAWRENTSCHUK, JOHAN GANI, RICHARD RIORDAN*, STEVEN ESLER* and DAMIEN M. BOLTON Surgery and Urology, and *Radiology, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia Accepted for publication 9 February 2005
OBJECTIVE undergoing surgery had pathological CONCLUSIONS confirmation of tumour thrombus extent. All To compare the findings of multidetector images were analysed originally, then re- Whilst there were few patients and further computed tomography (CT) with surgical analysed by two independent radiologists, an studies are needed, multidetector CT was pathology and magnetic resonance imaging experienced urologist and a urological trainee comparable with MRI in determining tumour (MRI), to determine the accuracy of unaware of the original reports and other thrombus level. More importantly, in the delineating the superior extent of inferior imaging results, with a final determination on eight patients with surgical pathological vena cava (IVC) thrombotic involvement in tumour thrombus level by consensus. confirmation, multidetector CT was accurate renal cell cancer (RCC). in all. Ultimately, it may replace MRI as the RESULTS ‘gold standard’ for imaging to delineate the PATIENTS AND METHODS upper limit of tumour thrombosis in RCC. The multidetector CT results were completely A prospective database was examined of 11 accurate when compared with surgical patients (median age 65 years, range 45–77) specimens and were in agreement with KEYWORDS being assessed for suspected IVC extension MRI on all but one occasion, where MRI of RCC tumour thrombus with both determined the renal vein to be clear when it renal cell carcinoma, RCC, spiral CT, MRI, multidetector CT and MRI. All had pathology was involved on CT and at surgery, giving MRI venous thrombosis, inferior vena cava, confirming RCC, and eight of those an accuracy of seven of eight samples. surgery
INTRODUCTION Nevertheless, CT remains the investigation PATIENTS AND METHODS of choice for most RCCs, as it is often clear RCC often invades the renal vein and may that there is no IVC invasion. More than 10 A prospective database of multidetector CT extend into the inferior vena cava (IVC) years ago, MRI was compared with CT to and MRI information was maintained from or right atrium [1]. Current staging delineate IVC involvement, but the quality 2001; additional data were specifically incorporates such invasion and aids in of CT imaging then was poorer, with collected on patients with RCC and tumour prognosis. Accurate staging is paramount reconstructed images unavailable. CT was thrombus, including demographics, surgery, when assessing patients and planning unable to delineate the exact level of the pathology and follow-up. Eleven patients surgical resection. Of patients undergoing upper limit of thrombus, the major factor (median age 65 years, range 45–77) were radical nephrectomy for RCC, 4–10% have in planning surgery [11,12]. However, with assessed for suspected IVC extension of RCC IVC involvement. The surgical approach advances in CT technology and multiple-plane with both methods (Table 1). Patients were and assistance of other specialist surgeons reconstructions now available, MRI may not staged according to the 1997 TNM is often crucial the further the tumour be necessary. In a review of renal imaging, classification; all had pathology confirming thrombus extends [2]. The superior extent Israel and Bosniak [8] commented that ‘with RCC, and eight had surgery, with operative of the thrombus determines the operative the advent of multidetector CT scanning, it is and pathological confirmation of thrombus approach [3,4]. Traditionally, venacavography unclear whether any proposed advantage of extent. There were no exclusions and ethics was the ‘gold standard’ investigation MRI still holds true’. committee approval was not required, as MRI to delineate thrombus level, with a is current best practice. reported sensitivity of 100% [5–7]. The purpose of the present study was to Since the advent of CT and MRI, compare the findings of multidetector CT, All CT was done on multidetector (-row) venacavography is now used rarely. In providing images in many planes, with machines (Multidetector GE Lightspeed plus, particular, multiple-plane imaging and surgical pathology and MRI to determine eight-slice, General Electric Medical Systems, accuracy has made MRI the ‘gold standard’ the accuracy of delineating the superior Milwaukee, USA). The protocol was identical, investigation of RCC with suspected extent of IVC thrombosis involvement in with four phases: non-contrast phase images thrombus [8–10]. RCC. were obtained from the aortic arch to the
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symphysis pubis at 2.5 mm intervals; an TABLE 1 Results comparing the superior extent of tumour thrombus in the renal vein and IVC on arterial phase with 100 mL of intravenous multidetector CT, MRI and surgery non-ionic contrast medium (iohexol), injected at 3 mL/s (timed bolus injection), with Age, years/sex CT Level MRI Level Surgery Stage Grade Type scanning starting once the contrast agent 69/F RV RV RV T3a 2 Clear was apparent in the aorta (usually 20 s); a 64/M RV Nil RV T3b 2 Clear delayed phase taken 90 s from the injection 65/M RV RV RV T3b 3 Clear with contrast agent, and scanning from 45/F INFRA INFRA INFRA T3b High Sarcomatoid the aortic arch to the symphysis pubis; 58/M INFRA INFRA INFRA T3a 2 Clear and finally an extra delayed phase, at 10 min 69/M INTRA INTRA INFRA T3a 2 Clear after injection with contrast agent, scanning 47/M INTRA INTRA INTRA T3b 3 Clear the kidneys and IVC only. From all scans 73/F INTRA INTRA INTRA T3b 4 Clear coronal reconstructions of the kidneys 65/M SUPRA SUPRA Nil T3c 2 Clear and IVC were produced. A thrombus was 51/F RV RV Nil T4 High RCC (metastasis) diagnosed in the IVC when a low-attenuation 77/M INTRA INTRA Nil T4 High RCC (metastasis) filling defect was apparent within the lumen [13]. Injection with contrast medium RV, renal vein; INFRA, infrahepatic vena cava; INTRA, intrahepatic vena cava; SUPRA, suprahepatic vena enhanced the thrombus, and when there was cava. incomplete obstruction of the blood flow, the intraluminal enhancement was peripheral and ring-like (‘doughnut’ appearance). Focal enhancement of the vena caval wall, or infiltration of adjacent soft tissue, indicated FIG. 1. vena caval wall invasion, as described Diagram depicting the delineation RA Right previously [12]. of the upper limit of tumour SUPRA Atrium thrombus extension in RCC as used For MRI, the same machine was used (GE in the study. RV, renal vein; INFRA, Echospeed, Software version 9). The protocol infrahepatic vena cava; INTRA, consisted of six phases: axial T1 breath-hold; INTRA intrahepatic vena cava; SUPRA, axial T2 breath-hold; coronal T1 breath-hold; Liver suprahepatic vena cava; RA, right dynamic axial T1 with intravenous contrast atrium. agent (20 mL of gadolinium); coronal IVC gadolinium venogram; and delayed axial T1 with fat suppression. Three-dimensional INFRA reconstructions were used for gadolinium images, with 2.5 mm slices. RV Kidney
RCCs had a varied MRI signal, the most common appearance being a mass with an intensity intermediate between the renal cortex and the medulla on T1-weighted images, and hyperintense on T2-weighted images. A thrombus was diagnosed in the venous system when there was a filling defect is more practical from a surgical planning thrombus was confirmed by two surgeons and several planes were consulted where perspective. before recording, using the levels of thrombus necessary. A tumour thrombus was diagnosed defined. when the signal intensity and contrast All images were analysed originally by two enhancement matched the primary tumour. experienced radiologists at the time of RESULTS For a bland or pure clot thrombus to be scanning, with data recorded. Images were diagnosed there had to be no enhancement then re-analysed by two independent Overall, CT accurately delineated the tumour after giving the contrast agent. radiologists unaware of the original reports thrombus level in the IVC in all eight patients, and other imaging results, with a final compared to MRI which was correct in seven There have been attempts to grade RCC determination on tumour thrombus level by of the eight (Table 1). The CT results for IVC thrombus by superior extent at two, consensus. An experienced urologist and thrombus level matched those of MRI three or four levels [1,14,15]. We chose urological trainee, also unaware of the (Fig. 2) on all but one occasion where MRI five levels, distinguishing supraheptic IVC reports, assessed the CT scans and recorded determined the renal vein to be clear when it extent from right atrial involvement, and their superior level of tumour thrombus. Two was involved on CT and at surgery. This was a described those at the junction of the renal pathologists reported all pathology difficult case, as tumour was encasing the vein and IVC as ‘renal vein only’ (Fig. 1) which specimens, and the operative level of the vein (noted on MRI) as well as being in the
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FIG. 2. Comparison of CT (left) and MRI (right) in the same patient, showing that with coronal reconstruction available with CT, making image using multidetector CT, the resultant images are almost identical to those generated by MRI. reconstruction difficult, whilst MRI could provide multiplanar images [2]. Attempts at combining CT with ultrasonography improved the sensitivity for tumour thrombus extent, but remained much less sensitive than MRI [22].
The CT level of RCC thrombus and pathological specimens has been compared using conventional CT, with an accuracy of 95% on axial scanning alone [1], but few other studies have reached such precision (Table 2) [11,12,19,23,24]. Studies have also assessed MRI and CT in parallel, but not directly against each other, with MRI having a lumen, making interpretation difficult. Of the vein is normally ligated near its junction with greater accuracy (complete) at diagnosing the remaining seven patients having surgery, the IVC, whilst on the left it is ligated where it superior extent of thrombus compared to CT there was concordance of opinion as to crosses the aorta. If tumour thrombus extends (76%) [2,7]. MRI has also been correlated with thrombus level on MRI and CT. One patient to these margins of the veins, there is a CT for overall staging accuracy (74–88% MRI was upstaged from T3a to T4 because of danger of ligating across the thrombus and vs 67–100% CT), but the superior extent disease extension, not detected on either CT dislodging it during surgery into the right of thrombus involvement has not been or MRI, for tumour extension beyond Gerota’s atrium or beyond [7]. Thrombus in the IVC specifically highlighted [13,21]. To date, fascia, but the thrombus level remained necessitates extensive mobilization of the only five studies have directly compared unchanged. Only tumour thrombi were involved region to gain control, aiming conventional CT to MRI in delineating the diagnosed on MRI. to remove the thrombus intact [3]. If thrombus level of extension into the IVC thrombus extends beyond the diaphragm, in RCC (Table 2) and these were undertaken Three patients had no surgical intervention cardiopulmonary or venous bypass is often >10 years ago in fewer than 50 patients but CT and MRI were in agreement as to necessary to allow control above the [11,12,19,23,24]. tumour thrombus level in the IVC. Two thrombus. RCC on the right side is more likely patients had significant widespread to extend into the IVC because of the shorter Overall, studies directly comparing MRI with metastatic disease and were considered vein, and because the left renal vein crosses CT found MRI to be completely accurate for inappropriate for nephrectomy and the pulsatile aorta [17]. the superior extent of tumour thrombus, immunotherapy. Finally, one patient refused whereas CT had a mean diagnostic accuracy surgery who had previously had a Thus, successfully removing a tumour of only 65% (Table 2). Of more concern for CT nephrectomy for T1 disease; he was thrombus remains a technical intraoperative was that it completely missed tumour undergoing tumour surveillance when at challenge and requires careful preoperative thrombus in four patients in three of the 18 months after surgery he developed a management [3]. In several studies studies [11,12,24]. These CT images were only tumour vein thrombus with extension into [2,9,10,14,18–20] MRI was as accurate as axial, and they would not compare to current the suprahepatic vena cava. venacavography in delineating thrombus multiplanar imaging. Other reasons for the level. It has the advantages of being inaccuracy of CT include incorrect timing and When the opinion of the experienced noninvasive, delivers no radiation to the an insufficient amount of intravenous urologist was compared with that of the patient and gives information in any of the contrast agent in the IVC. These areas have radiologists for CT, the delineation of three orthogonal anatomical planes, making it been improved, with better software and thrombus level was identical on all occasions. the ‘gold standard’ [8–10]. high-powered contrast bolus injectors. In There was no discordance between the support of this, a recent study comparing original reported level of thrombus on CT MRI has previously had advantages over multidetector CT and MRI for overall RCC or MRI and that made by independent conventional (single-detector) CT, including staging had similar accuracy with both radiologists through a consensus. those noted for venacavography, in that it methods, but tumour thrombus extension can delineate the exact level of thrombus into the IVC was not specifically assessed [15]. extension, which is critical to surgical DISCUSSION planning [4]. Furthermore, MRI can detect the Although in general MRI is completely patency of major vessels with no contrast accurate in delineating the level of tumour The 5-year survival rate for RCC when agent if necessary, as the signal from the thrombus in the vena cava in RCC, some completely resecting an IVC tumour thrombus blood flowing through vessels is much lower inaccuracies were reported. In two cases in patients with no metastases is 30–69% and than that from the tumour thrombus [21]. the extent of tumour thrombus was does not depend on the level of thrombus, but MRI may also sometimes delineate bland underestimated at the level of the hepatic on stage [3,16]. During a right radical thrombus from tumour thrombus [9,10]. veins [25,26]. In three other studies the use of nephrectomy with no thrombus, the renal Finally, in the past, only axial images were preoperative MRI in a total of 57 patients was
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90–96% accurate at determining thrombus TABLE 2 A summary of studies directly comparing CT with MRI and surgery to ascertain the accuracy of level, which was similar to the present delineating the superior extent of RCC tumour thrombus. Studies apart from the present used accuracy [21,27]. In the study with 10 conventional CT patients, only six from eight venacavography scans were accurate; clearly, no imaging Level of thrombus method is always completely accurate, and Study N patients Method Correct Understaged Missed Accuracy, n/N Surgery even ‘gold standards’ of imaging may be incorrect. Present 11 CT 11 0 0 11/11 8 MRI 10 1 0 10/11 MRI technology has also developed with time; [23] 8 CT 5 1 2 5/8 8* previously, MRI using spin-echo sequences MRI 8 0 0 8/8 was unable to overcome flow-related [11] 5 CT 0 4 1 4/5 0† intraluminal signals from thrombus and MRI 5 0 0 5/5 external compression of the vena cava, [24] 5 CT 3 1 1 3/5 5 creating artefacts that made assessing the MRI 5 0 0 5/5 signal difficult [18]. Also, respiratory and [12] 16 CT 11 3 2 11/16 16 cardiac motion artefacts compromised the MRI 16 0 0 16/16 delineation of tumour thrombus extent and [19] 15 CT 5 10 0 5/15 15 may explain the cases discussed above. To MRI 15 0 0 15/15 overcome these issues, gradient-recalled echo sequences were introduced for MRI of *two patients had thrombus extent confirmed at autopsy; †Extent of thrombus not specified, but all vascular structures, including tumour patients had surgery or biopsy to confirm RCC. thrombus in RCC, with success [26]. Furthermore, MR image acquisition has become faster, providing more images in a and conventional urography [31]. The benefits CONFLICT OF INTEREST single breath-hold, reducing movement outlined above also pose significant artefact. Further developments will result in challenges, including selecting the optimal None declared. even greater imaging capabilities of MRI, but imaging sequences, controlling radiation access and cost remain strong impediments exposure to the patient, and efficiently REFERENCES to its widespread use. managing the increased data. 1 Hatcher PA, Paulson DF, Anderson Other imaging methods have been Currently, MRI will remain the ‘gold standard’ EE. Accuracy in staging of renal cell investigated to delineate tumour thrombus, for delineating the level and extent of tumour carcinoma involving vena cava. Urology e.g. ultrasonography and transoesophageal thrombus in the IVC in the staging of patients 1992; 39: 27–30 echocardiography. Ultrasonography is not with RCC. While our experience is limited, 2 Pritchett TR, Raval JK, Benson RC appropriate, as many studies are technically multidetector CT was accurate when et al. Preoperative magnetic resonance indeterminate because they rely on operator compared with the surgical specimens and is imaging of vena caval tumor thrombi: and patient characteristics [7]. There are probably at least the equivalent of, if not experience with 5 cases. J Urol 1987; 138: limited data for transoesophageal better than, MRI in determining thrombus 1220–2 echocardiography but no study has shown level. Whilst encouraged by these early 3 Pritchett TR, Lieskovsky G, Skinner DG. that it adds any diagnostic advantage, and it results, the accuracy of multidetector CT in Extension of renal cell carcinoma into the may only have a small role during surgery in defining tumour thrombus in RCC must await vena cava: clinical review and surgical patients having a cardiopulmonary bypass further analysis from other centres, and so we approach. J Urol 1986; 135: 460–4 [28]. will continue to use both methods until we 4 Hricak H, Thoeni RF, Carroll PR, Demas are satisfied that it is equal to or better than BE, Marotti M, Tanagho EA. Detection Multidetector CT allows faster data MRI. Finally, with CT developing rapidly, the and staging of renal neoplasms: a acquisition than single-detector CT, with no challenge as clinicians will be to evaluate new reassessment of MR imaging. Radiology loss of image quality because of short gantry standards of imaging, so that patients have 1988; 166: 643–9 rotation intervals combined with multiple the simplest, most cost-effective and accurate 5 Lang EK. Comparison of dynamic and detectors at each level, providing increased staging technique available to them. conventional computed tomography, coverage [29]. This, along with short interscan angiography, and ultrasonography in the delays, allows image acquisitions in multiple staging of renal cell carcinoma. Cancer phases of renal parenchymal enhancement ACKNOWLEDGEMENTS 1984; 54: 2205–14 and contrast agent excretion in the collecting 6 Hietala SO, Ekelund L, Ljungberg B. system after giving one bolus of intravenous We gratefully acknowledge the contribution Venous invasion in renal cell carcinoma. A contrast agent [30]. Another advantage of CT of Dr Greg Fitt FRANZCR, University of correlative clinical and radiologic study. is improved spatial resolution, providing high- Melbourne, Department of Radiology, Austin Urol Radiol 1988; 9: 210–6 quality three-dimensional datasets of the Hospital, in helping to analyse the images for 7 Kallman DA, King BF, Hattery RR et al. renal vessels, comparable with angiography this study. Renal vein and inferior vena cava tumor
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thrombus in renal cell carcinoma: CT, US, study with histopathologic correlation. 25 Straton CS, Libertino JA, Larsen CR. MRI and venacavography. J Comput Assist J Comput Assist Tomogr 2004; 28: 333–9 Is magnetic resonance imaging alone Tomogr 1992; 16: 240–7 16 Libertino JA, Zinman L, Watkins E Jr. accurate enough in staging renal cell 8 Israel GM, Bosniak MA. Renal imaging Long-term results of resection of renal carcinoma? Urology 1992; 40: 351–3 for diagnosis and staging of renal cell cell cancer with extension into inferior 26 Roubidoux MA, Dunnick NR, Sostman carcinoma. Urol Clin North Am 2003; 30: vena cava. J Urol 1987; 137: 21–4 HD, Leder RA. Renal carcinoma. 499–514 17 Brun B, Joshi MS, Gronvall S, Holm HH. detection of venous extension with 9 Ergen FB, Hussain HK, Caoili EM et al. Dynamic ultrasound evaluation of tumor gradient-echo MR imaging. Radiology MRI for preoperative staging of renal thrombus in the inferior vena cava. Scand 1992; 182: 269–72 cell carcinoma using the 1997 TNM J Urol Nephrol 1983; 17: 115–7 27 Glazer A, Novick AC. Preoperative classification: comparison with surgical 18 Hricak H, Demas BE, Williams RD et al. transesophageal echocardiography for and pathologic staging. AJR Am J Magnetic resonance imaging in the assessment of vena caval tumor Roentgenol 2004; 182: 217–25 diagnosis and staging of renal and thrombi: a comparative study with 10 Aslam Sohaib SA, Teh J, Nargund VH, perirenal neoplasms. Radiology 1985; venacavography and magnetic resonance Lumley JS, Hendry WF, Reznek RH. 154: 709–15 imaging. Urology 1997; 49: 32–4 Assessment of tumor invasion of the vena 19 Goldfarb DA, Novick AC, Lorig R 28 Sigman DB, Hasnain JU, Del Pizzo JJ, caval wall in renal cell carcinoma cases by et al. Magnetic resonance imaging Sklar GN. Real-time transesophageal magnetic resonance imaging. J Urol 2002; for assessment of vena caval tumor echocardiography for intraoperative 167: 1271–5 thrombi: a comparative study with surveillance of patients with renal cell 11 Semelka RC, Shoenut JP, Kroeker MA, venacavography and computerized carcinoma and vena caval extension MacMahon RG, Greenberg HM. tomography scanning. J Urol 1990; 144: undergoing radical nephrectomy. J Urol Renal lesions. controlled comparison 1100–3 1999; 161: 36–8 between CT and 1.5-T MR imaging with 20 Horan JJ, Robertson CN, Choyke PL 29 Hu H, He HD, Foley WD, Fox SH. nonenhanced and gadolinium-enhanced et al. The detection of renal carcinoma Four Multidetector-Row Helical CT. fat-suppressed spin-echo and breath- extension into the renal vein and inferior Image quality, volume coverage and hold FLASH techniques. Radiology 1992; vena cava: a prospective comparison of speed. Radiology 2000; 215: 55–62 182: 425–30 venacavography and magnetic resonance 30 Foley WD. Special focus session. 12 Myneni L, Hricak H, Carroll PR. imaging. J Urol 1989; 142: 943–7 Multidetector CT for abdominal and Magnetic resonance imaging of renal 21 Karstaedt N, McCullough DL, Wolfman visceral imaging. Radiographics 2002; 22: carcinoma with extension into the vena NT, Dyer RB. Magnetic resonance 701–19 cava: staging accuracy and recent imaging of the renal mass. J Urol 1986; 31 Sheth S, Scatarige JC, Horton KM, advances. Br J Urol 1991; 68: 571–8 136: 566–70 Corl FM, Fishman EK. Current 13 Fein AB, Lee JK, Balfe DM et al. Diagnosis 22 Dal Bianco M, Breda G, Artibani W et al. concepts in the diagnosis and and staging of renal cell carcinoma: a Echography in vena cava invasion from management of renal cell carcinoma: comparison of MR imaging and CT. Am J renal tumors. Eur Urol 1985; 11: 95–9 role of multidetector CT and three- Roentgenol 1987; 148: 749–53 23 Rahmouni A, Mathieu D, Berger JF, dimensional CT. Radiographics 2001; 21 14 Ramchandani P, Soulen RL, Schnall RI Montazel JL, Chopin DK, Vasile N. Fast (Suppl): S237–54 et al. Impact of magnetic resonance on magnetic resonance imaging in the staging of renal carcinoma. Urology 1986; evaluation of tumoral obstructions of the Correspondence: Nathan Lawrentschuk, 27: 564–8 inferior vena cava. J Urol 1992; 148: 14–7 Surgery and Urology, University of Melbourne, 15 Hallscheidt PJ, Bock M, Riedasch G et al. 24 Kabala JE, Gillatt DA, Persad RA, Penry Austin Hospital, Heidelberg, Victoria, Diagnostic accuracy of staging renal cell JB, Gingell JC, Chadwick D. Magnetic Australia. carcinomas using multidetector-row resonance imaging in the staging of renal e-mail: [email protected] computed tomography and magnetic cell carcinoma. Br J Radiol 1991; 64: 683– resonance imaging: a prospective 9 Abbreviations: IVC, inferior vena cava.
© 2005 BJU INTERNATIONAL 295 Original Article EPOTHILONES AND TRIALS FOR PROSTATE CANCER BHANDARI and HUSSAIN
Epothilones and the next generation of phase III trials for prostate cancer
MANISH S. BHANDARI and MAHA HUSSAIN Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA Accepted for publication 20 April 2005
KEYWORDS chemotherapeutic agents which have involves anti-angiogenic effects on tumour- provided phase II activity in HRPC to date. associated endothelial cells [20]. Moreover, epothilones, chemotherapy, hormone- certain alterations, e.g. loss of p53 function, refractory prostate cancer The broad spectrum of anti-neoplastic activity which is common in many cancer cells, may and the diverse clinical applications of confer hypersensitivity to taxanes as a result taxanes have engendered significant interest of altered expression of genes that are INTRODUCTION in identifying mechanistically similar but regulated by p53 [19]. structurally distinct compounds. Epothilones During 2005, an estimated 232 090 men will emerged as a new class of putative anti- Epothilones also induce microtubule have prostate cancer diagnosed (one in six neoplastic drugs based on in vitro assays bundling, formation of multipolar spindles men), while 30 350 men will die from the designed to competitively inhibit the binding and mitotic arrest [12]. Epothilones compete disease in the USA [1]. Because of PSA of paclitaxel to microtubules [12]. Epothilones with paclitaxel for binding to microtubules screening, most patients present with are macrolides extracted from a variety of and suppress microtubule dynamics in a localized prostate cancer and are candidates myxobacteria including Myxococcus xanthus manner similar to paclitaxel [21]; cell lines for definitive local therapy. Despite local or Sorangium cellulosum [13]. Like paclitaxel selected for resistance to epothilones contain therapy for localized disease, the actuarial and docetaxel, the epothilones function by mutations in b-tubulin that map near the 10-year likelihood of biochemical disease stabilizing the polymerized microtubule [14]; taxane-binding site identified in a crystal recurrence is ª25% [2,3]. For patients however, the epothilones are structurally structure of a docetaxel-ab tubulin complex who progress to systemic disease, or less distinct. [22]. However, recent studies in yeast reveal commonly for those who initially present with differences in the interactions between advanced disease, androgen deprivation is While an excellent contemporary review taxanes and epothilones with microtubules; regarded as the optimum first-line treatment discusses in detail the mechanistic and epothilones stabilize Saccharomyces [4,5]. Unfortunately, androgen-ablative cell-culture-based observations in the cerevisiae microtubules whereas paclitaxel therapy is only palliative, with a median development of epothilones [15], we briefly does not, presumably as a result of duration of response of 12–24 months [4,5]. discuss here their target (tubulins) and differences of their individual binding Second-line hormonal manipulation in men biological observations that provide insights interactions on tubulin function [23]. who progress on androgen deprivation to the anti-neoplastic activity of epothilones. results mostly in a biochemical response Preclinical studies also show important [6–8], which is generally transient and has no Active anticancer drugs (Vinca alkaloids and differences between epothilones and taxanes demonstrable impact on survival. Hormone- taxanes) work by perturbing the dynamic in drug-resistance mechanisms, both at the refractory prostate cancer (HRPC) is a equilibrium of microtubule polymerization target site and in the drug-efflux pump, P- progressive morbid disease, leading to and depolymerization [16]. The formation of glycoprotein. Epothilone cytotoxicity is eventual death over a median of 12– microtubules is essential for normal mitosis unaffected by an alanine-to-threonine 18 months. Chemotherapy in this setting has and cell division. This involves polymerization substitution at reside 364 in b tubulin that been actively investigated over the last two to of heterodimeric a/b tubulin subunits, with confers resistance to paclitaxel [21]. This has three decades, and until recently was only multiple isoforms of both a and b tubulin led to a hypothesis that clinically, tumour cells palliative. The recent studies of docetaxel- present in proliferating human cells, and is resistant to taxanes will retain sensitivity to based chemotherapy in men with androgen- regulated by several microtubule-associated epothilones and hence provide a role for these independent prostate cancer showed a proteins. Intact microtubule function is class of compounds in the setting of clinical survival benefit for the first time in this required for the formation and functioning of progression after taxane therapy. However, disease state [9,10] and lifted the burden of the mitotic spindle, and cells treated with resistance to epothilones may also result from HRPC as a chemoresistant disease [11]. agents that interfere with polymerization or b tubulin mutations [24,25] and these cell depolymerization show changes in spindle lines were also found to be cross-resistant These studies also provided proof-of-principle formation, as well as arrest at the G2/M phase to paclitaxel. Another well established that targeting the tubulins is a fruitful of cell cycle, which via poorly understood mechanism of taxane resistance to values in strategy for effective therapy in HRPC. mechanisms is associated with induction of the sub- to nanomolar concentration Based on this optimism, investigations of apoptosis [17–19]. Also, recent data suggest range, and comparison of the inhibitory epothilones are rapidly advancing in that an important component of the useful concentrations, involves over-expression HRPC, and this is the only new class of anticancer activity of these types of drugs of the multidrug efflux pump, the
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TABLE 1 Ixabepilone in front-line HRPC. From Ixabepilone/ TABLE 2 [26]. Variable estramustine Ixabepilone The efficacy of ixabepilone/ N4547estramustine vs Efficacy Value Efficacy ixabepilone, and the PSA response (41) N (%) prominent adverse events. Confirmed, n (%) 14 (34) Objective response 11/23 (48) 8/25 (32) From [27] Unconfirmed, n (%) 2 (5) Bone scan stable 28/36 (78) 24/40 (60) Objective response (19), n (%) 3 (16) ≥50% PSA decline 31/45 (69) 21/44 (48) Time to treatment failure, months 3 Days to PSA progression 141 145 PFS, months 6 Adverse events Toxicity (grade 3 or 4), n (%) Grade 3/4, % Neutropenia 18/12 13/9 Neutropenia 7 (17) Febrile neutropenia 6/2 0/4 Neuropathy (grade 3) Thrombosis 7/2 0/0 Sensory 5 (12) Neuropathy 7/0 13/0 Motor 1 (2) Unspecified 1 (2) Infection 5 (12) every 21 days and three times daily every 21 patients had a PSA level after therapy in the days. There were anti-tumour responses in undetectable range (<0.2 ng/mL). There were patients with melanoma, ovarian, nonsmall partial responses in three of 19 patients with P-glycoprotein. Epothilones are more cell lung cancer and breast cancer, many measurable disease. The median progression- cytotoxic than paclitaxel in cell culture, with previously treated with paclitaxel- or free survival (PFS) was 6 months. Overall the concentration for 50% inhibition by docetaxel-containing regimens [15]. Phase I survival data were not mature at the time various epothilones being slightly higher than evaluations of this agent in cytotoxic of reporting. The primary side-effects of those of paclitaxel in P-glycoprotein- combinations (e.g. with carboplatin) are also ixabepilone were haematological and expressing cell lines [15,26]. These results ongoing. A dosing schedule of 40 mg/m2 once neurological (Table 1). Seven patients (17%) have led to hypothesis that epothilones may every 3 weeks as a single agent was most had grade 3 or 4 neutropenia, while grade 3 be more active than taxanes in patients with prominently recommended and subsequently sensory neuropathy was reported in five malignancies characterized by high levels of adopted for phase II testing. (12%). Grade 3 motor neuropathy and P-glycoprotein expression. neuropathy of unspecified pathology SINGLE-AGENT PHASE II TRIAL IN HRPC occurred in one patient each (2%). Epothilones exist in at least four forms (A-D) [15]. Four epothilone analogues are currently The most mature study reported for front-line in human clinical trials in various phases of activity in phase II settings for any epitholone RANDOMIZED PHASE II TRIAL OF development, including aza-epothilone B was for BMS-247550 via two presentations at IXABEPILONE ALONE OR COMBINED (BMS-247550), a water-soluble semisynthetic the annual American Society of Clinical WITH ESTRAMUSTINE analogue of epothilone B (BMS-310705), Oncology (ASCO) meeting, 2004. A phase II epothilone B (EPO906), and epothilone D single-agent trial (South-West Oncology After earlier data showing that adding oral (KOS-862). In the following sections we Group, SWOG, 0111) was reported by Hussain estramustine to microtubule stabilizers is discuss the early clinical results and et al. [27]. The primary objective of this study associated with apparently greater activity in observations on the future development of was to assess the PSA response. Eligible prostate cancer, the combination of these agents. patients were those who had metastatic ixabepilone and estramustine in HRPC was prostate cancer and in whom androgen- investigated in another phase II multicentre CLINICAL DEVELOPMENT OF EPOTHILONE deprivation therapy and antiandrogen trial by Kelly et al. [28]. Eligible patients were withdrawal had failed; previous chemotherapy-naïve with progressive AZA-EPOTHILONE B (BMS-247550; chemotherapy was an exclusion criterion. disease. Treatment was with ixabepilone at IXABEPILONE) Patients were treatment at 40 mg/m2 i.v. over 35 mg/m2 i.v. on day 2 with or without 3 h every 3 weeks. Premedication with 50 mg estramustine 280 mg orally three times daily This agent has shown potent cytotoxic effects of diphenydramine and 150 mg ranitidine on days 1 to 5 every 3 weeks. Low-dose on paclitaxel-sensitive and -insensitive cells, was administered 1 h before treatment. Forty- prophylactic warfarin (2 mg/day) was given and in taxane-resistant tumour cell lines one patients (median age 73.1 years; median orally to patients receiving estramustine. over-expressing the P-glycoprotein [14]. PSA 126.5 ng/mL) were enrolled. There was There were 45 patients treated in the Phase I trials of BMS-247550 have been anti-tumour activity in 16 patients (39%) combination arm and 47 in the ixabepilone conducted for a cremophor-based with a ≥50% PSA decline, and 14 of the arm (92 in all). There was an objective formulation in a variety of schedules, responding patients (34%) had a confirmed response in eight of 25 patients (32%) treated including a single 60-min infusion every PSA decrease (Table 1). Of these 14 patients, with ixabepilone alone and in 11 of 23 (48%) 21 days, a weekly schedule, five-times daily 10 had a decrease in PSA of >80%. Two in the combined arm (Table 2). PSA response
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occurred in 48% of patients treated with Variable Placebo Atrasentan* TABLE 3 ixabepilone alone and in 69% in the Median days to disease progression 86 115 Results of the meta- combination arm. The time to PSA Incidence of bone pain, % 54 45 analysis of atrasentan vs progression was similar in both arms (141 Median days to bone pain 127 224 placebo in HRPC [49] days in the combined arm and 145 days in the ixabepilone-only arm). Neutropenia and *All endpoints were significant vs placebo. neuropathy were also the main adverse events in this study (Table 2). Neuropathy occurred in 84% of patients but was tolerable (grade 1 or 2); grade 3 neuropathy occurred in 7–13% of patients. The severity of neuropathy reported less neurotoxicity (6% grade III/IV polyethylene glycol-300, minimizing the improved over time and after a median toxicity) than a single dose given every 21 potential for carrier-associated adverse follow-up of 413 days, grade 2 or 3 days [30]; however, whether these schedules reactions. Despite being structurally very neuropathy had improved to grade 0 or differ in terms of anticancer efficacy in HRPC similar to ixabepilone, patupilone is 1 in 18 of 19 patients; 9% of patients in remains to be determined. associated primarily with diarrhoea, whereas the estramustine arm had a grade 3 or 4 ixabepilone is associated with neuropathy as thrombotic event. BMS-310705 (WATER-SOLUBLE its primary dose-limiting toxicity. This EPOTHILONE B ANALOGUE) important distinction may favourably affect the further development of this agent, given RESPONSE TO TAXANES AFTER BMS-310705 is a water soluble, semisynthetic that its toxicity does not overlap with that of IXABEPILONE THERAPY IN HRPC analogue of epothilone B and hence does not other taxanes. require a cremophor-based formulation. It Because preclinical data showed no cross- has been evaluated in phase I trials with two Hussain et al. [34] reported the results of a resistance between epothilones and taxanes, different schedules, involving a 15-min multicentre phase II study of weekly patients in the phase II study by Kelly et al. infusion given every 3 weeks [31] or weekly patupilone in patients with HRPC. A [28] who went on to receive second-line for 3 consecutive weeks every 28 days [32]. maximum of one previous chemotherapy taxane therapy were analysed retrospectively No premedications were used and there were regimen was allowed in this trial. Patients [29]. Of the 49 patients evaluated, those who no hypersensitivity reactions. For the every-3- were treated with six cycles of patupilone had been treated with either ixabepilone week schedule, neuropathy was dose-limiting 2.5 mg/m2 per week for 3 of 4 weeks. Forty- alone (23 men) or combined with and led to a recommendation of 40 mg/m2 as five patients (median age 69 years) were estramustine (28 men) benefited from taxane the phase II dose. When administered weekly enrolled and 29 (64%) had received previous therapy. There were PSA responses from for 3 consecutive weeks every 28 days, grade chemotherapy. Patupilone was associated second-line taxane therapy in 51% of patients 3 diarrhoea was dose-limiting at 30 mg/m2. At with grade 3 diarrhoea in 22% of patients, (95% CI 33–66%), with a median time to PSA the 20 mg/m2 dose using this schedule, 25% resulting in grade 3 or 4 dehydration in 11%. progression of 4.6 months. There were PSA of patients missed the third weekly dose No grade 3 or 4 neuropathy was reported. responses in 61% of first-line responding because of diarrhoea. Weekly treatment was associated with a 50% patients, but significantly there were PSA PSA response in seven of 28 patients (25%; responses also in a third of those who did not Also, at this dose sensory neuropathy Table 3). Importantly, three of the seven respond to first-line ixabepilone therapy. occurred during the fourth course in two- responders had received previous taxane- thirds of the patients. Based on these results, based chemotherapy. The median duration The median survival in this cohort was evaluation of a 2-weeks on, 1-week off of PSA response was 2.2 months. Also, 10.7 months from the initiation of second- schedule for BMS-310705 is ongoing. the preliminary results of several phase line taxane-based therapy. Hence, this Responses were documented with both II trials of EPO906 in refractory solid analysis supports the hypothesis that schedules, including partial responses in tumours were reported at the 20th epothilones and taxanes are not cross- patients with ovarian, bladder, stomach and Chemotherapy Foundation Symposium resistant, and may be useful in tandem. A breast cancer, and a complete response in a (http://www.mssm.edu.proxy.lib.umich.edu/ multicentre National Cancer Institute- patient with nonsmall cell lung cancer. Based tcf/archives/symposiumxx/index.shtml). These sponsored phase 2 trial currently recruiting is on the encouraging activity of BMS-247550, early phase II results suggest that EPO906 is examining the use of second-line ixabepilone further evaluation of BMS-310705 is also a broadly active drug and is able to induce vs mitoxantrone and prednisolone in patients planned in HRPC. responses in at least some patients with with metastatic disease and progressive taxane-resistant disease. Further clinical disease after taxane therapy. EPOTHILONE B (EPO906; PATUPILONE) development has not been publicly disclosed, but is anticipated. These preliminary phase II results are Patupilone (EPO 906; epothilone B) is a more consistent with preclinical data and suggest potent microtubule stabilizer than paclitaxel that BMS-247550 is a broadly active and in preclinical studies was found to EPOTHILONE D (KOS-862) anticancer drug. A schedule involving daily accumulate in intracellular concentrations administration for 5 days every 3 weeks in several hundred times greater than in the The phase I evaluation of KOS-862 included second-line nonsmall cell lung cancer extracellular medium [33]. It is formulated in several dosing schedules: a single dose every
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3 weeks, a daily dose three times every not to be expressed, probably due to gene Prostate, were also significantly improved 3 weeks, a fixed-rate dose every 3 weeks, and silencing through methylation of the with atrasentan, most notably in the pain a weekly dose for 3 weeks with a 1-week rest promoter [36,42,43]. Hence, the endothelin component of the prostate cancer subscore. [15]. There was significant toxicity in patients axis is hyperactive in prostate cancer, while As with the earlier trial, the most common treated with the single-dose every 3 weeks, the pathway has an important and perhaps adverse events were rhinitis, headache and which included impaired gait and cognitive/ essential role in the progression of bone peripheral oedema. A pooled intent-to-treat perceptual abnormalities, sensory metastases from prostate cancer [37,38]. meta-analysis of all 1097 patients neuropathies, and fatigue. There were Atrasentan (ABT-627) is an orally bioavailable randomized to receive either atrasentan or responses observed in heavily pre-treated inhibitor of the endothelin-A receptor [44]. placebo in the two trials [47,48] was patients with testicular, ovarian, pancreatic Atrasentan inhibits prostate cancer cell- conducted to more precisely estimate the and breast cancers. Dose-limiting toxicities related paracrine mitogenic stimulation of co- treatment effect of the agent and to increase have not been reported yet. Phase II studies in cultured osteoblasts mediated in part through the power to detect a modest but clinically front-line HRPC settings are planned. the insulin growth factor pathway and is meaningful effect [49]. thought to be important in the initiation of WHERE DO WE GO FROM HERE? bone metastases [45,46]. Atrasentan also Results of the meta-analysis showed a NEXT-GENERATION (PHASE III) TRIALS inhibits cascading self-stimulatory autocrine significant increase in the time to disease IN HRPC effects of endothelin-1 during the metastatic progression with atrasentan (P = 0.013), process seen in model systems [45]. which translated into a 19% reduction A new generation of clinical trials will (hazard ratio 1.19) in the risk of disease evaluate a variety of newer agents against Atrasentan has completed randomized, progression. Of note, the improvement was traditional targets (e.g. epothilones against placebo-controlled phase 2 and 3 studies in detected by 3 months and was sustained the mitotic spindle), and against entirely new men with HRPC, with time to progression as throughout the study period. targets in validated prostate-cancer pathways the clinical endpoint. The phase 2 randomized, (angiogenesis and endothelin pathway, controlled trial evaluated the activity of There were also significant decreases in the among others) based on a deeper 2.5 mg or 10 mg of atrasentan in patients incidence of and the onset to pain in the understanding of the biology of androgen- with metastatic HRPC. In that study of 288 atrasentan vs placebo groups (P = 0.003). The independent prostate cancer. This area of patients, there was a significantly longer median pain-free duration in the atrasentan ‘rational therapy development’ based on an median time to disease progression (196 arm was 7 months, which was 97 days longer understanding of the basic biology of prostate days vs 129 days, P = 0.021) and to PSA than in the placebo arm. Patients receiving cancer, rather than empirical evaluation of progression (155 days vs 71 days; P = 0.002) atrasentan had a lower incidence of pain and chemotherapeutic agents, is the new frontier in the 84 evaluable patients enrolled in the remained pain-free longer, for a median of which holds the most promise in advancing 10-mg arm and the placebo arm (104 men), 224 vs 127 days in the placebo arm (Table 3). the systemic treatment of HRPC. This next respectively [47]. Both measures were also generation of phase III trials in HRPC are longer in the 10-mg group, although the There is good preclinical evidence for an described, along with their rationale and median time to PSA progression was not additive effect of atrasentan and taxanes. In study designs. statistically significant in this arm. Atrasentan ovarian cell-line models pretreatment with was well tolerated, with the most common atrasentan sensitizes the cells to paclitaxel- TESTING TARGETED THERAPY IN PHASE III and significant treatment-related adverse induced apoptosis [50]. In xenograft models, SETTINGS: THE SWOG 0421 TRIAL events being headache, rhinitis and peripheral the combination has additive effects on oedema. tumour detumescence, apoptotic indices and The endothelin pathway is particularly angiogenesis [51]. Based on this, and the important in several phases of prostate cancer Results from the recently reported phase III independent activity of both agents in HRPC, development and progression, but appears trial evaluating the 10-mg dose of atrasentan the SWOG designed a protocol (SWOG 0421) to be especially important in the progression (408 men) vs placebo (401) in patients with to evaluate, in a randomized, placebo- of bone metastases [35–38]. In the normal metastatic HRPC continued to show controlled and direct comparison, treatment prostate gland, mature endothelin beneficial results in favour of atrasentan, with docetaxel with or without atrasentan (endothelin-1) is produced by epithelial cells. although the primary endpoint of disease (Fig. 1). With the PFS as the primary outcome The highest concentrations of endothelin-1 progression (i.e. new lesions, clinical and median survival as the main secondary in the body are found in seminal fluid. symptoms, skeletal complications, or pain) outcome, this trial with 706 patients is In prostate cancer, key components of were not statistically significant in the intent- powered at 96% to detect a 33% increase in endothelin-1 clearance, endothelin-B to-treat analysis [48]. Nevertheless, increases PFS (from 6 to 8 months) and powered at receptor binding [39] and neutral in bone alkaline phosphatase, total alkaline 85% to detect a 30% increase in median endopeptidase activity are diminished [40], phosphatase and PSA were significantly survival with the addition of atrasentan to resulting in an increase in local endothelin-1 reduced in patients treated with atrasentan, docetaxel-based chemotherapy. Additional concentrations. There is also increased suggesting that this agent delays disease outcomes, such as improvement in pain, endothelin-A-receptor expression with progression. quality of life, PSA response and its surrogates advancing tumour stage and grade in both for survival, objective tumour response and primary and metastatic prostate cancer Quality-of-life variables, as measured by the bone turn-over markers, will also be [35,41]. By contrast, endothelin-B tends Functional Assessment of Cancer Therapy – ascertained.
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TESTING BIO-CHEMOTHERAPY IN PHASE SWOG 0421 FIG. 1. III SETTINGS: THE CANCER AND Phase III study of Docetaxel + Placebo VS. The details of the SWOG LEUKAEMIA GROUP B (CALGB) Docetaxel + Atrasentan in HRPC 0421 trial. 9040 TRIAL Design: N = 706 patients An essential step in the metastasis of solid Stratify: Arm A: • Type of progression R tumours is the growth of new blood vessels, • Docetaxel 75 mg/m2 Q 3 weeks • PS: 0-1 vs 2-3 A which must be generated for metastases to • Prednisone 10 mg qd • Prior RP N grow. Vascular growth factors, including D • Atrasentan 10 mg qd • Bisphosphinate use O vascular endothelial growth factor (VEGF), • Alk Phos < 5 vs. > 5 ULN M matrix metalloproteins and integrins, regulate I Arm B: Primary Endpoint: Z • Docetaxel 75 mg/m2 Q 3 weeks the process of angiogenesis. Inhibiting these PFS E • Prednisone 10 mg qd targets can arrest tumour growth and inhibit Secondary Endpoints: • Placebo metastatic spread. These vascular growth Survival Pain, PSA, QOL, factors are expressed in both the tissue and bone markers, etc. serum of patients with prostate cancer [52]. Elevated VEGF levels portend a poor prognosis in HRPC. Bevacizumab, a humanized CALGB 9040 FIG. 2. monoclonal antibody directed against VEGF, is Phase III study of Docetaxel + Prednisone with The details of the CALGB active in combination with chemotherapeutic or without Bevacizumab (Avastin®) in HRPC 9040 trial. agents in advanced colorectal carcinoma. A Design: similar therapeutic approach has been N = 1020 patients Stratify: Arm A: undertaken with bevacizumab in prostate R ¥ • Halabi nomogram • Dexamethasone 8 mg po 3 doses cancer. A trial by the CALGB found promising A • Docetaxel 75 mg/m2 on D#1 q21d N • Prednisone 10 mg po daily activity in HRPC with the combination of Primary Endpoint: D • Bevacizumab 15 mg/kg on D#1 q21d docetaxel 70 mg/m2 every 3 weeks, Overall survival Secondary Endpoints: O estramustine 280 mg oral three times daily on PSA response M PFS I Arm B: days 1–5 and bevacizumab 16 mg/kg every ¥ Objective response Z • Dexamethasone 8 mg po 3 doses 3 weeks [53]; 79 patients were enrolled and E • Docetaxel 75 mg/m2 on D#1 q21d nine of 17 evaluable patients had a partial • Reported participation • Prednisone 10 mg po daily radiographic response. Of 20 patients from ECOG and NCIC • Placebo IV on D#1 q21d evaluable for PSA decline, 13 (65%) had a Courtesy: Dr. Kevin Kelly, Memorial Sloan-Kettering Cancer Center, New York confirmed PSA decline by half. At the time that this trial was reported, the trial had yet to mature and the median survival was not HRPC, including no cross-resistance with in the care of these patients to enrol them reported. Encouraged by this early indication taxanes. This class of compounds is the only into key clinical trials investigating exciting of significant activity, the CALGB initiated the new chemotherapeutic to have provided the new classes of compounds. CALGB 9040 phase III trial (Fig. 2) to evaluate most advanced data in phase II settings in the first bio-chemotherapy combination in HRPC. Therefore, the logical next step will be ACKNOWLEDGEMENTS phase III settings in HRPC. In cooperation with to pursue definitive phase III trials to confirm the Easter Oncology Cooperative Group and the activity of epothilones in tandem with Manish Bhandari was supported by the the National Cancer Institute of Canada, docetaxel, given the experience to date. Such American Society of Clinical Oncology the trial is designed to enrol 1020 patients, trials will lay the foundation for defining the Hartford Foundation grant. stratified by the Halabi nomogram [54]. The role of epothilones in the first- and second- primary outcome is overall survival with a line settings in HRPC. The distinct toxicity 95% power to detect a 25% increase in profiles of each of these drugs will probably CONFLICT OF INTEREST median survival (from 19 to 24 months). influence their future development and Secondary outcomes include PSA response, combination therapy with existing Maha Hussein received research support from PFS and response rate. This trial is designed to chemotherapy regimens. BMS. recruit over 36 months and have data on follow-up for at least 24 months. Also, for the first time, phase III trials in rationally designed combinations of targeted therapeutics (SWOG 0421 and CALGB 9040) REFERENCES SUMMARY are being undertaken in the USA for patients with HRPC, under the auspices of the major 1 Jemal A, Murray T, Ward E et al. Cancer While the phase II trials of epothilones are cooperative groups. However, we will not be statistics 2005. CA Cancer J Clin 2005; 55: currently ongoing, ixabepilone (BMS-247550) able to rapidly develop and provide these 10–30 and patupilone (EPO906) have provided the agents for patients with cancer unless there is 2 Han M, Partin AW, Pound CR, Epstein most convincing phase II data for activity in a concerted and serious effort by all involved JI, Walsh PC. Long-term biochemical
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Abstracts of the 40th Annual Meeting of displays heterogeneous, site specific antagonists. World J Urol 2005; 23: the American Society of Clinical Oncology; methylation patterns in normal and 19–27 June 5–8, 2004; New Orleans, Louisiana. tumor cells. Hum Mol Genet 2001; 10: 50 Rosano L, Spinella F, Salani D et al. Abstract 4563 903–10 Therapeutic targeting of the endothelin a 35 Nelson J, Bagnato A, Battistini B, 43 Jeronimo C, Henrique R, Campos receptor in human ovarian carcinoma. Nisen P. The endothelin axis: emerging PF et al. Endothelin B receptor Cancer Res 2003; 63: 2447–53 role in cancer. Nat Rev Cancer 2003; 3: gene hypermethylation in prostate 51 Del Bufalo D, Di Castro V, Biroccio 110–6 adenocarcinoma. J Clin Pathol 2003; 56: A et al. Endothelin-1 protects ovarian 36 Nelson JB, Lee WH, Nguyen SH et al. 52–5 carcinoma cells against paclitaxel- Methylation of the 5¢ CpG island of the 44 Wessale JL, Adler AL, Novosad EI et al. induced apoptosis: requirement for Akt endothelin B receptor gene is common in Pharmacology of endothelin receptor activation. Mol Pharmacol 2002; 61: 524– human prostate cancer. Cancer Res 1997; antagonists ABT-627, ABT-546, A-182086 32 57: 35–7 and A-192621: ex vivo and in vivo studies. 52 Lara PN Jr, Twardowski P, Quinn DI. 37 Mundy GR, Yin JJ, Mohammad KS Clin Sci (Lond) 2002; 103 (Suppl. 48): Angiogenesis-targeted therapies in et al. A. Endothelin-1 and osteoblastic 112S–117S prostate cancer. Clin Prostate Cancer metastasis. Proc Natl Acad Sci USA 2003; 45 Pirtskhalaishvili G, Nelson JB. 2004; 3: 165–73 100: 10588–9 Endothelium-derived factors as paracrine 53 Picus J, Halabi S, Rini BI et al. The use of 38 Yin JJ, Mohammad KS, Kakonen SM mediators of prostate cancer progression. bevacizumab (B) with docetaxel (D) and et al. A causal role for endothelin-1 in Prostate 2000; 44: 77–87 estramustine (E) in hormone refractory the pathogenesis of osteoblastic bone 46 Fizazi K, Yang J, Peleg S et al. Prostate prostate cancer (HRPC): initial results of metastases. Proc Natl Acad Sci USA 2003; cancer cells–osteoblast interaction shifts CALGB 90006. Proc Am Soc Clin Oncol 100: 10954–9 expression of growth/survival-related 2004; 22: 1578A 39 Nelson JB, Chan-Tack K, Hedican genes in prostate cancer and reduces 54 Halabi S, Small EJ, Kantoff PW et al. SP et al. Endothelin-1 production expression of osteoprotegerin in Prognostic model for predicting survival and decreased endothelin B receptor osteoblasts. Clin Cancer Res 2003; 9: in men with hormone-refractory expression in advanced prostate cancer. 2587–97 metastatic prostate cancer. J Clin Oncol Cancer Res 1996; 56: 663–8 47 Carducci MA, Padley RJ, Breul J et al. 2003; 21: 1232–7 40 Papandreou CN, Usmani B, Geng Y et al. Effect of endothelin-A receptor blockade Neutral endopeptidase 24.11 loss in with atrasentan on tumor progression in Correspondence: Maha Hussain, Oncology metastatic human prostate cancer men with hormone-refractory prostate and Urology, University of Michigan contributes to androgen-independent cancer: a randomized, phase II, placebo- Comprehensive Cancer Center, 1500 E. progression. Nature Med 1998; 4: controlled trial. J Clin Oncol 2003; 21: Medical Center Dr/7314 CCGC, Ann Arbor, MI 50–7 679–89 48109–0946, USA. 41 Nelson JB, Hedican SP, George DJ 48 Carducci M, Nelson JB, Saad F et al. e-mail: [email protected] et al. Identification of endothelin-1 Effects of atrasentan on disease in the pathophysiology of metastatic progression and biological markers Abbreviations: HRPC, hormone-refractory adenocarcinoma of the prostate. Nature in men with metastatic hormone- prostate cancer; SWOG, South-West Med 1995; 1: 944–9 refractory prostate cancer: phase 3 Oncology Group; CALGB, Cancer and 42 Pao MM, Tsutsumi M, Liang G, Uzvolgyi study. Proc Am Soc Clin Oncol 2004; Leukaemia Group B; PFS, progression-free E, Gonzales FA, Jones P. A. The 23: 396, A4508 survival; VEGF, vascular endothelial growth endothelin receptor B (EDNRB) promoter 49 Nelson JB. Endothelin receptor factor.
302 © 2005 BJU INTERNATIONAL Original Article TUMOUR MARKERS FOR METASTATIC PROSTATE CANCER AND LOW PSA BIRTLE et al.
Tumour markers for managing men who present with metastatic prostate cancer and serum prostate-specific antigen levels of <10 ng/mL
ALISON J. BIRTLE, ALEX FREEMAN*, JOHN R.W. MASTERS, HEATHER A. PAYNE†, STEPHEN J. HARLAND† and CONTRIBUTORS TO THE BAUS SECTION OF ONCOLOGY CANCER REGISTRY‡ The Prostate Cancer Research Centre, The Institute of Urology, *Department of Histopathology, University College London, †The Meyerstein Institute of Oncology, The Middlesex Hospital, and ‡British Association of Urological Surgeons, Royal College of Surgeons, Lincolns Inn Fields, London, UK Accepted for publication 8 March 2005
OBJECTIVE immunostained for PSA, prostatic acid nine of the 12 in which PSA staining was phosphatase (PAP), prostate-specific equivocal. There was strong AR expression in To define immunohistochemical features of membrane antigen (PSMA), androgen 30 (91%) cases and it was present in areas the primary cancers that might help in the receptor (AR), chromogranin A and CD 56. where PSA was absent. differential diagnosis and monitoring of treatment in men presenting with metastatic RESULTS CONCLUSION prostate cancer and low serum levels of prostate-specific antigen (PSA), who can be The combined Gleason scores were 8–10 In this patient group, immunohistochemical difficult to diagnose and manage. in 25 men (76%) and 6 or 7 in the other assessments of PSMA and AR are potentially eight (24%). Morphologically, there useful as diagnostic markers. PATIENTS AND METHODS were no neuroendocrine features. PSA immunostaining was equivocal in 12 (36%) KEYWORDS Paraffin blocks of prostate biopsies were cases and in a further 19 (58%) was strong obtained for 33 patients presenting with but focal and could be missed on biopsy PSA-negative prostate cancer, prostate- untreated metastatic prostate cancer and sampling. PSMA was expressed in 90% of specific membrane antigen, androgen serum PSA levels of <10 ng/mL. Sections were cases, and staining was widely distributed in receptor
INTRODUCTION neuroendocrine differentiation might be Hospital, providing a combined total of 33 useful in patients in whom the serum PSA men. Paraffin-embedded formalin-fixed PSA provides a reliable serum marker for most levels are misleadingly low. The two primary archival prostatic tissue specimens were men with metastatic prostate cancer [1–3], candidates as alternative markers were obtained. Serial sections of each case were cut but there is a small group who present with prostatic acid phosphatase (PAP) and and slides stained with haematoxylin and low serum levels of PSA in the presence of prostate-specific membrane antigen (PSMA), eosin (H&E) and reviewed by a pathologist metastatic disease [4,5]. The clinical features neither of which has been evaluated in the with a special interest in urological pathology, of the ‘PSA-negative group’ have been context of low serum levels of PSA. PAP was in to confirm the diagnosis and grade of described and include men presenting with widespread clinical use before the advent of carcinoma. The Local Ethics Committee of the untreated metastatic disease with serum PSA PSA testing, but is less sensitive and specific University College of London National Health levels of <10 ng/mL [6]. These cancers have a [7] and was superseded. PSMA is more highly Service Trust and the South-East Multi-Centre worse prognosis because they tend to be expressed in malignant than in benign Research Ethics Committee approved the aggressive and to respond poorly to hormone prostatic tissue [8], but is not used routinely study. ablation, and can be difficult to manage as a tissue or serum marker. because of the lack of a reliable serum marker For immunohistochemical staining, 3 mm [6]. The series of cases presented here is the serial tissue sections from each case were largest group of these patients yet studied [6]. mounted onto Vectabond-coated slides and PATIENTS AND METHODS stained using antibodies to PSA, AR, PSMA, The primary aim of this study was to use PSA PAP, chromogranin A and CD56 (Table 1). In and androgen receptor (AR) immunostaining Patients presenting with untreated addition, cytokeratin-7 and -20 and 34bE12 to determine to what extent ‘PSA-negative histopathologically confirmed metastatic antibodies were used to exclude TCC in three cancers’ are typical of prostate prostate cancer and a serum PSA level of cases with no classical morphological features adenocarcinoma. We then investigated <10 ng/mL were identified from the BAUS of prostate cancer [9]. Appropriate positive whether immunohistochemical staining of Cancer Registry 2000 and 2001 databases, and negative controls were included for each alternative prostate proteins and markers of and from local referrals to the Middlesex antibody, and standard methods of antigen
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retrieval and previously validated antibody Primary Antigen TABLE 1 concentrations for all antibodies other than antibody Concentration Species/catalogue id retrieval* Details of primary PSMA were used. The optimum dilution of AR 1/100 Mouse/Dako M3562 High pH antibodies and antigen and preferred method of antigen retrieval PSA 1/20 Mouse/Dako M0750 NR retrieval for PSMA were determined by titrating PSMA 1/100 Goat/sc-101271 High pH the antibody using a high-grade radical PAP 1/1000 Mouse/Dako M0792 NR prostatectomy sample as a positive Chr A 1/10 Mouse/Dako M0869 NR control. CD56 1/10 Mouse/MON9006-1 PC CK7 1/100 Mouse/Dako N1626 TE In brief, the tissue sections were dewaxed in CK 20 1/100 Mouse/Dako N1627 TE xylene and taken through a series of graded 34bE12 1/50 Mouse/Dako M0630 MWD alcohols to water. The method of antigen retrieval, primary antibody concentration and *High pH, 25 min microwaving at full power, stand 10 min, in Dako high method of staining are also summarised in pH retrieval solution (S3007); NR, no antigen retrieval used; TE, 20 min Table 1. After antigen retrieval, endogenous microwave at full power in Tris-EDTA buffer, pH 9.0; MWD, 25 min peroxidase activity was quenched by microwave at full power, 10 min stand, in Dako Retrieval Solution incubation with peroxidase blocking solution (S1699); PC, 2 min pressure cooking at full pressure in citrate buffer S2023, DAKO, Glostrup, Denmark) and pH 6.0. sections were rinsed with washing buffer (DAKO K5006). Then 200 mL of each primary antibody was incubated at the required concentration in antibody diluent (DAKO S2022) for 60 min at room temperature. The EnVision system (DAKO), using a one-step unaware of sample origin, using a (58%) cases there was strong staining (++ or system for the secondary antibody, and semiquantitative assessment and considering +++), but it was focal and could easily have streptavidin-biotin complex and reducing the intensity (0, negative; +, low intensity, just been missed by a needle biopsy sampling. In background staining from endogenous biotin above level of background staining; ++, only two cases was there widespread staining [10], was used for all immunohistochemical moderate intensity; +++, high intensity) and for PSA in the malignant cells. The association staining except PSMA. For the EnVision extent (focal/diffuse) of staining. Focal areas of PSA staining with AR, PSMA, PAP, technique, the EnVision horseradish containing <10 cells with low intensity chromogranin A and Gleason score is peroxidase rabbit/mouse reagent (DAKO staining were classified as negative (Fig. 1). summarised in Table 2. K5007), containing dextran coupled to peroxidase and goat secondary antibody There was strong staining for AR in most of molecules against rabbit and mouse, was RESULTS the nuclei in 29 (88%) cases, with moderate or incubated at room temperature for 60 min. strong staining in nine that were negative or The immunoperoxidase antigen-antibody In 19 (58%) cases archival tissue was obtained focally + for PSA (Table 2). In the three cases reaction products were visualised by from TRUS-guided prostatic biopsy that were focally + for PSA, the AR staining incubation in diaminobenzidine for 10 min specimens, with a further 13 specimens was present in areas that were negative for at room temperature. The tissue was derived from TURP and one from a bladder PSA. Only three cases were negative for both counterstained with Harris’ haematoxylin for neck resection; 27 of 33 (81%) patients had PSA and AR, and one was re-classified as a 2 min, dehydrated in alcohols and cleared in bone metastases and four presented with urothelial tumour on the basis of staining for xylene. soft-tissue metastases. All patients received cytokeratin-7 and 34bE12 staining. primary hormonal treatment [6]. PSMA was visualised using a goat peroxidase- Twenty-four (73%) cases were positive for antiperoxidase system [11]. After antigen Twenty-five men (76%) had a combined PAP, although the staining was classified as retrieval and washing as described above, Gleason score of 8–10 with the remaining focal in all of these. There was an association slides were incubated with normal rabbit eight (24%) having a score of 6 or 7. between PSA and PAP staining in 19 cases, serum 1 : 10 for 10 min at room temperature. No case had morphological features of with 16 cancers showing moderate or strong Primary antibody (goat) was then added for neuroendocrine differentiation. One case focal staining for both PSA and PAP and three 60 min followed by a 1 : 200 dilution of initially classified as a prostatic carcinoma being negative for both markers. rabbit antigoat secondary antibody in excess. with a combined Gleason score of Then 200 mL of 1 : 100 goat-peroxidase- 10 was subsequently re-classified as a There was PSMA staining in 30 (90%) of the antiperoxidase was added for 60 min at room urothelial carcinoma on the basis of cases, and it was widespread in 21 of these temperature with diaminobenzidine detection immunohistochemical expression of positive cases. In the 12 cases that were as before. cytokeratin-7 and 34bE12. negative or focal + for PSA, PSMA was diffusely positive in 10. The only case that was Two of the authors (A.F. and A.J.B.) Of the 33 cases, nine (27%) were completely negative for both PSA and PSMA was re- independently assessed the negative for PSA and a further three were classified as a urothelial cancer on the basis of immunohistochemical staining while classified as focal + (Table 2). In a further 19 cytokeratin staining.
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FIG. 1. Two cases are shown, a typical PSA-negative cancer (A-E) and one that stained for PSA (F-J). A,F: H&E, Chromogranin A immunostaining was ¥200. B,G PSA; B is PSA-negative, ¥200; G is PSA +++ focal positive, ¥100. C,H: AR; C and H are +++ diffuse negative in 24 cases (72%), eight of which nuclear staining, ¥200. D,I: PAP; D is +++ focal positive, ¥100; I is + focal positive, ¥100. E,J: PSMA, E is +++ were also negative for PSA (Table 2). In six diffuse, ¥100; J is ++ diffuse, ¥200. cases (18%) there was strong but focal immunostaining for the neuroendocrine marker. However, the extent of staining was not considered sufficient to classify these tumours as neuroendocrine. CD56 was focally positive in only three (9%) cases.
Three cases were examined with urothelial markers, as they had no classical morphological features of prostate cancer. Two cases were cytokeratin-7 positive and cytokeratin-20 negative, the other cytokeratin-7 negative and cytokeratin-20 positive. 34bE12 was positive in one cytokeratin-7 positive case, which was re- classified as a urothelial tumour, as it also lacked expression of PSA, PSMA, PAP and AR.
DISCUSSION
All 12 of the 33 tumours in which PSA immunostaining was classified as negative or focal + were of high-grade. Although PSA- negative prostate cancers are rare, they are more likely to be found amongst cancers that are high-grade [12]. It has been suggested that such cases undergo ‘de-differentiation’, losing characteristics of prostate epithelial cells and hence altering the relationship between serum PSA levels and tumour volume [13]. This ‘functional de- differentiation’ [14] has been associated with a poor hormonal response and more aggressive biological behaviour. Similarly, first-line hormonal responses and overall survival are shorter in this group of patients [6].
Despite the low serum PSA levels, there was at least some evidence of staining for PSA in >70% the cases, although in many of these the staining was focal and could be missed on prostatic biopsy sampling. Although PSA and PAP are usually concordant in advanced prostate cancer [1], occasional discordance in immunohistochemical studies has been described [15]. The results were concordant for PSA and PAP in most cases, although in only six (18%) was there widespread PAP immunostaining. Thus, PAP staining could also be subject to sampling error on prostate biopsy.
In contrast to PAP and PSA, there was staining for PSMA in all but three cases, and it was
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diffuse in the vast majority, in agreement with PSA 0 Focal + Focal ++/+++* TABLE 2 previous studies [8,16]. In tumours where AR Summary of there were both PSA-negative and -positive 03†00immunohistochemistry areas PSMA staining occurred in both regions. Focal + 00 1 results in 33 cases Focally positive areas of PSA staining might Diffuse ++/+++ 63 20 be missed on biopsy, so the present results PSMA suggest that PSMA staining may be of value 01†02 in this patient group to aid diagnosis and Focal + 10 8 confirm prostatic origin despite the low Diffuse ++/+++ 73 11 serum PSA level. PAP 0303 Alterations in the AR by mutation, deletion or Focal + 10 2 over-expression have all been implicated in ++/+++ 53 16 the development of hormone-refractory (No diffuse staining) prostate cancer [17]. Given that PSA is an Chromogranin A androgen-dependent gene [18], we 08412 postulated that AR deletion is a potential Focal + 10 2 mechanism to explain the low levels of serum Focal ++/+++ 01 5‡ PSA in untreated metastatic prostate cancer. (No diffuse staining) *Diffuse staining in two However, there was strong and widespread Gleason score cases only; †One case staining of nuclei for AR in 88% of cases and 6001which was AR-/PSA-/ it was present in all but three of the cases that 7016PSMA-negative was were negative or weakly positive for PSA. The 8003positive for urothelial widespread AR staining might, like that for 9517markers; ‡Very scattered PSMA, be of value in the diagnosis of prostate 10 4 1 4 staining. cancer in patients with low serum levels of PSA.
It was postulated that neuroendocrine differentiation is one mechanism responsible have a poor prognosis. We identified 33 CONFLICT OF INTEREST for low PSA production in poorly cancers in this category, the largest series yet differentiated prostate tumours [19]. In a described, and used immunohistochemistry recent study, tissue neuroendocrine markers, on the primary tumours. The results show REFERENCES including chromogranin A and neurone- that PSMA and AR immunostaining are specific enolase, were identified in 18 patients widespread in most of these tumours, 1 Stamey TA, Yang N, Hay AR, McNeal with clinically progressive androgen- including cases in which PSA and PAP staining JE, Freiha FS, Redwine E. Prostate- independent prostate cancer and low serum is negative or weak and focal. Thus, these specific antigen as a serum marker for PSA levels [20], suggesting that a proportion markers may be of value in the diagnosis of adenocarcinoma of the prostate. N Engl J of low serum PSA and metastatic prostate prostate cancer in patients with clinical Med 1987; 317: 909–16 cancers were neuroendocrine in origin. In suspicion of disease but low serum levels of 2 Catalona WJ. Prostate cancer screening. contrast, in the present men with untreated PSA. In addition, the potential value of PSMA BJU Int 2004; 94: 964–6 metastatic prostate cancers and low serum as a serum biomarker of prostate cancer 3 Kirby R, Fitzpatrick J. Prostate-specific levels of PSA, no tumour had a predominantly merits further investigation. antigen testing for the early detection of neuroendocrine phenotype. prostate cancer. BJU Int 2004; 94: 966–7 4 Oommen R, Geethanjali FS, CD56, which has been used to detect Gopalakrishnan G et al. Correlation of neuroendocrine differentiation [21], was ACKNOWLEDGEMENTS serum prostate specific antigen levels and focally positive in only three (9%) cases. Thus, bone scintigraphy in carcinoma prostate. whilst neuroendocrine differentiation may be Sarah Fowler BAUS Cancer Registry Database Br J Radiol 1994; 67: 469–71 one mechanism by which prostate cancers Manager. The contributors to the BAUS 5 Yamamoto S, Ito T, Akiyama A, Aizawa develop resistance after androgen ablation, it Section of Oncology Cancer Registry, in T, Miki M, Tachibana M. M1 prostate does not appear to be a significant factor particular E Ahiaku, RA Blades, FJ Bramble, SP cancer with a serum level of prostate- explaining the low serum levels of PSA in this Bramwell, NR Boucher, WG Bowsher, TE specific antigen less than 10 ng/mL. Int J group of untreated patients. Briggs, C Bunce, C Carter, D Chadwick, RA Urol 2001; 8: 374–9 Corfield, B Ellis, JGW Feggetter, MJ James, WG 6 Birtle AJ, Freeman A, Masters JR, Payne In conclusion, men presenting with Jones, RP Kulkarni, HG Kynaston, SS HA, Harland SJ. Clinical features of untreated metastatic prostate cancer and Matanhelia, GS McIntosh, GE Mobb, ML patients who present with metastatic inappropriately low levels of serum PSA Pantelides, A Paracha, RD Pocock, KK Prasad, G prostate carcinoma and serum prostate- (<10 ng/mL) are rare, difficult to manage and Sole, B Waymont. specific antigen (PSA) levels <10 ng/mL:
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the ‘PSA negative’ patients. Cancer 2003; properties of soluble antigen-antibody adenocarcinoma: a study of 184 cases. 98: 2362–7 complex (horseradish peroxidase- Cancer 1998; 82: 2256–61 7 Bogdanowicz JF, Bentvelsen FM, antihorseradish peroxidase) and its use in 17 Feldman BJ, Feldman D. The Oosterom R, Schroeder FH. Evaluation identification of spirochetes. J Histochem development of androgen-independent of prostate-specific antigen and prostatic Cytochem 1970; 18: 315–33 prostate cancer. Nat Rev Cancer 2001; 1: acid phosphatase in untreated prostatic 12 Aihara M, Lebovitz RM, Wheeler TM, 34–45 carcinoma and benign prostatic Kinner BM, Ohori M, Scardino PT. 18 Balk SP, Ko YJ, Bubley GJ. Biology of hyperplasia. Scand J Urol Nephrol Suppl Prostate specific antigen and gleason prostate-specific antigen. J Clin Oncol 1991; 138: 97–103 grade: an immunohistochemical study of 2003; 21: 383–91 8 Chang SS, Reuter VE, Heston WD, prostate cancer. J Urol 1994; 151: 1558– 19 Sciarra A, Mariotti G, Gentile V et al. Gaudin PB. Comparison of anti-prostate- 64 Neuroendocrine differentiation in human specific membrane antigen antibodies 13 Kageyama Y, Kihara K, Kamata S et al. prostate tissue. Is it detectable and and other immunomarkers in metastatic [Relationship between pretreatment treatable? BJU Int 2003; 91: 438–45 prostate carcinoma. Urology 2001; 57: serum levels of prostate specific antigen 20 Sella A, Konichezky M, Flex D, Sulkes A, 1179–83 and bone metastasis in prostate cancer]. Baniel J. Low PSA metastatic androgen- 9 Varma M, Morgan M, Amin MB, Hinyokika Kiyo 1996; 42: 197–9 independent prostate cancer. Eur Urol Wozniak S, Jasani B. High molecular 14 Gaffney EF, O’Sullivan SN, O’Brien 2000; 38: 250–4 weight cytokeratin antibody (clone A. A major solid undifferentiated 21 Kaufmann O, Georgi T, Dietel M. Utility 34betaE12). a sensitive marker for carcinoma pattern correlates with of 123C3 monoclonal antibody against differentiation of high-grade invasive tumour progression in locally advanced CD56 (NCAM) for the diagnosis of small urothelial carcinoma from prostate prostatic carcinoma. Histopathology cell carcinomas on paraffin sections. Hum cancer. Histopathology 2003; 42: 1992; 21: 249–55 Pathol 1997; 28: 1373–8 167–72 15 Mettlin C, Murphy GP, Lee F et al. 10 Vyberg M, Nielsen S. Dextran polymer Characteristics of prostate cancers Correspondence: John R. Masters, The conjugate two-step visualisation system detected in a multimodality early Prostate Cancer Research Centre, The Institute for immunohistochemistry. A comparison detection program. The Investigators of of Urology, 3rd Floor Charles Bell House, 67 of Envision+ with two three-step avidin- the American Cancer Society-National Riding House Street, London W1W 7EJ, UK. biotin techniques. Applied Immunol 1998; Prostate Cancer Detection Project. Cancer e-mail: [email protected] 6: 3–10 1993; 72: 1701–8 11 Sternberger LA, Hardy PH Jr, 16 Bostwick DG, Pacelli A, Blute M, Roche Abbreviations: PSMA, prostate-specific Cuculis JJ, Meyer HG. The unlabeled P, Murphy GP. Prostate specific membrane antigen; AR, androgen receptor; antibody enzyme method of membrane antigen expression in prostatic PAP, prostatic acid phosphatase; H&E, immunohistochemistry: preparation and intraepithelial neoplasia and haematoxylin and eosin.
© 2005 BJU INTERNATIONAL 307 Original Article PSA AND PROSTATE VOLUME IN HEALTHY ARAB MEN KEHINDE et al.
Age-specific reference levels of serum prostate-specific antigen and prostate volume in healthy Arab men
ELIJAH O. KEHINDE, OLUSEGUN A. MOJIMINIYI*, MEHRAJ SHEIKH†, KALEEL A. AL-AWADI, ABDALLAH S. DAAR‡, ADEL AL-HUNAYAN, JEHORAM T. ANIM* and AISHA A. AL-SUMAIT* Departments of Surgery (Division of Urology), *Pathology and †Radiology, Faculty of Medicine, Kuwait University, Kuwait, and ‡College of Medicine, Sultan Qaboos University, Muscat, Oman Accepted for publication 18 February 2005
OBJECTIVE measured using commercial kits, and age- CONCLUSION specific ranges for PSA levels and prostate To determine age-specific reference ranges volume determined. These results indicate that Arab men have for serum prostate-specific antigen (PSA) lower PSA levels and prostate volumes than concentration and prostate volumes in a RESULTS Caucasians. The levels are slightly lower than population of healthy Arab men. those reported in the Japanese and, as in the The serum PSA ranges (ng/mL) for each age Japanese, low PSA levels and small prostate SUBJECTS AND METHODS range in Arab men were: 40–49 years, 0–0.9; volumes might be related to the low incidence 60–69, 0–2.7; 70–79, 0–5.5 ng/mL; the of clinical prostate cancer in Arab men. Blood samples were taken from 396 healthy respective prostate volumes were 8–22, Arab men (from Kuwait and Oman) aged 9–30 and 10–33 mL. The serum PSA level KEYWORDS 15–79 years and from across the social and prostate volume correlated with age spectrum. Men aged >40 years had a (P < 0.001). Arab men had lower serum prostate-specific antigen, prostate volume, digital rectal examination and transrectal PSA levels and prostate volumes than those Arab, Caucasian, Asian ultrasonography of the prostate to determine reported for Caucasians, but similar to those prostate volume. The serum PSA level was reported for Asians (Japanese and Chinese).
INTRODUCTION Central Blood Banks in Kuwait and Oman to fertility. Each patient's weight and height donate blood. We selected volunteers from all were also recorded. Factors responsible for differences in the governorates or districts in both countries incidence of prostate cancer in different parts and representative samples from across Serum total and free PSA levels were of the world remain unclear. The incidence is different social classes. To be included in the measured using third-generation kits low in Asia (3–8 per 100 000 men per year), study, men aged >40 years did not have LUTS (Immulite, Diagnostic Products Corp. Inc. intermediate in Africa and Eastern Europe, and had normal urinary flow rates (maximum Webster, TX, USA). Serum samples were and high in Western Europe and North urinary flow rate >15 mL/s with a voided aliquoted in 2.5-mL batches and stored at America (Fig. 1) [1–4]. PSA remains the most volume of >150 mL). Men aged >40 years had -80 ∞C until analysis within 6 months of useful clinical tumour marker in the diagnosis a DRE and TRUS to determine prostate volume sample collection. The study was approved by of prostate cancer and strategies to enhance using the formula for a prolate ellipsoid the Local Ethics Committee and informed its performance include age- and race- (width ¥ length ¥ height ¥ 0.52). All TRUS consent was obtained from all volunteers. The specific ranges, measurement of free to total examinations were by one radiologist (M.S.) volunteers were further informed that, should PSA ratio (f/tPSA), PSA density and PSA using a Logic 500 Scanner (GE Medical a disease be diagnosed as a result of these velocity [5–7]. The aim of the present study Systems, Milwaukee, WI, USA) with a 7.5 MHz tests, they would be informed and additional was to determine age-specific reference endocavity transducer (model E721), scanning tests conducted before recommending ranges for serum PSA levels and prostate the gland in sagittal and axial planes. The further treatment. volumes in apparently healthy Arab men aged DRE was performed by three experienced 15–79 years. urologists (E.O.K., K.A.A. and A.A.). None of the Volunteers found to have an abnormal DRE volunteers had any known serious systemic irrespective of PSA value, or a PSA level of disease or were on any medications known to >10 ng/mL, had a sextant prostate biopsy SUBJECTS AND METHODS affect normal hormone production or serum with TRUS guidance. Similarly, volunteers PSA levels, in accordance with previously with an abnormal echo pattern at TRUS had a Venous blood samples were taken from 396 established standards [8]. Other demographic prostate biopsy. The biopsies were taken from healthy indigenous Arab men from Kuwait data collected from each volunteer included the apex, middle and base of the right and left and Oman, aged 15–79 years. Most were social habits, particularly smoking, marital lobes in the parasagittal plane. If a hypoechoic selected from healthy men attending the status and whether they had problems with lesion was detected in the peripheral or
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FIG. 1. Incidence (age standardized rate) of prostate cancer by world region (using data from [1]). the median (2.5–97.5 percentile). Pearson product-correlation coefficients were USA Blacks calculated to measure the association between serum PSA levels and age, prostate USA Whites volume and age, and PSA levels and prostate volume. For all analyses, P < 0.05 was Australia considered to indicate significance. Germany Nomograms showing the distribution of England Wales serum PSA levels and prostate volumes as a Zimbabwe (White) function of age were generated from least- squares regression models. A nomogram of Zimbabwe (Black) the distribution of serum PSA levels as a function of prostatic volume was also Kuwait constructed similarly. China (Shanghai)
0 50 100 150
Number of cases per 100 000 men/year RESULTS
Table 1 shows the mean (SD) total PSA, free PSA and f/tPSA levels in normal healthy Arab TABLE 1 Mean (SD) serum levels of total PSA, free PSA, and f/tPSA, and prostate volumes in normal Arab men* men aged 15–79 years, and the number of men sampled in each age group, which Age group, N Total PSA, Free PSA, f/tPSA, Prostate volume, Range, ranged from 52 in those 15–19 years old to years patients ng/mL ng/mL % mL mL 12 in those aged 70–79 years. The few men in 15–19 52 0.32 (0.25) 0.07 (0.05) 25 (6.12) – – the latter group reflects the scarcity of this 20–29 68 0.56 (0.32) 0.12 (0.11) 21.1 (3.11) – – age group in Kuwait and Oman, where the 30–39 64 0.49 (0.33) 0.11 (0.08) 21.2 (4.22) – – population distribution is skewed, with more 40–49 62 0.55 (0.68) 0.13 (0.25) 23.2 (5.22) 14.4 (2.3) 8–22 than half the population aged <25 years, and 50–59 78 1.12 (2.09) 0.18 (0.17) 14.2 (2.67) 17.8 (3.3) 9–27 thus finding volunteers aged >60 years who 60–69 60 2.76 (4.26) 0.43 (0.43) 14.8 (3.11) 22.4 (6.1) 9–30 were suitable for inclusion in this study 70–79 12 4.14 (3.49) 0.68 (0.58) 14.2 (2.31) 22.9 (4.1) 10–33 proved difficult. The mean (SD) PSA level was 0.56 (0.70) ng/mL for men aged 40–49 years *Arab men (Kuwaitis and Omanis), none had symptoms of prostatism, all had normal urinary flow rates. and 4.79 (3.65) ng/mL for men aged 70– 79 years. Figure 2 shows the frequency distribution of total PSA in these Arab men; it is not a normal distribution, hence the median FIG. 2. Frequency distribution of total PSA profile in daily for 3 days. Men found to have prostate PSA of 0.47 ng/mL and reference range of normal Arab men. Median 0.47, 396 men, reference cancer were excluded from the analysis. 0.05–5.51 (2.5 and 97.5 percentiles) is more range 0.05–5.51. appropriate than using the mean. Figure 3 All assays were carried out while unaware of shows the good correlation (r = 0.520) 300 sample origin. Quality control samples were between total PSA level and age in Arab men, included within assay runs, as specified by the with the total PSA value for age derivable as kit's manufacturers. The number of serum 0.076 (age) – 1.754 ng/mL (P < 0.001). Free 200 samples analysed for PSA or free PSA was PSA values closely mirrored those of total PSA
ency determined when a statistically significant (Figs 4 and 5); like total PSA, free PSA u trend was established with age from increased with age (P < 0.001), but f/tPSA Freq 100 regression plots. The interassay coefficients of declined with age (Table 1). variation for PSA and free PSA were 2.1% and 5.1% respectively, and the intra-assay Table 1 also shows that the mean prostate
0 0.0 2.0 4.0 6.0 8.0 10. 12.014.016.018.020.022.024.026.0 coefficients of variation were 3.1% and 3.2%, volume and range increased with age in Arab 0 respectively. men; the mean (SD) volume was 14.4 (2.3) mL Total PSA, ng/mL for men aged 40–49 and 22.9 (4.1) mL for Descriptive statistical methods were applied men aged 70–79 years. central zone on TRUS, 3–6 biopsies of those for the entire study cohort. For normally areas were also taken. Before biopsies, distributed variables the reference range was The relationships between serum levels of PSA patients received oral ciprofloxacin 500 mg, the mean ± 2 SD, while for those with non- and fPSA and age were similar to the trends 1 h before the procedure and 500 mg twice normal distribution the reference range was previously reported for Caucasians. The
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numbers of serum samples analysed for PSA 3 FIG. 3. and free PSA were determined when a Serum PSA level as a function of statistical significant trend (P < 0.001) 2 age in healthy Arab men; r with age was established, as shown in = 0.520, P < 0.001, total Figs 3 and 5. Thus total and free PSA levels PSA = 0.076 (age) -1.754.
ng/mL 1 showed progressive increases with age
(Figs 3 and 5). l PSA,
a 0
- DISCUSSION 1 Log 10 tot
The present study shows that, as in other -2 communities, the reference range for total PSA levels and prostate volume must be -3 0 20 40 60 80 100 established for each community, as there are Age, years substantial differences in normal reference values. For clarity, the values determined in the present study are tabulated with values reported previously for White men from the 70 FIG. 4. USA, Japanese, and Chinese (Table 2). In all Frequency distribution of free PSA four populations, PSA levels and prostate 60 profile in normal Arab men; median 0.09, 152 men, reference volumes increased with age. For Arab men, 50 the normal median total PSA level of 0.45 ng/ range 0.01–1.22. mL is lower than the 0.8 ng/mL reported for 40 ency
Japanese men [5]. Similarly Arab men aged u 30
>59 years have smaller prostates than Freq Japanese men (P < 0.06) and White men (P < 0.001). As shown by studies in other 20 populations, the present study also confirmed 10 that there is a significant (P < 0.05) correlation between patient age, total PSA 0 level (r = 0.387) and prostate volume 0.0 0.1 0.3 0.4 0.5 0.6 0.8 0.9 1.0 1.1 1.3 1.4 (r = 0.29) [5,9–11]. Free PSA, ng/mL
In 1993, Oesterling et al. [9] and Dalkins et al. [10] developed age-specific reference ranges 1.5 FIG. 5. for serum PSA levels for White men from the Serum free PSA level as a USA; the reference ranges are higher than for 1.0 function of age in healthy Arab Japanese men, which in turn are higher than = < 0.5 men; r 0.563, P 0.001, free for Arab men (Table 2). Chinese men appear to PSA = 0.006219 (age) -0.06902. have the lowest age-specific reference ranges ng/mL 0.0 for PSA levels, as reported by He et al. [12] SA, - (Table 2). For each age group, from 40–79 0.5 years, the upper limit of normal for serum -1.0 PSA levels for Arab men is lower than in
Japanese or in White men. The clinical Log 10 free P -1.5 implication of this finding is that the serum -2.0 PSA value for an Arab man has a different clinical meaning than the same value for a -2.5 similarly aged Japanese or a White man. 0 20 40 60 80 100 Hence, whereas a PSA level of 2 ng/mL will be Age, years considered normal for a White man or a Japanese man aged 40–49 years, for an Arab man of the same age and PSA value, the [9] by the Tandem-R PSA assay (Hybritech Inc. PSA is fairly stable, especially if the serum has possibility of prostate cancer needs to be San Diego, CA, USA), whereas we used third- been separated early after blood sample excluded. The Japanese PSA values were generation Immulite kits. However, it is collection and stored appropriately. This measured with the IMx PSA assay (Abbott unlikely that the lower values in Arab men can implies that the assay technique should not Laboratories, Abbott Park, IL, USA) and those be attributed solely to the diagnostic kits used substantially affect the values of PSA of the White men reported by Oesterling et al. [5,9,13,14]; as Jacobsen et al. [13] showed, measured, and this was confirmed by Junker
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of prostate cancer. This high mean f/tPSA TABLE 2 Comparison of serum PSA levels and prostate volumes as a function of age in healthy White men in Arab men might be another reason for from the USA [9], Japanese [5], Chinese [12] and Arab men their low incidence of prostate cancer. Alternatively, it might reflect an underlying Age range, Serum PSA range, ng/mL Prostate volume range, mL biological difference between Arab and years USA White* Japanese* Arab Chinese† USA White* Japanese* Arab Caucasian prostates. 40–49 0–2.5 0–2 0–0.9 0–1.2 13–51 9–33 8–22 50–59 0–3.5 0–3 0–1.6 0–2.4 15–60 9–35 9–27 1 2 1,2 In conclusion, the present study confirms 60–69 0–4.5 0–4 0–2.9 0–3.2 17–70 10–37 9–30 earlier reports that serum PSA levels and 70–79 0–6.5 0–5 0–5.5 0–3.4 20–82 11–40 10–33 prostate volume are age- and race-
1 2 dependent, so it is appropriate to have age- * Data from [5,9]; † Data from [12]; P < 0.001 (Arab vs USA White); P < 0.06 (Arab vs Japanese); specific reference ranges for these variables in P calculated using Student's t-test. various communities around the world. This will enhance the positive predictive value of PSA estimation in the diagnosis of prostate cancer in each community. The present results et al. [14], who compared four different total aged 55–69 years than for their Japanese indicate that Arab men have lower PSA levels and free PSA assays and found no significant counterparts, because the former have higher and prostate volumes than reported difference in the mean values obtained, normal PSA levels [19]. previously for White men. The levels are only especially when the total PSA level slightly lower than those found in Japanese was < 25 ng/mL. Furthermore, as prostate The f/tPSA in the Arab men studied also men. As in Japanese and Chinese men, low glands in Arab men are smaller than in White declined with age, from 25% in those 15–19 PSA levels and small prostate volumes might or Japanese men, and as it is known that the years old to 14.2% in those aged 70–79 years. partly explain the low incidence of prostate larger the prostate the higher the PSA level, There is considerable disagreement about the cancer in Arab men. the smaller prostate in Arab men is the most effect of age on f/tPSA in healthy men; some likely explanation for the low PSA levels [15]. have reported an increase with age [20,21], Prostate volume was measured with the some a decrease [22], and others claim that CONFLICT OF INTEREST formula used by Oesterling et al. [9] for White f/tPSA is independent of age [23]. Reasons men and by Oesterling et al. [5] for Japanese given for these differences include that in None declared. Source of funding: Kuwait men, so the differences in PSA values and some of the studies [23] prostate cancer University Research Grant MS 01/99. prostate volumes are probably real. After was not excluded in men whose sera were adjusting for prostatic size and patient's used for the analysis. The present study age, there is still a significant difference in included only men who did not have clinically ACKNOWLEDGEMENTS PSA values between White and Arab men detectable prostate cancer, so the present (P < 0.001). The higher levels of serum PSA finding that age independently influences This work was supported by Kuwait University beyond that which can be accounted for f/tPSA is likely to be more accurate, and is Research Grant MS 01/99. We thank Mrs by prostate size alone might also reflect consistent with the findings of Lein et al. [22]. Ramani Varghese, Mr Mathew Abraham and differences in the cellular composition of Dr Anjum Menon, Faculty of Medicine, Kuwait the prostate glands in the three communities. However, it would appear that the only reason University for assistance with specimen This has clinical implications for prostate to determine the f/tPSA is as a guide as to processing, data processing and advice pathology; e.g. while the autopsy prevalence whether to take a prostate biopsy, to exclude regarding statistical methods, respectively. of latent prostate cancer shows little racial prostate cancer for men with PSA levels in the or geographical variation, the autopsy ‘grey zone’ of 4–9.9 ng/mL. Thus, it is used to prevalence of ‘proliferative’ (more extensive enhance the specificity of total PSA values in REFERENCES and less well differentiated) latent prostate the grey zone [24,25]. cancer shows racial and geographical 1 Parkin DM, Whelan SL, Ferlay J, variations similar to those seen for clinically The value of estimating f/tPSA in normal men Raymond L, Young J, eds. Cancer diagnosed prostate cancer [16,17]. Similarly, is at present unclear. However, Carter et al. Incidence in Five Continents, Vol. VII, no. from local experience of TURP for BPH in Arab [26] argued that men with no prostate cancer 143. Lyons, France: IARC Scientific men over a 10-year period, the prostate but with very low f/tPSA levels are at greater Publications, 1997: 5–9 causing symptoms of BOO is smaller than in risk of developing prostate cancer. They 2 Memon A, Al Muhanna AN. 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Original Article PROSTATE CELLS IN PERIPHERAL BLOOD AFTER AUTOLOGOUS TRANSFUSION DURING RP STOFFEL et al.
Analysis of peripheral blood for prostate cells after autologous transfusion given during radical prostatectomy
JOHN T. STOFFEL, LINDA TOPJIAN and JOHN A. LIBERTINO Department of Urology, Lahey Clinic, Burlington, MA, USA Accepted for publication 29 March 2005
OBJECTIVES peripheral blood samples were collected from samples collected 3–5 weeks after surgery. patients before RP, in the recovery room Analysis of data with 40 months of follow-up To determine if cells expressing prostate- afterward, and at 3–5 weeks after surgery. A showed IAT was not an independent predictor specific antigen (PSA) can be detected in reverse-transcriptase-polymerase chain of biochemical failure in multivariate analysis. blood collected by a cell-saver during radical reaction assay for PSA mRNA was used to prostatectomy (RP) or in the peripheral blood detect prostate cells in cell-saver and CONCLUSIONS after intraoperative autotransfusion (IAT). peripheral blood samples. Patients were followed after surgery with PSA Although IAT blood contains PSA-expressing PATIENTS AND METHODS measurements to assess biochemical failure. cells, none could be detected 3–5 weeks after surgery. IAT during RP was not associated In all, 112 men with clinical T1c–T2 prostate RESULTS with a greater risk of biochemical failure. cancer undergoing RP were prospectively assessed. A cell-saver system was used in PSA-expressing cells were detected in 88% of KEYWORDS each to collect blood from the surgical field cell-saver reservoir and 13% of preoperative after prostate manipulation. IAT was given blood samples. No PSA-expressing prostate prostate cancer, surgery, transfusion, PSA, based on clinical indications. Standardized cells were detected in any peripheral blood cells
INTRODUCTION PATIENTS AND METHODS or pre-donated units if >200 mL of intraoperatively collected blood was available. Substantial blood loss during radical Men with clinical T1c–T2 prostate cancer Standardized 5 mL samples from the Cell prostatectomy (RP) frequently necessitates undergoing RP were assessed prospectively Saver of each patient were collected in EDTA- immediate resuscitation. Intraoperative between 1994 and 1997; enrolment was dosed specimen tubes after the blood was autotransfusion (IAT) of blood collected based on informed patient consent and processed and centrifuged. Standardized 5 mL from the surgical field has been proposed patient availability after RP. Exclusion criteria samples of blood were also collected from as an alternative method of volume included previous pelvic external beam each patient’s peripheral venous circulation support, but its use has been limited radiation therapy and radiological evidence of 1 h before surgery, in the recovery room after because of the theoretical possibility of metastasis on CT or bone scan. completing RP, and 3–5 weeks after surgery. haematogenous tumour dissemination [1]. Long-term retrospective studies support All patients had a retropubic RP using All samples were maintained at 4 °C and the safety of IAT use during RP [2–4] the standardized technique defined by analysed within 24 h of collection using an but prospective analysis of possible Walsh et al. [8]. A Brat2 Cell Saver (Cobe RT-PCR assay for PSA mRNA, previously haematogenous dissemination from IAT Cardiovascular, Arvadawa, CO) was used to described by Katz et al. [5]. Briefly, samples during the perioperative and immediate collect blood from the surgical field after were diluted with PBS, layered and postoperative state has not been explored. dividing the dorsal venous complex. All IAT centrifuged. The nucleated cell layer was RT-PCR offers a unique tool for studying this blood was processed with centrifugation then recovered and washed again with PBS. question, as it can be used to identify prostate and saline washes by the device before RNA was extracted from the cells using tumour cells within the peripheral circulation repackaging; no additional filters were used. the guanidinium thiocyanate/phenol/ before, during and after prostate cancer Indications for transfusion were based on chloroform extraction technique described surgery [5–7]. The goal of the present study clinical assessment by the anaesthesiologist by Chomezynski et al. [9]. A sample of 1 μg of was to use RT-PCR to determine if PSA- using intraoperative haematocrit, blood RNA was used for the reverse transcription, expressing prostate cells could be detected in pressure and heart rate as guidelines. If with PCR then used for 35 cycles, using the the peripheral blood immediately after IAT or immediate transfusion was required, IAT PSA-specific oligonucleotide primers: PSA after RP. was used preferentially over allotransfusions 3′:5′-CACAGACACCCCATCCTATC-3′ and PSA
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5′:5′-GATGACTCCAGCCACGACCT-3′. Samples Variable Total Group 1 Group 2 P TABLE 1 of β2-microglobin were used as internal N patients 112 48 64 Patient demographics controls for the reaction. Aliquots of the Mean age, years 61 61 61 reaction were then separated with Mean PSA, ng/mL 8.37 7.84 8.77 0.6 electrophoresis on 2.5% agarose gels, stained Gleason score 0.6 with ethidium bromide and the 710 bp target ≤ 6341618 identified under ultraviolet light. The identity 7602634 of the amplified product was established ≥ 818612 through radiolabelled PSA oligonucleotide Tumour stage 0.08 probes. A positive assay was defined as any Organ-confined (T2) 71 35 36 detectable PSA-expressing cells in the sample. Extracapsular (T3, T4) 41 13 28 Additional blood samples from 11 patients, Estimated mean blood 1393 1640 1210 0.007 including five men and six women undergoing loss, mL surgery unrelated to prostate cancer, were also analysed for PSA before surgery.
In all, 112 men were assessed prospectively; 48 received IAT (group 1) and 64 were not Predictor Adjusted hazard ratio (95% CI) P TABLE 2 transfused (group 2). Age, PSA level before RP, IAT 0.766 (0.33–1.80) 0.54 Independent predictors of operative blood loss, volume of IAT used, Advanced stage (T3, T4) 3.51 (1.43–8.61) 0.006 biochemical failure: pathological cancer grade and stage, and PSA Gleason score 1.69 (0.90–3.18) 0.10 adjusted hazard risk level after RP were recorded for each patient. Preoperative PSA 1.02 (0.99–1.06) 0.24 Patients were assessed with serum PSA for biochemical failure at the first visit after RP, 6 months after surgery and then yearly. Biochemical failure was defined as a PSA level respectively; samples could not be obtained on the risk of haematogenous tumour of >0.2 ng/mL or initiation of adjuvant from the remaining patients because there dissemination. Several in vitro studies therapy with radiation or hormonal was no follow-up by the primary surgeon suggested that tumour cells are not cleared manipulation. within the study period. Immediately after during Cell Saver blood processing [6,10,11], surgery, three patients (16%) in group 1 had but retrospective studies showed no greater Continuous and categorical variables were PSA-producing cells in their peripheral blood, risk of prostate cancer recurrence when IAT analysed statistically using Student’s t-test, vs only one (4%) of those in group 2 was used [2,3]. Other specialities have also Fisher’s exact tests, or the chi-square test. (P = 0.29). However, at 3–5 weeks after reported no greater rate of tumour recurrence Multivariate analysis used Cox proportional surgery, no PSA-producing cells were or metastasis when IAT is used during hazard models to determine hazard ratios detected in the peripheral blood from either oncological surgery [12–14]. The present associated with any increased risk of group. Two of the 40 control samples from 11 prospective study confirms findings from biochemical failure, with P < 0.05 considered different patients with no known prostate both the in vitro and retrospective studies. In to indicate significance in all tests. cancer (5%) tested positively for PSA. the present patients, PSA-producing cells were found in Cell Saver blood samples but RESULTS Both groups of patients were followed for a none were detected in the peripheral blood mean of 43 and 46 months, respectively, and by the first visit after RP, and IAT was not There was no statistically significant data were collected for 47 and 53 patients in an independent predictor of biochemical difference in age, preoperative PSA level, each respective group. There were nine failure. Gleason score and tumour stage after RP biochemical failures in group 1 and 17 in between the groups. Patients in group 1 group 2. Data were unavailable for three To explain these findings we suggest that receiving IAT had a larger mean estimated patients in each group. Cox adjusted hazard PSA-producing cells identified in the Cell blood loss (1645 mL) than those in group 2 models showed that IAT was not an Saver samples sustained structural damage (1205 mL, P < 0.007), with those in group 1 independent predictor of biochemical failure, during IAT processing that ultimately made receiving a mean IAT transfusion volume of with an adjusted hazard ratio of 0.766. them nonviable in an in vivo environment. 566 mL. Table 1 compares the demographics Advanced pathological stage was an Karczewski et al. [15] examined this premise of the two groups. independent predictor of biochemical failure, and noted that 62% of tumour cells suffered and pathological Gleason score was nearly lethal trauma after processing by an Molecular analysis was available on 97 statistically significance as an independent autotransfusion device, and the remaining preoperative peripheral and Cell Saver blood predictor (Table 2). cells had morphological changes. The samples. PSA-producing cells were identified damaged PSA-expressing cells in the present in 13% and 88% of the respective samples. DISCUSSION study may also have been rapidly cleared after Peripheral blood taken immediately after and transfusion by the patient’s cellular immune 3–5 weeks after surgery was analysed for 19 The use of IAT during RP has remained system [16]. More studies are needed to and 28 patients in groups 1 and 2, controversial because of conflicting evidence confirm these findings and discover possible
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mechanisms by which PSA cells are cleared surgical field. Arch Surg 1995; 130: 387– Assessment of the availability of from the peripheral circulation after IAT. 93 intraoperative autotransfusion in 2 Davis M, Sofer M, Gomez-Marin O, urological operations. J Urol 1997; 157: A theoretical limitation in the present study Bruck D, Soloway MS. The use of cell 1777–80 was the use of RT-PCR to identify PSA- salvage during radical prostatectomy: 12 Fujimoto J, Okamoto E, Yamanaka producing cells in the peripheral circulation. does it influence cancer recurrence. BJU N. Efficacy of autotransfusion in In other studies, RT-PCR assays have been Int 2003; 91: 474–6 hepatectomy for hepatocellular shown to have inconsistent detection rates of 3 Gray CL, Amling CL, Polston GR. carcinoma. Arch Surg 1993; 129: PSA-producing cells [17]. However, we could Intraoperative cell salvage in radical 1065–9 reproducibly detect 10 PSA-producing cells retropubic prostatectomy. Urology 2001; 13 Connor JP, Morris PC, Alagoz T. per 106 human B-lymphocytes with only a 5% 58: 740–5 Intraoperative autologous blood false-positive rate. Consequently, we are 4 Velagapudi SR, Frydenberg M, collection and autotransfusion in the confident in our ability to detect relevant Oesterling JE. Homologous blood surgical management of early cancers of levels of circulating PSA-producing cells. transfusion in patients with prostate the uterine cervix. Obstet Gynecol 1995; cancer. no effect on tumor progression or 86: 373–8 Although we found that IAT was not an survival. Urology 1994; 43: 821–7 14 Mirhashemi R, Averette HE, Deepika K independent predictor of biochemical failure 5 Katz AE, Olsson CA, Raffo AJ et al. et al. The impact of intraoperative after RP, the few patients and relatively short Molecular staging of prostate cancer with autologous blood transfusion during type follow-up prevented the detection of small the use of an enhanced reverse III radical hysterectomy for early-stage changes in survival rate between the groups. transcriptase-PCR assay. Urology 1994; cervical cancer. Am J Obstet Gynecol However, interestingly, tumour stage was an 43: 765–75 1999; 181: 1310–5 independent predictor of biochemical failure, 6 Oefelein MG, Kaul K, Herz B et al. 15 Karczewski DM, Lema MJ, Glaves D. The and tumour Gleason score approached Molecular detection of prostate epithelial efficiency of an autotransfusion system significance as an independent predictor. cells from the surgical field and peripheral for tumor cell removal from blood As these variables are well known as circulation during radical prostatectomy. salvaged during cancer surgery. Anesth independent predictors of biochemical failure J Urol 1996; 155: 238–42 Analg 1994; 78: 1131–5 after RP [18], we suggest that the study could 7 Oefelein MG, Ignatoff JM, Clemens JQ, 16 Peller S, Sayfan J, Levy Y. identify strong predictors of failure. Watkin W, Kaul KL et al. Clinical and Immunological profile changes following molecular follow-up after radical perioperative autologous vs homologous In conclusion, although IAT samples contain retropubic prostatectomy. J Urol 1999; blood transfusion in oncologic patients. PSA-expressing cells, few cells can be 162: 307–11 J Surg Oncol 1994; 56: 98–101 detected in the peripheral circulation hours 8 Walsh PC, Quinlan DM, Morton RA, 17 Raj GV, Moreno JG, Gomella LG. after transfusion. No cells can be detected Steiner MS. Radical retropubic Utilization of polymerase chain reaction by the first visit after RP. In the present prostatectomy. Improved anastomosis technology in the detection of solid patients, the use of IAT during RP was not and urinary continence. Urol Clin North tumors. Cancer 1998; 82: 1419–42 associated with a greater risk of biochemical Am 1990; 17: 679–84 18 Babaian RJ, Troncoso P, Bhadkamkar failure. 9 Chomezynski P, Sacchi N. Single-step VA, Johnston DA. Analysis of method of RNA isolation by acid clinicopathologic factors predicting CONFLICT OF INTEREST guanidinium thiocyanate-phenol- outcome after radical prostatectomy. chloroform extraction. Anal Biochem Cancer 2001; 91: 1414–22 None declared. 1987; 162: 156–9 10 Pak K, Kim CJ, Konishi T et al. Correspondence: John T. Stoffel, Department REFERENCES Experimental study on intraoperative of Urology, Lahey Clinic, Burlington, MA, USA. autotransfusion during urological e-mail: [email protected] 1 Hansen E, Wolff N, Knuechel R, operation. Nippon Hinyokika Gakkai Ruschoff J, Hofstaedter F, Taeger K. Zasshi 1991; 82: 1972–7 Abbreviations: RP, radical prostatectomy; IAT, Tumor cells in blood shed from the 11 Park KI, Kojima O, Tomoyoshi T. intraoperative autotransfusion.
© 2005 BJU INTERNATIONAL 315 Original Article NEW MANAGEMENT TO REDUCE BLEEDING IN RRP SCHOSTAK et al.
New perioperative management reduces bleeding in radical retropubic prostatectomy
MARTIN SCHOSTAK, KLAUDIA MATISCHAK, MARKUS MÜLLER†, MICHEL SCHÄFER*, MARK SCHRADER, FRANK CHRISTOPH and KURT MILLER Departments of Urology and *Anaesthesia and Intensive Care Medicine, Charité – Campus Benjamin Franklin, Universitätsmedizin Berlin, and †Department of Urology, Klinikum Ludwigshafen, Germany Accepted for publication 21 March 2005
OBJECTIVE after (group 2). If transfusions were required (P < 0.001). The complication rate did not the haemoglobin value was corrected, differ between the groups. To describe the effect of modifications to whereby 1 mL of erythrocyte concentrate radical retropubic prostatectomy (RRP, known increased the patient’s haemoglobin by CONCLUSION to be associated with severe bleeding) on 0.03 g/L. blood loss in a retrospective analysis This new method minimizes the comparing RRPs by one experienced surgeon intraoperative blood loss during RRP; before and after the changes. RESULTS transfusions are only necessary in rare cases and the complication rate remained PATIENTS AND METHODS Assessment was possible in 201 of 234 unaltered. patients, 110 from group 1 and 91 from group The new method comprised reducing the 2. The mean transfusion-corrected difference intravenously applied volume, using a in haemoglobin was 53 g/L in group 1 (20% KEYWORDS peridural catheter and maintaining a 25–30∞ transfusion rate) and 35.2 g/L in group 2 Trendelenburg position. The difference in (1.09% transfusion rate; P > 0.001). The prostate cancer, radical retropubic haemoglobin before and after RRP was median intravenous volume applied was prostatectomy, bloodless surgical technique, analysed before the changes (group 1) and 5.96 L in group 1 and 3.49 L in group 2 blood transfusions
INTRODUCTION PATIENTS AND METHODS anaesthetic protocol permitted clear assignment to one of the groups and whose Radical retropubic prostatectomy (RRP) is In January 2001, the perioperative routine for documented laboratory values enabled a known to involve severe bleeding; even RRP was modified as follows: (i) we reduced follow-up, particularly of their haemoglobin experienced surgeons report a blood the intraoperative fluid volume, particularly level. The examination covered the transfusion rate of up to 20% [1–5]. up to the time of resection; (ii) we inserted a haemoglobin loss calculated from the Santorini’s plexus and other venous peridural catheter (T12–L2) and administered difference between that before RRP and that plexuses of the pelvic floor have to be bupivacaine; (iii) we used 25–30∞ of on the evening after RRP. The value after RRP severed before the intervention. Moreover, Trendelenburg positioning. The analysis of patients with blood transfusions during potency-sparing surgery requires keeping included 234 patients who had RRP between surgery was corrected by 0.03 g/L per mL coagulation or any mechanical haemostasis 1998 and 2003 (120 before and 114 after the of transfused erythrocyte concentrate, at a minimum in the area of the fragile change), all by one very experienced urologist. considering that 1000 mL of erythrocyte neurovascular bundles that must be preserved concentrate contains 15 g of haemoglobin, [6]. No basic changes were made in the surgical and that a 63-year-old man has a mean technique that could have affected the intravascular volume of 5 L; e.g. the We modified our perioperative method results. An extensive lymphadenectomy was transfusion of 250 mL raises the haemoglobin in various ways in January 2001, with used routinely in all patients. Patients were level by 7.5 g/L. In addition, during the follow- the aim of minimizing vessel-filling in excluded from further analysis if they had a up, thrombocytes and serum creatinine levels the minor pelvis and thus reducing the haemorrhagic disease or idiopathic anaemia, were analysed. probability of bleeding. We describe the effect or if they had additional interventions of these modifications on blood loss in a potentially involving severe bleeding or long The retrospective morbidity analysis of the retrospective analysis comparing ª100 RRPs operating times under the same anaesthesia intervention was based on the complications by one experienced surgeon before the (e.g. hemicolectomy). Another exclusion listed in the patient’s records. Preoperative change (group 1) with ª100 thereafter criterion was previous radiotherapy or TURP. comorbidity was documented using the (group 2). Patients were included only if their written Charlson Comorbidity Scores [7].
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DISCUSSION Haemoglobin difference, g/L N patients Mean value TABLE 1 Group 1 Blood loss (haemoglobin Large series of open RRP have reported very Measured 110 38.3 difference in g/L) good oncosurgical results, but even highly Transfusion-corrected 110 53.0 experienced surgeons have an average Group 2 transfusion rate of 4–50% [8–13]. The present Measured 91 35.0 technique might be a first step to solve this Transfusion-corrected 91 35.2 problem. The combination of reduced intraoperative fluid, use of an epidural catheter and of the Trendelenburg position resulted in significantly less blood loss and transfusions, while complications did not Complication Group 1 Group 2 TABLE 2 differ. The novel aspect of the present Major Morbidity, as N (%) compared with previous studies is the Rectal lesion 3 (2.7) 1 (1.1) evaluation of the effect of combining Ureteric lesion 1 (0.9) 1 (1.1) commonly used techniques, e.g. reduced Thrombosis 0 1 (1.1) intraoperative fluid, epidural anaesthesia and Pulmonary embolism 0 1 (1.1) Trendelenburg position. In a study by Shir et Acute renal failure 0 0 al. [14], the influence of epidural anaesthesia Abscess 0 1 (1.1) combined with general anaesthesia during Intestinal atony 1 (0.9) 0 RRP gave no significant difference in blood Total 5 (4.5) 5 (5.5) loss from general anaesthesia alone, but when Minor (multiple entries possible) epidural anaesthesia only was used there was Anastomotic leak > 7 days 14 (12.7) 11 (12.1) a positive influence. Unfortunately, that study Lymphocele 6 (5.5) 7 (7.7) had no additional information about possible Urinary retention 18 (16.4) 20 (22.0) changes in blood pressure during surgery. The Secondary wound healing 12 (10.9) 7 (7.7) reduction in blood pressure in the present UTI 36 (32.7) 11 (12.1) study underscores the effectiveness of epidural anaesthesia and is thus an indirect sign of effective sympathicolysis. However, it did not result in hypotension that required therapeutic intervention. RESULTS Table 1 shows the blood loss as the difference in haemoglobin; there was a very significant The failure to detect positive effects when After applying inclusion and exclusion criteria, difference in the transfusion-corrected combining general and epidural anaesthesia 201 patients were assessable, 110 in group 1 haemoglobin difference (53 vs 35.2 g/L; [14] might be a result of various factors, e.g. and 91 in group 2; most patients excluded P < 0.001) and in the transfusion rate, at 20% insufficient epidural anaesthesia, the absence from the analysis had surgery in the in group 1 and 1.09% in group 2 (P < 0.001). of Trendelenburg positioning or reduced transitional phase and could not be clearly The applied volume during RRP was 5.96 L in intraoperative fluid. The combination of these assigned to a specific group. A few had no group 1 and only 3.49 L in group 2 (P < 0.001). three factors appears to contribute the most laboratory values to document the change in The remaining variables did not differ to the present findings. Earlier studies in the haemoglobin, or had additional major significantly between the groups, e.g. epidural 1960s, examining the effect of a peridural interventions under the same anaesthesia. catheter period (median 4 days, SD 1.4), catheter and/or relative hypotension during other laboratory variables, number of open prostate enucleation, showed less blood The epidemiological variables did not differ complications, etc. In particular, in group 2 loss during surgery [15,16]. between the groups; the patients had a with a restricted intraoperative volume, there median age of 63 years, a preoperative PSA was no increase in acute pre-renal failure. Findings reported by Barré et al. [17] show level of 9 ng/mL and a Charlson Comorbidity The serum creatinine level did not differ that Trendelenburg positioning alone likewise Score of 0 (maximum of 2 points in all significantly between the groups at the time markedly reduced the probability of bleeding. patients). Patients of both groups mostly had of discharge, at 90.2 mmol/L in group 1 and They determined the absolute blood loss and clinical stage T1c (half in each group); the 85.1 mmol/L in group 2 (P = 0.1). Epidural that through drainage, while in the present highest stage being cT2c (three patients in anaesthesia reduced the mean arterial study we assessed haemoglobin loss, and thus each group). pressure, but not to a degree that required the results are not directly comparable. In the therapeutic intervention. present study we also reduced fluid volume No basic changes were made in the surgical and used an epidural catheter to enhance the technique during the observation period, The complications are listed in Table 2; there effect of low vessel filling in the minor pelvis. although the fraction of nerve-preserving were major complications in 4.5% of group 1 operations was increased from 51% in group and 5.5% of group 2, and the difference was The study by Barré et al. [17] also describes the 1 to 75% in group 2. not statistically significance. use of Trendelenburg positioning with no leg-
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down tilt. In the present study we used ª10∞ comparing those before and 24 h after in patients undergoing retropubic of leg-down tilt to improve visualization of surgery. prostatectomy: a double-blind placebo- the minor pelvis, without reducing the effect controlled randomised trial. Lancet 2003; of the head-down position. The abdomen and The present study detected the relative 361: 201–5 upper body were tilted downward by 25–35∞. sympatholytic effect of the epidural catheter 3 Williams D, McCarthy R. Recombinant The result was always a head-down position, by a decrease in arterial pressure. A markedly activated factor VII and perioperative and in relation to the legs. This position reduced arterial pressure can impair ‘sensitive’ blood loss. Lancet 2003; 361: 1745 initially impairs visibility in the minor organs like the brain, heart and kidneys 4 Chang SS, Duong DT, Wells N, Cole EE, pelvis, but the disadvantage can easily be [21,22], but the incidence of acute renal Smith JA Jr, Cookson MS. Predicting overcome by using a xenon head-lamp, failure and myocardial infarction was no blood loss and transfusion requirements by which none of the interventions in greater, possibly because cardiovascular during radical prostatectomy: the group 2 required a temporary or permanent patients were not included. Brain function significant negative impact of increasing change of Trendelenburg position to improve was not objectively assessed either before or body mass index. J Urol 2004; 171: 1861– visibility. after surgery; there were no reported possible 5 adverse effects of Trendelenburg positioning, 5 Waters JH, Lee JS, Klein E, O’Hara J, Even patients who have laparoscopic surgery e.g. oedema in the upper extremities or face. Zippe C, Potter PS. Preoperative are placed in a (sometimes extreme) The complication rate was in the range autologous donation versus cell salvage Trendelenburg position. The low blood loss reported by others [23,24]. in the avoidance of allogeneic transfusion reported [18,19] may also be attributable to in patients undergoing radical retropubic this positioning and not only to the high CO2 Theoretically, as more nerve-sparing RRPs prostatectomy. Anesth Analg 2004; 98: pressure. Another option to achieve effective are conducted an equal increase of blood 537–42 sympathicolysis is a combination of a higher loss subsequent to such surgery might 6 Graefen M, Huland H. Technique of dose of inhalative narcotics and opiates. be expected. In contrast, blood loss was nerve-sparing radical retropubic Our department is currently performing a significantly lower than in former, prostatectomy. Urologe A 2004; 43: prospective randomized study to determine non-nerve sparing procedures, underlining 156–9 which of the individual factors is crucial and the effectiveness of the new perioperative 7 Wirth M, Frohner M. The significance which can be omitted. In a first approach, management of patients undergoing RRP. of comorbidity and age in radical the influence of general anaesthesia in prostatectomy. Urologe A 2004; 43: combination with a peridural catheter is There were three intraoperative rectal 935–41 compared to general anaesthesia alone. lesions in group 1 but only one in group 2. 8 Khan MA, Han M, Partin AW, Epstein Patients in both groups are in a Trendelenburg All cases had local spread of a tumour with JI, Walsh PC. Long-term cancer control position and have relative hypovolaemia. extracapsular extension. Better selection of radical prostatectomy in men younger helps to minimize such major complications. than 50 years of age: update. Urology In the present study, the haemoglobin 2003; 62: 86–91 difference measured was corrected for any In conclusion, blood loss during open 9 Lepor H, Kaci L. Contemporary transfusion (as 1 L of erythrocyte concentrate RRP is minimized by using the present evaluation of operative parameters and contains 15 g of haemoglobin and the method, involving both urologists and complications related to open radical intravascular volume of a 63-year-old man is anaesthesiologists, and comprising reduced retropubic prostatectomy. Urology 2003; ª5 L). However, the variability of the latter intraoperative fluids, a peridural catheter 62: 702–6 factor could reduce the accuracy of the and Trendelenburg positioning; with this 10 Noldus J, Hammerer P, Graefen M, present retrospective analysis. Thus, the combination, blood transfusions are required Huland H. Surgical therapy for localized recently initiated prospective study will only in rare cases. prostatic carcinoma. J Cancer Res Clin analyse not only the laboratory values but Oncol 1997; 123: 180–4 also the volume in the aspirator, the weight of 11 Oefelein MG, Colangelo LA, Rademaker the abdominal pads and the volume, as well CONFLICT OF INTEREST AW, McVary KT. Intraoperative blood as the haemoglobin fraction in the drainage. loss and prognosis in prostate cancer However, analysis of the change in None declared. patients undergoing radical retropubic haemoglobin alone appears to be valid, as prostatectomy. J Urol 1995; 154: 442–7 the blood loss is known to be frequently 12 Walsh PC. Surgery and the reduction of underestimated with the other variables REFERENCES mortality from prostate cancer. N Engl J (volume in the aspirator, etc.) [20]. Patients Med 2002; 347: 839–40 in group 1 received significantly more 1 Schwartz K, Bunner S, Bearer R, 13 Zincke H, Oesterling JE, Blute ML, intravenous fluids, which may lead to a Severson RK. Complications from Bergstralh EJ, Myers RP, Barrett DM. dilution and misinterpretation of the treatment for prostate carcinoma among Long-term (15 years) results after radical intraoperative haemoglobin levels. As the men in the Detroit area. Cancer 2002; 95: prostatectomy for clinically localized effect from intravenous dilution will 82–9 (stage T2c or lower) prostate cancer. J Urol disappear 24 h after surgery, the difference in 2 Friederich PW, Henny CP, Messelink EJ 1994; 152: 1850–7 haemoglobin level was evaluated by et al. Effect of recombinant activated 14 Shir Y, Raja SN, Frank SM, Brendler CB. factor VII on perioperative blood loss Intraoperative blood loss during radical
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retropubic prostatectomy: epidural versus 19 Cathelineau X, Cahill D, Widmer H, of the morbidity of radical retropubic general anesthesia. Urology 1995; 45: Rozet F, Baumert H, Vallancien G. prostatectomy: retrospective analysis 993–9 Transperitoneal or extraperitoneal of 100 consecutive operations during 15 Urquhart-Hay D, Marsland JM. approach for laparoscopic radical the period 1996–97. Prog Urol 1999 ; 9: Comparison of epidural and hypotensive prostatectomy: a false debate over a real 662–7 anaesthesia in open prostatectomy: 1. N Z challenge. J Urol 2004; 171: 714–6 24 Augustin H, Hammerer P, Graefen M Med J 1969; 69: 281–7 20 McCullough TC, Roth JV, Ginsberg PC, et al. Intraoperative and perioperative 16 Urquhart-Hay D, Marshall NG, Harkaway RC. Estimated blood loss morbidity of contemporary radical Marsland JM. Comparison of epidural underestimates calculated blood loss retropubic prostatectomy in a consecutive and hypotensive anaesthesia in open during radical retropubic prostatectomy. series of 1243 patients: results of a single prostatectomy: Series 2. N Z Med J 1969; Urol Int 2004; 72: 13–6 center between 1999 and 2002. Eur Urol 70: 223–8 21 Bellomo R, Giantomasso DD. 2003; 43: 113–8 17 Barre C, Pocholle P, Chauveau P. Noradrenaline and the kidney: friends or Minimal blood loss in patients undergoing foes? Crit Care 2001; 5: 294–8 Correspondence: Martin Schostak, radical retropubic prostatectomy. World J 22 Elert O, Tschirkov F, Satter P. The effect Department of Urology, Charité – Campus Surg 2002; 26: 1094–8 of ischemic and cardioplegic heart Benjamin Franklin, Universitätsmedizin Berlin, 18 Bhayani SB, Pavlovich CP, Hsu TS, standstill on the myocard metabolism in Hindenburgdamm 30, D-12200 Berlin, Sullivan W, Su LM. Prospective normal and less perfused heart (author’s Germany. comparison of short-term convalescence: transl). Thoraxchir Vask Chir 1975; 23: e-mail: [email protected] laparoscopic radical prostatectomy versus 318–21 open radical retropubic prostatectomy. 23 Guillonneau B, Cathelineau X, Cour Abbreviations: RRP, radical retropubic Urology 2003; 61: 612–6 F, Veillon B, Vallancien G. Update prostatectomy.
© 2005 BJU INTERNATIONAL 319 Original Article HIGH-GRADE PIN ON PROSTATIC BIOPSY IZAWA et al.
Do all patients with high-grade prostatic intraepithelial neoplasia on initial prostatic biopsy eventually progress to clinical prostate cancer?
JONATHAN I. IZAWA*†, ILIANA LEGA*, DONAL DOWNEY‡, JOSEPH L. CHIN*† and PATRICK P. LUKE* *Departments of Surgery & Oncology, †Divisions of Urology and ‡Radiology, University of Western Ontario, London, Ontario, Canada Accepted for publication 21 March 2005
OBJECTIVE followed every 6–12 months with prostate- significant cancer. Five of these patients went specific antigen (PSA) testing and digital on to a third prostate biopsy, with no evidence To assess the clinical outcome of patients rectal examinations (DRE). of cancer. One patient died from unrelated with a diagnosis of high-grade prostatic causes during this period. intraepithelial neoplasia (PIN) on initial RESULTS prostatic biopsy, with a minimum of 5 years of follow-up, as such patients are at greater A mean (range) of 7 (2–8) cores were taken at CONCLUSION risk of having prostate cancer on subsequent initial biopsy; the mean age of the patients biopsy. was 63 (53–77) years and mean PSA level This study affirms our current practice of 9.1 (4.9–17.6) ng/mL. Six patients had an following patients with PIN conservatively if a PATIENTS AND METHODS abnormal DRE at presentation. A mean of 8 second or third subsequent prostate biopsy is (7–10) cores were obtained on the second negative. Whether PIN is a premalignant Between November 1992 and October 1998, biopsy; six patients were diagnosed with lesion or merely a lesion associated with 21 patients were identified as having PIN on cancer, with a mean Gleason score of 6 (5–7), cancer needs to be addressed in multicentre their initial transrectal ultrasonography- while three were diagnosed with persistent studies with a follow-up of >10 years. guided prostate biopsy. None of these PIN. These three patients had a third prostate patients had a focus of cancer on the initial biopsy which showed cancer of Gleason score biopsy. Their medical data were reviewed 6 in one and benign prostatic hyperplasia KEYWORDS retrospectively to determine the natural in two. After a mean follow-up of 72.2 history of PIN in these patients. Patients who (60–84) months, none of the remaining 12 prostatic intraepithelial neoplasia, were not identified as having cancer were patients was diagnosed with clinically carcinogenesis, prostate neoplasm
INTRODUCTION of PIN on initial prostate biopsy and with up data. The decision to proceed with a third ≥5 years of follow-up. prostate biopsy was based on latest PSA level, Patients with high-grade prostatic change in PSA level, DRE, age, comorbidities intraepithelial neoplasia (PIN) on initial and patient preference. There was no specific prostatic biopsy are at greater risk of having PATIENTS AND METHODS or consistent rate of PSA change that prostate cancer on subsequent biopsy. The prompted another biopsy. mean (range) incidence of PIN is 9 (4–16)% of To obtain data with ≥5 years of follow-up, all prostate biopsies [1]. When PIN is found on patients who, between November 1992 and initial sextant prostate biopsy, there is a October 1998, had a TRUS-guided prostate RESULTS 22–58% risk of finding cancer on subsequent biopsy by one radiologist (D.D.) were biopsies [2–4]. With extended prostate evaluated. All patients with a focus of cancer A mean (range) of 7 (2–8) cores were taken at biopsies, the chance of finding cancer on on their initial biopsy were excluded. Twenty- the initial prostate biopsy. The mean age of immediate repeat prostate biopsies appears to one patients were identified to have PIN on the patients was 63.5 (53–77) years and be significantly less [5,6]. PIN has been their initial prostate biopsy; none of these the mean PSA level 9.1 (4.9–17.6) ng/mL. estimated to precede the onset of cancer by 5 patients had a focus of cancer on the initial Six patients had an abnormal DRE at to >10 years [1]. It is unknown if men will biopsy. Their medical data were reviewed presentation. All 21 patients had a second significantly benefit from therapy for PIN. To retrospectively to determine the natural prostate biopsy within 18 months of their our knowledge there are no published long- history of PIN in these patients; they were initial biopsy, at which a mean of 8 (7–10) term reports studying the outcome of men followed every 6–12 months with PSA testing cores were obtained. Six patients were diagnosed with PIN in initial TRUS-guided and a DRE. Patients and their family diagnosed with cancer, with a mean Gleason prostate biopsy. Therefore, we assessed the physicians were contacted to ascertain and score of 6 (5–7). One of these patients was the clinical outcome of patients with a diagnosis confirm the most up-to-date clinical follow- only man to also have atypical small acinar
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the presence of microscopic foci of disease, TABLE 1 The patients’ characteristics at the time of the initial prostate biopsy, the pathological results of and therefore these patients will require subsequent prostate biopsies and the length of follow-up continuing follow-up for their PIN until their life expectancy is such that they may not Patient/age, Biopsy benefit from any of the present therapies for years DRE PSA, ng/mL 12 3Gleason score Follow-up, months prostate cancer. Nonetheless, following 1/59 nodule 6.7 PIN cancer n/a 6 116 patients conservatively with routine biannual 2/58 BPH 7.5 PIN cancer n/a 6 60 or annual history, physical examination 3/69 BPH 9.2 PIN cancer n/a 6 62 (including a DRE), and PSA determinations 4/53 BPH 9.5 PIN* cancer n/a 7 75 appears to be a safe strategy in the 5/64 BPH 9.6 PIN cancer n/a 5 91 management of men found to have PIN 6/71 BPH 15.0 PIN BPH BPH n/a 77 on initial prostate biopsy with a negative 7/71 indurated 8.5 PIN BPH n/a n/a 65 subsequent biopsy. 8/77 indurated 6.8 PIN BPH n/a n/a 63 9/70 BPH 8.2 PIN BPH n/a n/a 80 There is emerging data that with the current 10/57 BPH 17.0 PIN BPH BPH n/a 71 use of extended prostate biopsy, even 11/65 indurated 4.9 PIN BPH BPH n/a 64 immediately repeating the prostate biopsy 12/65 BPH 17.6 PIN BPH BPH n/a 84 may be unnecessary [5,6]. This differs from 13/60 BPH 6.6 PIN cancer n/a 6 62 the sextant biopsy, in which repeat biopsies 14/56 BPH 6.7 PIN BPH n/a n/a 60 for the initial biopsy finding of PIN was 15/61 BPH 14.5 PIN BPH BPH n/a 78 recommended because of the 22–58% chance 16/63 BPH 5.9 PIN BPH n/a n/a 76 of identifying cancer on a subsequent biopsy 17/56 BPH 4.9 PIN PIN PCa 6 80 [2–4]. It may also be possible to follow 18/65 BPH 8.6 PIN BPH n/a n/a 68 conservatively men who have had an 19/57 BPH 8.3 PIN PIN BPH n/a 77 extended TRUS prostate biopsy, with no 20/72 indurated 9.3 PIN BPH n/a n/a 80 immediate second biopsy. The history, DRE 21/65 indurated 6.0 PIN PIN BPH n/a 108 and PSA levels, as well as the rate of PSA change, can then direct when to take a repeat *This patient also had atypical small acinar proliferation on initial biopsy; n/a, not applicable. prostate biopsy in these patients. Saturation biopsies have been reported, but the true biological potential of cancer diagnosed by such biopsy is not known [12]. proliferation on his initial biopsy. Three cancer, as many genetic alterations in PIN are patients were diagnosed with persistent PIN; also present in prostate cancer [7–10]. In There is no definitive data that correlates PIN they went on to have a third prostate biopsy, addition, progressive abnormalities in with the development of lethal prostate which revealed cancer Gleason score 6 in one phenotype in PIN also appear to be an cancer to support therapy for isolated PIN and BPH only in the other two. All seven intermediate stage before the onset of cancer, [13,14]. In addition, if PIN is truly a precursor patients who were diagnosed with cancer in terms of impairment of cell differentiation lesion to cancer, and if the latency period to during the study period had a radical and regulatory control towards prostate develop overt malignancy is 5 to >10 years prostatectomy and all had organ-confined carcinogenesis [11]. Despite this evidence, it is [1], men can potentially be followed with pT2a–pT2c disease. After a mean follow-up of not definitive whether PIN is a premalignant conservative management and may never 72.2 (60–84) months, none of the remaining lesion or merely a lesion associated with require any therapy for cancer that they 14 patients was diagnosed with clinically cancer. This question needs to be addressed in might develop. This would also depend upon significant cancer. Five of these patients went multicentre studies with a long-term follow- the length of follow-up, age and other on to have a third prostate biopsy, with no up. Furthermore, it is unknown if PIN is a medical comorbidities developed during the evidence of cancer. One patient died from precursor to a subsequent or occult follow-up, in addition to the predictors of the unrelated causes during this period; the concomitant prostate cancer that will become biology of prostate cancer, e.g. Gleason score, patients’ characteristics and results are clinically significant and cause morbidity or PSA level and DRE findings [15]. summarized in Table 1. mortality. Lefkowitz et al. [16] reported that eight of 31 Despite the association of prostate cancer men with PIN were subsequently identified as DISCUSSION with PIN, none of the present patients who having prostate cancer, using a 3-year follow- had a negative second or third prostate biopsy up interval for prostate biopsy, regardless There is significant evidence that implicates progressed to a diagnosis of clinically of PSA level or DRE findings. The clinical PIN as the most likely histologically significant cancer over ≥5 years of follow-up. outcome was not reported after radical identifiable precursor lesion of prostate Indeed, most patients (14 of 21) did not have prostatectomy in four men, and radiotherapy cancer [1]. Abnormalities in the genotype of clinically significant cancer with the relatively in the remaining four. It is unknown if PIN lesions appear to be an intermediate long follow-up of >5 years. The biopsies taken detecting and treating prostate cancer at this between normal prostate epithelium and in these patients cannot definitively exclude particular time in the natural history of their
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disease would result in a better outcome, associated with prostate cancer, needs to be Preneoplastic lesions of the prostate - rather than using the history, DRE, PSA levels addressed with multicentre studies with a clinical, pathological and molecular and the rate of PSA change to direct when follow-up of >10 years. biological aspects. In Vivo 2002; 16: 557– to take a repeat prostate biopsy, with 66 subsequent therapies for any detected cancer CONFLICT OF INTEREST 12 Chrouser KL, Lieber MM. Extended and administered then. saturation needle biopsy for the diagnosis None declared. of prostate cancer. Curr Urol Rep 2004; 5: It is also unknown if the outcome of prostate 226–30 cancer would be better if men were treated REFERENCES 13 Bostwick DG. Prostatic intraepithelial for a finding of isolated PIN rather than the neoplasia (PIN): current concepts. J Cell conservative approach described. Radical 1 Bostwick DG, Qian J. High-grade Biochem Suppl 1992; 16H: 10–9 prostatectomy in men with PIN alone shows prostatic intraepithelial neoplasia. Mod 14 Balaji KC, Rabbani F, Tsai H, Bastar H, that significant proportions have cancer Path 2004; 17: 360–79 Fair WR. Effect of neoadjuvant hormonal present [1]. There is no data to suggest 2 Kronz JD, Allan CH, Shaikh AA, Epstein therapy on prostatic intraepithelial sthat radical prostatectomy and pelvic JI. Predicting cancer following a diagnosis neoplasia and its prognostic significance. lymphadenectomy for isolated PIN resulted in of high-grade prostatic intraepithelial J Urol 1999; 162: 753–7 identifying understaged locally advanced or neoplasia on needle biopsy: data on men 15 Partin AW, Kattan MW, Subong EN metastatic prostate cancer. Androgen with more than one follow-up biopsy. Am et al. Combination of prostate-specific deprivation or 5a-reductase inhibitors may J Surg Pathol 2001; 25: 1079–85 antigen, clinical stage, and Gleason score also be therapies for PIN, but because the 3 Davidson D, Bostwick DG, Qian J et al. to predict pathological stage of localized results are conflicting, it is unknown if these Prostatic intraepithelial neoplasia is a risk prostate cancer. A multi-institutional therapies will abolish PIN [14,17–22]. It is also factor for adenocarcinoma: predictive update. JAMA 1997; 277: 1445–51 unknown if radiation therapy can abolish PIN, accuracy in needle biopsies. J Urol 1995; 16 Lefkowitz GK, Taneja SS, Brown J et al. although the prevalence and extent of PIN 154: 1295–9 Followup interval prostate biopsy 3 years appears to be decreased [23–25]. Because of 4 Shepherd D, Keetch DW, Humphrey PA, after diagnosis of high grade prostatic the long latency period between PIN and Smith DS, Stahl D. Repeat biopsy intraepithelial neoplasia is associated cancer, any therapies may be delivered before strategy in men with isolated prostatic with high likelihood of prostate cancer, they are necessary. Furthermore, all of these intraepithelial neoplasia on prostate independent of change in prostate therapies can result in significant side-effects needle biopsy. J Urol 1996; 156: 460–2 specific antigen levels. J Urol 2002; 168: that can adversely affect quality of life, and 5 Mian BM, Naya Y, Okihara K, Vakar- 1415–8 therefore using therapy for isolated PIN is not Lopez F, Troncoso P, Babaian RJ. 17 Ferguson J, Zincke H, Ellison E, advocated [1]. One proactive management Predictors of cancer in repeat extended Bergstrahl E, Bostwick DG. Decrease option may involve chemoprevention multisite prostate biopsy in men with of prostatic intraepithelial neoplasia strategies for PIN, which are under study and previous extended multisite biopsy. following androgen deprivation therapy hold much promise if carcinogenesis can be Urology 2002; 60: 836–40 in patients with stage T3 carcinoma selectively inhibited in these patients at 6 Naya Y, Ayala AG, Tamboli P, Babaian treated by radical prostatectomy. Urology apparently higher risk of developing cancer. RJ. Can the number of cores with high- 1994; 44: 91–5 grade prostate intraepithelial neoplasia 18 Vailancourt L, Ttu B, Fradet Y et al. The present study was retrospective and with predict cancer in men who undergo Effect of neoadjuvant endocrine therapy relatively few patients, and therefore selection repeat biopsy? Urology 2004; 63: 503–8 (combined androgen blockade) on normal bias will be an inherent limitation. Also, the 7 Emmert-Buck MR, Vocke CD, Pozzatti prostate and prostatic carcinoma. A number and location of biopsy cores obtained RO et al. Allelic loss on chromosome randomized study. Am J Surg Pathol 1996; introduced sampling bias. All patients did not 8p12–21 in microdissected prostatic 20: 86–93 have prostate biopsies taken at regular intraepithelial neoplasia. Cancer Res 19 Van der Kwast TH, Labrie F, Tetu B. intervals or at the end of the study to obtain 1995; 55: 2959–62 Persistence of high-grade prostatic more accurate results in terms of the 8 Kim NW, Hruszkewycz AM. Telomerase intraepithelial neoplasia under combined development of histologically confirmed activity modulation in the prevention of androgen blockade therapy. Hum Pathol prostate cancer. However, based on the length prostate cancer. Urology 2001; 57: 148– 1999; 30: 1503–7 of follow-up, the patients’ advancing age and 53 20 Civantos F, Watson RB, Pinto JE et al. comorbidities developed, routine prostate 9 Willman JH, Holden JA. Finasteride effect on benign prostatic biopsies were not deemed to be necessary in Immunohistochemical staining for DNA hyperplasia and prostate cancer. A all patients who were unlikely to develop topoisomerase II-alpha in benign, comparative clinico-pathologic study of clinically significant cancer. premalignant, and malignant lesions of radical prostatectomies. J Urol Pathol the prostate. Prostate 2000; 42: 280–6 1997; 6: 1–8 The current practice of following patients 10 Ge K, Minhas F, Duhadaway J et al. Loss 21 Yang XJ, Lecksell K, Short K et al. Does with PIN conservatively if subsequent of heterozygosity and tumor suppressor long-term finasteride therapy affect the prostate biopsies are negative appears to be a activity of Bin1 in prostate carcinoma. Int histologic features of benign prostatic reasonable management option. Whether PIN J Cancer 2000; 86: 155–61 tissue and prostate cancer on needle is a premalignant lesion, or merely a lesion 11 Nasir A, Copeland J, Gillespie JW et al. biopsy? PLESS Study Group: Proscar
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Long-Term Efficacy and Safety Study. chemoprevention. Eur Urol 1999; 35: beam radiation therapy on benign and Urology 1999; 53: 696–700 492–5 malignant prostate tissues. Am J Surg 22 Montironi R, Pomante R, Diamanti L, 24 Arakawa A, Song S, Scardino PT, Pathol 1999; 23: 1021–31 Hamilton PW, Thompson D, Bartels PH. Wheeler TM. High grade prostatic Evaluation of prostatic intraepithelial intraepithelial neoplasia in prostates Correspondence: Jonathan Izawa, neoplasia after treatment with 5-alpha- removed following irradiation failure Department of Surgery & Oncology, reductase inhibitor (finasteride). A in the treatment of prostatic University of Western Ontario, London, methodologic approach. Anal Quant Cytol adenocarcinoma. Pathol Res Pract 1995; Ontario, Canada. Histol 1996; 18: 461–70 191: 868–72 e-mail: [email protected] 23 Bostwick DG, Neumann R, Qian J, 25 Gaudin PB, Zelefsky MJ, Leibel SA, Fuks Cheng L. Reversibility of prostatic Z, Reuter VE. Histopathologic effects of Abbreviations: PIN, prostatic intraepithelial intraepithelial neoplasia: implications for three-dimensional conformal external neoplasia.
© 2005 BJU INTERNATIONAL 323 Original Article MORE BIOPSIES INCREASES THE CONCORDANCE RATE OF PROSTATE BIOPSIES COOGAN et al.
Increasing the number of biopsy cores improves the concordance of biopsy Gleason score to prostatectomy Gleason score
CHRISTOPHER L. COOGAN, KALYAN C. LATCHAMSETTY*, JASON GREENFIELD, JOHN M. CORMAN*, BARLOW LYNCH† and CHRISTOPHER R. PORTER* Departments of Urology, Rush University Medical Center, Chicago, IL,*Virginia Mason Medical Center, Seattle, WA, and †Veterans Affairs Medical Center, Washington, DC, USA Accepted for publication 7 February 2005
OBJECTIVE 107 and Chicago 135) who had RP for (31%), and 95/181 (52.5%), respectively prostate cancer. Six, eight or 10 biopsies were (P < 0.001, 10-core vs six core). To evaluate taking more biopsy cores for taken based on the physician’s preference and predicting the radical prostatectomy (RP) the patient’s characteristics. CONCLUSIONS Gleason score compared with the biopsy Gleason score, as although random sextant Taking more biopsy cores improves the biopsies are the standard for a tissue RESULTS accuracy of the biopsy Gleason score in diagnosis of prostate cancer, and taking more predicting the final Gleason score at RP; the biopsies increases the detection rate, it is Before RP, 158 (39%) patients had six, 65 predictive accuracy of the final Gleason score uncertain whether taking more cores (16%) had eight and 181 (45%) had 10 biopsy may be increased from 41% to 58% by improves the prediction of the RP Gleason cores taken. The accuracy of the Gleason sum increasing the number of biopsies from six score. of the three groups was 65/158 (41%), 26/65 to 10. (40%) and 104/181 (57.5%), respectively PATIENTS AND METHODS (P < 0.004, 10-core vs six-core). However, KEYWORDS when comparing the Gleason score separately We analysed retrospectively 404 patients (i.e. 4 + 3 is not equal to 3 + 4), the accuracy prostate cancer, Gleason sum, Gleason score, from three centres (Seattle 162, Washington of the three groups was 48/158 (30%), 20/65 biopsy
INTRODUCTION appropriate clinical features, including PSA patient’s management of their prostate level, age, clinical stage, comorbidities and the cancer. Prostate cancer is the second commonest histological features on needle biopsy. malignancy in men, with an estimated Unfortunately, the accuracy of predicting the incidence in the USA of 230 110 in 2004 [1]; final RP specimen Gleason score from the PATIENTS AND METHODS with a positive biopsy rate of 25–30% [2,3], biopsy Gleason score is currently reported to this translates into >600 000 prostate be ª43% [9]; biopsies under-graded the We retrospectively reviewed 404 patients who biopsies being taken annually in the USA. The prostate cancer in 39% and over-graded it in had RP and had either six, eight or 10 prostate standard of prostate cancer diagnosis has 16% of biopsies [9]. Because of the strong needle biopsies taken at the time of diagnosis. been the sextant biopsy technique described prognostic significance of the Gleason score All surgery was performed between 1996 and by Hodge et al. [4]. Recently, urologists have [10,11], increasing the predictive value of 2002 at the authors’ institutions (Seattle, 162 been taking more biopsy cores to enhance the prostate biopsies would better enable patients patients; Washington, 107, and Chicago, 135). detection of prostate cancer [5–8], but it is and urologists to make a more informed The number of needle biopsies taken was debatable whether taking more biopsies decision about the treatment options and the determined at the time of biopsy, based on improves not only the detection rate, but also disease. the patient’s clinical characteristics and the accuracy of predicting the final radical physician’s preference. Initially, TRUS was prostatectomy (RP) specimen Gleason score. In this study we examined whether taking used to estimate prostate volume, followed by more prostate biopsies would increase the prostate biopsy; six biopsies were taken using There are many options for treating localized predictive value of the biopsy Gleason score the standard sextant technique [4]. Patients prostate cancer, including RP, brachytherapy, when compared with the RP specimen who had eight cores taken had one biopsy at external beam radiation therapy, watchful Gleason score. An increase in the predictive the apex, two (both laterally and medially) in waiting and androgen-deprivation therapy. In value of the prostate biopsies would benefit the mid-section of the prostate, and one at choosing among these options the patient patients by helping to guide urologists the lateral aspect of the base. This was then and urologist must carefully evaluate all through the decision algorithm for each repeated on the opposite side of the prostate.
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4 + 3 is not equal to 3 + 4; Table 1), the Cores taken TABLE 1 difference between the 10-core and the other Variable All patients six eight 10 The clinical stage, groups was statistically significant (P < 0.001 pathological stage, Gleason N 404 158 65 181 and <0.004, respectively), with again no sum, accuracy, and grading Clinical stage, % difference between the six- and eight-core discrepancy of patients T1a–b 1.5 2.5 3.1 0.0 groups (P = 0.954). Thus, the predictive who had six, eight or 10- T1c 51.0 65.2 50.8 38.5 accuracy of the Gleason sum and individual core biopsy T2a 33.2 21.5 26.2 46.2 Gleason score was better in patients who had T2b 12.9 9.5 13.9 15.4 10 biopsy cores taken. T2c 1.5 1.3 6.15 0.0 RP pathological stage, % The discrepancy in grading is also shown in T2a 20.0 13.3 15.4 27.6 Table 1; the improvement in under-grading by T2b 26.5 30.4 27.7 22.7 taking more cores was not statistically T2c 36.4 29.7 33.9 43.1 significant (P > 0.05), but that in over-grading T3a 10.2 17.1 15.4 2.2 was between the 10-core and the other two T3b 5.0 8.9 3.1 2.2 groups (P < 0.03 and <0.02, respectively). T3c 2.0 0.6 4.6 2.2 Mean Gleason sum: Biopsy 6.4 6.4 6.6 6.3 DISCUSSION RP 6.6 6.6 6.8 6.5 Nodes (+/-) 1.98 1.90 1.54 2.21 Because of the differences in success rates Accuracy, n (%) and morbidities of the various procedures for Gleason sum – 65 (41) 26 (40) 104 (57.5) treating prostate cancer, counselling before Gleason score – 48 (30) 20 (31)* 95 (52.5)† therapy about the aggressiveness and extent % over-grading and under-grading, % of disease is paramount for patients. Given Over 16.3 19.6 23.1 11.0 the prognostic significance of the Gleason Under 35.4 39.2 36.9 31.5 score [6,7], increasing the accuracy of biopsies Equal 48.3 41.1 40.0 57.5 will better enable patients to make a more informed decision about their treatment *P < 0.02; †P < 0.004. algorithm. While many authors have tried to increase the detection rate of prostate cancer by taking more prostate biopsies [5–8], we Patients who had 10 biopsies taken had two at clinical characteristics and physician propose that it will also increase the accuracy the base and mid-section of the prostate preference. The patients’ median (range) age of predicting the Gleason score and Gleason (both laterally and medially), and one at the at surgery was 63 (42–79) years, the mean sum of the final RP specimen. apex, again repeated on the opposite side of follow-up 2.3 (0.17–6.4) years and median the prostate. Eight patients had transitional preoperative PSA level 6.5 (0.28–113.9) ng/mL, The present results show that taking more zone biopsies and were excluded from the which was similar in the three biopsy groups cores (10 rather than six) improved the study. (P > 0.05). accuracy of predicting the Gleason sum, from 41% to 57.5%, and the Gleason score, from The patients’ characteristics before and after The clinical preoperative stage and RP 30% to 52.5%. Both of these improvements RP, including age, PSA level, clinical stage, pathological stage are summarized in Table 1. were statistically significant when comparing race, biopsy Gleason score, RP Gleason score, Those who had 10 cores taken had a slightly the 10-core with the other two groups. There number of biopsies and margin status, were higher pathological stage, probably because was no large difference in the other variables recorded. Patients who had fewer than six of the higher clinical stage before RP. among the three groups, in age, clinical stage, biopsies or more than 10 were excluded from However, there was no statistically significant pathological stage, mean biopsy Gleason the study. We then compared the Gleason difference among the three groups in age, score and mean RP Gleason score. The mean scores before and after RP for each patient clinical stage, pathological stage, mean biopsy PSA level was lower in the 10-core group and determined the concordance rate of Gleason score, and mean RP specimen (6.7 ng/mL) than in the other two (10.0 and the Gleason score and Gleason sum. The Gleason score (Table 1). 11.1 ng/mL, respectively). We attribute this results were analysed statistically using the difference to a few outliers with extremely chi-square and Mantel-Haenszel chi-square The accuracy of the Gleason sum of the three high PSA levels in the six- and eight-core tests. groups compared with the RP Gleason sum is groups. For clinical and pathological stage, also shown in Table 1; the difference between those who had 10 cores taken had a higher the 10-core and the other two groups stage on final analysis, but this was not RESULTS was significant (P < 0.004 and <0.02, statistically significant (P > 0.05). respectively), but that between the six-core All 404 patients either had six, eight or 10 and eight-core group was not (P = 0.875). Grossklaus et al. [12] and Egevad et al. [5] also prostate needle biopsies taken, based on Comparing the Gleason score separately (i.e. reviewed the value of taking more biopsies to
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better predict the pathological Gleason score, Francisco et al. [15] reported that the to 52.5%. This improvement in accuracy will finding that this prediction was only percentage of cores positive for prostate be of benefit to patients when choosing marginally improved by doing so. However, cancer was a better predictor of cancer among their treatment options for prostate their studies only assessed a total of 135 and recurrence than PSA level. The percentage was cancer. 121 patients. As in the study by Egevad et al., calculated by the number of cores positive for under-grading still appears to be a major cancer divided by the total number of cores, CONFLICT OF INTEREST problem, occurring in 35% of all the present multiplied by 100. Patients with >28% patients, with over-grading in 16% (Table 1). positive cores were at significantly greater risk None declared. Because there is such a large proportion of prostate cancer recurrence. Clearly this of under-grading of prostate cancer, finding, with a greater concordance rate with REFERENCES many patients and urologists may be 10 biopsy cores, will add to the value of underestimating the severity of the patients’ prostate cancer biopsies. 1 Jemal A, Tiwari RC, Murray T et al. disease when discussing their treatment Cancer statistics, 2004. CA Cancer J Clin options, based on the pathological Gleason Furthermore, nomograms for predicting final 2004; 54: 8–29 score and sum of the prostate biopsy. pathological stage and failure are available 2 Keetch DW, Catalona WJ, Smith DS. for use by urologists and patients [16–19]. It is Serial prostate biopsies in men with While the Gleason score still has strong clear that biopsy Gleason score and PSA are persistently elevated serum prostate prognostic significance, other authors have important preoperative predictors for these specific antigen values. J Urol 1994; 151: evaluated other clinical predictors for nomograms. Increasing the concordance rate 1571–4 prostate cancer. Sebo et al. [13] recently of prostate biopsies by taking more cores will 3 Catalona WJ, Richie JP, Ahmann reported that the percentage of needle-biopsy also increase the accuracy of the preoperative FR et al. Comparison of digital rectal cores and surface area positive for cancer are nomograms and physicians will be better able examination and serum prostate specific the strongest predictors of pathological stage to counsel patients on their disease. antigen in the early detection of prostate and tumour volume on multivariate analysis. cancer. Results of a multicenter clinical Grossklaus et al. [12] also concluded that the One of the limitations of the present study is trial of 6,630 men. J Urol 1994; 151: percentage of positive cores is the best that it was a retrospective review of the 1283–90 predictor of both pathological stage and charts of patients who had had RP for 4 Hodge KK, McNeal SE, Terris MK, tumour volume. We did not analyse the prostate cancer. As such, there was no Stamey TA. Random systematic versus percentage of positive cores for its predictive standard protocol devised for obtaining directed ultrasound-guided transrectal value of pathological stage and tumour prostate biopsies. There were also many core biopsies of the prostate. J Urol 1989; volume, but are currently updating our pathologists from different institutions 142: 71–4 database. reviewing both the prostate biopsies and the 5 Presti JC Jr, O’Dowd GJ, Miller MC, prostate specimen after surgery. Mattu R, Veltri RW. Extended peripheral A recent study agreed with the present zone biopsy schemes increase cancer conclusions; San Francisco et al. [14] reviewed The optimum number of prostate biopsies to detection rates and minimize variance in 466 men who had retropubic RP, dividing the be taken remains unknown. Because of recent prostate specific antigen and age related patients into two groups based on the studies delineating an increase in detection cancer rates: results of a community number of needle biopsies. One group rate by taking more biopsy cores, the patients multi-practice study. J Urol 2003; 169: comprised 126 men who had extended needle who were treated more recently had more 125–9 biopsies (≥10 cores) and the second 340 biopsies (10 cores) than those treated earlier 6 Eskew LA, Bare RL, McCullough DL. patients diagnosed with prostate cancer by in the study (six cores). Arguably, 12 or 14 Systematic 5 region prostate biopsy restricted needle biopsies (£ nine cores); the biopsies could increase the accuracy of is superior to sextant method for concordance rate was 76% and 63%, predicting the final Gleason sum and Gleason diagnosing carcinoma of the prostate. respectively. The present study is unique in score even further. In the present patients J Urol 1997; 157: 199–202 that we evaluated and compared patients there was no identifiable increase in morbidity 7 Presti JC Jr, Chang JJ, Bhargava V, who had exactly six, eight or 10 biopsy cores when taking six rather than 10 biopsies. Shinohara K. The optimal systematic at the time of diagnosis. The study by San Berger et al. [20] reported that, except for prostate biopsy scheme should include 8 Francisco et al. had only 34/126 (27%) haematospermia, there was no increase in rather than 6 biopsies. results of a patients who had exactly 10 biopsy cores, morbidity when taking six rather than 15 prospective clinical trial. J Urol 2000; 163: while 75/126 (59.5%) in the extended group cores. We are currently expanding our 163–6 had 12–14 cores taken. These patients were database to further evaluate the accuracy of 8 Gore JL, Shariat SF, Miles BJ et al. combined and compared with those who had taking 12 biopsy cores. Optimal combinations of systematic nine or fewer cores. This may be why they had sextant and laterally directed biopsies for a high concordance rate of 76%, vs 57.5% in In conclusion, taking more biopsy cores the detection of prostate cancer. J Urol the present study. improved the accuracy of predicting the final 2001; 165: 1554–9 RP specimen Gleason sum, from 41% to 9 Egevad L, Norlen BJ, Norberg M. The Not only does taking more cores improve the 57.5% for six and 10 cores (P < 0.004), but value of multiple core biopsies for concordance rate, but it also may indirectly when comparing the Gleason score predicting the Gleason score of prostate help to predict recurrence after RP. San separately, the accuracy improved from 30% cancer. BJU Int 2001; 88: 716–21
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10 Epstein JI, Pizov G, Walsh PC. 14 San Francisco IF, DeWolf WC, Rosen S, 18 Nelson CP, Rubin MA, Strawderman M, Correlation of pathologic findings with Upton M, Olumi AF. Extended prostate Montie JE, Sanda MG. Preoperative progression after radical retropubic needle biopsy improves concordance of parameters for predicting early prostate prostatectomy. Cancer 1993; 71: 3582– Gleason grading between prostate needle cancer recurrence after radical 93 biopsy and radical prostatectomy. J Urol prostatectomy. Urology 2002; 59: 740–5 11 Epstein JI, Partin AW, Sauvageot J, 2003; 169: 136–40 19 Partin AW, Kattan MW, Subong EN Walsh PC. Prediction of progression 15 San Francisco IF, Regan MM, Olumi AF, et al. Combination of prostate-specific following radical prostatectomy. A DeWolf WC. Percent of cores positive for antigen, clinical stage, and Gleason score multivariate analysis of 721 men with cancer is a better preoperative predictor to predict pathological stage of localized long-term follow-up. Am J Surg Pathol of cancer recurrence after radical prostate cancer. A multi-institutional 1996; 20: 286–92 prostatectomy than prostate specific update. JAMA 1997; 277: 1445–51 12 Grossklaus DJ, Coffey CS, Shappell SB, antigen. J Urol 2004; 171: 1492–9 20 Berger AP, Gozzi C, Steiner H et al. Cookson MS. Prediction of tumour 16 Kattan MW, Eastham JA, Stapleton Complication rate of transrectal volume and pathological stage in radical AM, Wheeler TM, Scardino PT. A ultrasound guided prostate biopsy: a prostatectomy specimens is not improved preoperative nomogram for disease comparison among 3 protocols with 6, 10 by taking more prostate needle-biopsy recurrence following radical and 15 cores. J Urol 2004; 171: 1478–81 cores. BJU Int 2001; 88: 722–6 prostatectomy for prostate cancer. J Natl 13 Sebo TJ, Brian JB, Cheville JC, Lohse C, Cancer Inst 1998; 90: 766–71 Correspondence: Kalyan C. Latchamsetty, Wollan P, Zincke H. The percent of cores 17 D’Amico AV, Whittington R, Malkowicz Department of Urology, Virginia Mason positive for cancer in prostate needle SB et al. Biochemical outcome after Medical Center, 1100 9th Ave, C7-URO, biopsy specimens is strongly predictive of radical prostatectomy, external beam Seattle, WA 98101, USA. tumor stage and volume at radical radiation therapy, or interstitial radiation e-mail: [email protected] prostatectomy. J Urol 2000; 163: therapy for clinically localized prostate 174–8 cancer. JAMA 1998; 280: 969–74 Abbreviations: RP, radical prostatectomy.
© 2005 BJU INTERNATIONAL 327 Original Article SERUM THYROID-STIMULATING HORMONE AND PROSTATE CANCER LEHRER et al.
Serum thyroid-stimulating hormone is elevated in men with Gleason 8 prostate cancer
STEVEN LEHRER, EDWARD J. DIAMOND*, NELSON N. STONE† and RICHARD G. STOCK Departments of Radiation Oncology, *Medicine and †Urology, Mount Sinai Medical Center, and the Veterans Affairs Medical Center, Bronx, New York, NY, USA Accepted for publication 7 February 2005
OBJECTIVE commercially available instrument (Immulite, of the elaboration of TSH by cancer cells. Bone Diagnostic Products Corporation, Los mineral density in the face of normal levels of To measure the levels of serum thyroid- Angeles). thyroid hormone depends on an intact stimulating hormone (TSH) in men with response to TSH, which ordinarily suppresses prostate cancer, as those with a Gleason score RESULTS both osteoblast and osteoclast differentiation, of ≥8 are at high risk of skeletal metastases thereby exerting control over bone (and should be considered for bone There was significant variation in TSH levels remodelling. However, with abnormally high scintigraphy at diagnosis), and because the with Gleason score (P = 0.004); men with TSH levels this process may become deranged, structural integrity of the skeleton depends Gleason 8 tumours had the highest serum TSH promoting the development of bone on constant remodelling controlled by many levels. Because serum TSH levels increase with metastases. If TSH production by prostate local and systemic factors, including TSH, an age, we used a multivariate analysis of cancer cells could be suppressed, the important regulator of this process. variance with both age and Gleason score as incidence of bone metastases might be covariates. The effect of Gleason score on reduced. PATIENTS AND METHODS TSH level was significant (P = 0.036) and independent of the effect of age (P = 0.392). KEYWORDS We evaluated 51 men referred for treatment of localized prostate cancer and 10 with CONCLUSION prostate, cancer, thyroid-stimulating biopsy-confirmed benign prostatic hormone, bone metastasis hypertrophy. Serum TSH was determined with We propose that the high serum TSH levels in a chemoluminescent immunoassay and a men with Gleason 8 prostate cancer is a result
INTRODUCTION we measured serum TSH levels in men with RESULTS prostate cancer or BPH. Men with prostate cancer of Gleason score The serum TSH levels of the patients stratified ≥8 have a high risk of skeletal metastases PATIENTS AND METHODS by Gleason score is shown in Fig. 1; there was and should be considered for bone a significant variation in TSH level in the scintigraphy at diagnosis [1]. However, the The participants of the study were identified groups (P = 0.004) and men with Gleason 8 mechanism for these metastases is uncertain through radiation oncology and other clinics, tumours had the highest serum TSH levels. and various causes have been suggested [2]. and were accrued between 2001 and 2004; all Because serum TSH levels increase with age The skeleton is a dynamic organ whose eligible patients were asked to participate. All [5] (Fig. 2) we used a multivariate ANOVA with structural integrity depends on constant patients with prostate cancer had been both age and Gleason score as covariates. The remodelling, controlled by many local and initially diagnosed on the basis of a rising PSA effect of Gleason score on serum TSH levels systemic factors. Thyroid-stimulating level or abnormal physical examination, with was significant (P = 0.036) and independent hormone (TSH) is an important regulator a histological diagnosis confirmed in all. All of the effect of age (P = 0.392). of this process [3]. The established function participants gave informed consent and the of TSH is to promote thyroid follicle study had Institutional Review Board development and hormone secretion. approval. In all, we evaluated 51 men (mean DISCUSSION However, there is evidence for direct effects age 68 years, SD 9, range 50–84) referred for of TSH on both components of skeletal treatment of localized prostate cancer and 10 Bone metastases in prostate cancer are remodelling, i.e. osteoblastic bone formation with biopsy-confirmed BPH. Serum TSH levels predominantly osteoblastic, with more and osteoclastic bone resorption [4]. Because were measured using a chemoluminescent irregular bone trabeculae; markers of bone of the relationship of Gleason 8 prostate immunoassay and a commercially available resorption also increase, although there are cancer to bone metastases, and the instrument (Immulite, Diagnostic Products similar numbers of osteoclasts [2]. Prostate relationship of TSH to bone remodelling, Corporation, Los Angeles, CA). cancer cells release PSA, a kallikrein serine
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FIG. 1. 4 process may become deranged, promoting the The mean (SEM) serum TSH level in development of bone metastases. If TSH 15 51 men with prostate cancer and production by prostate cancer cells could be 10 with biopsy-confirmed BPH, 3 suppressed, the incidence of bone metastases stratified by Gleason score. might be reduced. 10 The variability is significant 10 13
(P = 0.004, one-way ANOVA). The IU/mL CONFLICT OF INTEREST
m 2 number of men in each group 13
is indicated above the TSH, None declared. corresponding error bar. 1 REFERENCES
1 Abuzallouf S, Dayes I, Lukka H. Baseline 0 staging of newly diagnosed prostate BPH 5 6 7 8 Gleason Score cancer: a summary of the literature. J Urol 2004; 171: 2122–7 2 Roodman GD. Mechanisms of bone FIG. 2. 6 metastasis. N Engl J Med 2004; 350: Serum TSH level plotted against 1655–64 age in 51 men with prostate 5 3 Novack DV. TSH, the bone suppressing cancer (r = 0.291, P = 0.056). The hormone. Cell 2003; 115: 129–30 TSH values for normal men, 4 4 Abe E, Marians RC, Yu W et al. TSH is a assayed at our laboratory, is negative regulator of skeletal remodeling.
0.4–4 mIU/mL. IU/mL m 3 Cell 2003; 115: 151–62 5 Sawin CT, Chopra D, Azizi F, Mannix TSH, TSH, 2 JE, Bacharach P. The aging thyroid. Increased prevalence of elevated serum 1 thyrotropin levels in the elderly. JAMA 1979; 242: 247–50 0 6 Correale P, Micheli L, Vecchio MT et al. 40 50 60 70 80 90 A parathyroid-hormone-related-protein Age, years (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour- protease that can cleave parathyroid from the elaboration of TSH by the cancer infiltrating lymphocytes derived from hormone-related peptide, released by tumour cells within the bone itself. The very high local prostate cancer metastases, with epitope cells [6], at the N-terminal. This cleavage may level of TSH in the bone is reflected in the peptide-loaded autologous dendritic cells block tumour-induced bone resorption. In elevated serum TSH levels of patients with and low-dose IL-2. Br J Cancer 2004; 85: patients with prostate cancer high PSA levels Gleason 8 tumours. 1722–30 are associated with bone metastases, but levels of bone resorption markers are also Bone mineral density in the face of normal Correspondence: Steven Lehrer, Box 1236, high in patients with bone metastases and levels of thyroid hormone depends on an Mount Sinai Medical Center, New York, NY reflect the extent of metastases more intact response to TSH [4]. TSH ordinarily 10029, USA. accurately than PSA level [2]. suppresses both osteoblast and osteoclast e-mail: [email protected] differentiation, thereby exerting control over We suggest that the elevated serum TSH levels bone remodelling. However, in the presence of Abbreviations: TSH, thyroid-stimulating in men with Gleason 8 prostate cancer result abnormally high TSH concentrations, this hormone.
© 2005 BJU INTERNATIONAL 329 Original Article INGUINAL HERNIA REPAIR WITH MESH DURING RADICAL PROSTATECTOMY ANTUNES et al.
Inguinal hernia repair with polypropylene mesh during radical retropubic prostatectomy: an easy and practical approach
ALBERTO AZOUBEL ANTUNES, MARCOS DALL’OGLIO, ALEXANDRE CRIPPA and MIGUEL SROUGI Division of Urology, Federal University of Sao Paulo, Brazil Accepted for publication 7 February 2005
OBJECTIVE maximum size 15 ¥ 7.5 cm and a small slit on (4%) hernias recurred. There were no its medial side was then created and placed in complications after surgery. To report the results of the simultaneous the preperitoneal space, embracing the inguinal hernia repair during radical spermatic cord and covering the myopectinal retropubic prostatectomy (RRP) with the orifice. Preoperative risk factors, e.g. CONCLUSION preperitoneal tension-free Stoppa technique, constipation, pulmonary disease or urinary using a polypropylene mesh. obstructive symptoms, were collected Preperitoneal hernia repair with retrospectively from the files. Complications polypropylene mesh is safe, effective and PATIENTS AND METHODS after surgery, including wound infection, practical. The procedure simultaneous with pelvic collections, urinary fistula and RRP gave a 96% success rate and with no During 855 consecutive RRPs, 40 (5%) recurrence of the hernia, were assessed. significant increase in operating time or patients (median age 66.9 years, range 52–81) additional complications. with 49 inguinal hernias had a simultaneous RESULTS inguinal hernioplasty. The RRP was performed according to the Walsh modified technique. Preoperative risk factors for hernia KEYWORDS After the prostate and seminal vesicles were development were identified in 23 (58%) removed and the urethrovesical anastomosis patients; three had recurrent hernias. With a prostatectomy, inguinal hernia, surgical mesh, completed, a polypropylene mesh of median 23.1 months of follow-up period two polypropylene
INTRODUCTION and predispose the patient to developing have also contributed to stimulate urologists hernias [3,4,7]. to choose different methods, and even to With the increased use of PSA testing, cases avoid simultaneous procedures, are the risk of of localized prostate cancer have become The simultaneous correction of inguinal infection, the risk of recurrence of the hernia more frequent and currently nearly 70% of hernia during prostate surgery was first defects, a longer operation and anaesthetic these tumours are diagnosed at stage T1c [1]. described in 1949 by McDonald and Huggins time, unfamiliarity with the techniques and The most frequent treatment for localized [8], who used two separate incisions. concerns over performing procedures usually prostate cancer is radical retropubic However, after the description of a done by general surgical specialists [3,11]. prostatectomy (RRP), with half of patients so simultaneous preperitoneal approach with Therefore, different methods have been used treated [2]. It is estimated that inguinal the Nyhus technique to correct the hernia by many authors [3–5,11,12]. hernias are present in 5–12% of patients who defect during prostate surgery [3], this are candidates for radical surgical treatment procedure became more popular. It was recently proposed that a modified for localized prostate cancer [3–5]. Subsequently, the simultaneous correction of Pfannenstiel incision with no use of the hernia defects during prostate surgery, using preperitoneal approach is an ideal method for Data from the National Center for Health the tension-free preperitoneal technique with inguinal hernia repair concurrent with RRP Statistics show that there were ª800 000 a prosthetic repair as described by Stoppa [13]. In the present study we report the results groin hernia repairs in the USA in 2003, and it et al. [9], was reported [4,5,10]. of inguinal hernia repair during RRP with the is the most common operation by general preperitoneal approach, using a surgeons in the country [6]. If these hernias Despite the clear advantages of the polypropylene mesh. are left untreated they can potentially result simultaneous approach in avoiding future in serious complications, e.g. bowel complications from the hernia defect and strangulation or ischaemia, and a 14% potential emergency surgery, to date there is PATIENTS AND METHODS mortality rate for emergency operations is no published consensus about the best reported in these cases. Also, any abdominal method to treat inguinal hernias during From September 1999 to August 2004, 855 incision tends to weaken the abdominal wall prostate surgery. The reported concerns that RRPs were performed at the authors’
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excess mesh discarded by cutting with Type Detail TABLE 1 scissors. No stay sutures were used to I Infantile indirect inguinal hernias with no distension of the The Nyhus classification immobilize the mesh. For bilateral repair the deep inguinal ring [14] procedure was repeated on the opposite side. II Indirect inguinal hernias with distension of the deep inguinal No antiseptic lavage of the surgical field was ring used after placing the mesh. A Penrose drain III A Direct inguinal hernias was inserted in the prevesical space, III B Large indirect inguinal hernias externalized through the lower extremity of III C Femoral hernias the incision and removed 4 days after IV Recurrent hernias surgery; care was taken to avoid drain contact with the mesh. The median (range) follow-up was 23.1 (1–60) months; complications, including wound infection, pelvic collections, FIG. 1. The polypropylene mesh, with a small slit on retrospectively from the files. Inguinal hernias urinary fistula and recurrence of the hernia, its medial side to accommodate the cord structures. were symptomatic and diagnosed on physical were assessed. examination before or incidentally discovered during surgery, by inspecting the direct or indirect inguinal regions and the femoral RESULTS canal. Hernia types were classified according to the Nyhus system (Table 1) [14]. Most There were 49 inguinal hernias diagnosed and hernia defects were considered as type IIIA repaired in the 40 patients (median age and IIIB (direct inguinal hernias and large 66.9 years, range 52–81). Preoperative risk indirect inguinal hernias, respectively) and the factors for hernia were identified in 23 (58%) recurrent hernias as type IV. patients; all reported LUTS, two reported intestinal constipation and one reported All the patients routinely received i.v. chronic pulmonary disease through tobacco prophylactic antibiotics (first-generation abuse. Sixteen hernias were on the right, 15 cephalosporin), beginning 2 h before surgery on the left and nine were bilateral. The FIG. 2. The mesh is placed in the preperitoneal space and continued until the indwelling catheter diagnosis was before surgery in 36 (90%) to cover the myopectinal orifice. was removed. For the procedure the patients patients; nine had had a previous inguinal were placed supine with hyperextension of hernia repair, four each on the right and left, the hips. After bladder catheterization, a and one bilateral. Three patients had recurrent median longitudinal incision was made and hernias. The hernia repair added a mean of bilateral pelvic lymph nodes dissected. RRP 10 min to the operative duration. was done according to the Walsh modified technique [15]. After the prostate and seminal With a median 23.1-month follow-up, two vesicles were removed and urethrovesical (4%) patients had evidence of recurrence; anastomosis completed, the spermatic cord both complained of LUTS before surgery, had was dissected, the hernia sac identified, and unilateral right inguinal hernias and were treated according to the position and local younger than the median age of the whole characteristics. If an indirect hernia sac was group (66 years). The first had had a previous present it was dissected off and the hernia repair at the same side and this was peritoneum closed at the neck, while if there the second recurrence. The recurrences were was a direct hernia, the sac was teased from at 18 and 24 months. Both patients had a its envelope of transversalis fascia in the repeat herniorrhaphy through an inguinal abdominal wall. The spermatic cord elements approach. were separated from the peritoneum through the parietalization manoeuvre. If there was There were no complications after surgery, a lipoma of the chord it was also dissected e.g. wound infection, pelvic collections and off. urinary leakage, despite using the mesh. Three patients reported mild and transient testicular The hernias were repaired according to the pain at the side of the hernia repair, but institution; 40 patients (5%) had a technique of Stoppa et al. [9]. A polypropylene required no treatment. simultaneous inguinal hernioplasty, all mesh (maximum 15 ¥ 7.5 cm) was used, with procedures being performed by the same a small slit made on its medial side to surgeon. The preoperative data of these accommodate the cord structures (Fig. 1) and DISCUSSION patients, including risk factors such as placed in the preperitoneal space to cover the intestinal constipation, pulmonary disease or myopectinal orifice (Fig. 2). Care was taken to To date there is no consensus on the urinary obstructive symptoms, were collected avoid contact with the anastomosis and any ideal method for correcting inguinal
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hernias during RRP. In the present study, However, one important limitation of the With a mean follow-up of 24 (6–66) months with a 23-month follow-up, the recurrence Nyhus procedure is the resultant high tension there was no recurrence in the mesh group rate was 4%, which is comparable to that on the repair, which is often unacceptable for and five (14%) in the no-mesh group. All of other methods with the same follow-up, a large defect when the supporting tissues are recurrent hernias were detected within a year and with no complications during this extremely weakened. This tension may also be of the initial operation. There were no period. worsened after closing the abdominal complications. More recently, Drachenberg incision. A study with 1186 patients (aged and Bell [5] reported their experience with the A groin hernia begins within one weak area, 18–96 years) treated with this technique preperitoneal mesh-plug herniorraphy in 15 termed the myopectinal orifice; this area is showed a recurrence rate of 6.6% with a patients undergoing RRP. With a median limited superiorly by the internal oblique and mean follow-up of 3.5 years [18]. follow-up of 18 months there were no transverse abdominal muscles, laterally by the recurrences or orchalgia. The laparoscopic ilio-psoas muscle, medially by the rectus Some authors indicate the use of the Nyhus repair of inguinal hernias, which is almost muscle and inferiorly by the pecten of the technique to repair inguinal hernias during always based on the Stoppa operation, was pubis. The femoral vessels and the spermatic RRP. Schlegel and Walsh [3] performed 41 also described simultaneously with cord cross this area, which is divided in half by preperitoneal herniorrhaphies in 32 patients transperitoneal laparoscopic RP [20]. the inguinal ligament and sealed on its inner simultaneously with 343 RRPs and 26 radical surface by the transversal fascia. Any failure cystoprostatectomies, using the preperitoneal Recently, Manoharan et al. [13] described a of the transversalis fascia or in the shutter Nyhus technique. They had no evidence of modified Pfannenstiel incision to allow mechanism (a movement produced by the recurrence and no complications related to inguinal hernia repair during RRP. The authors transverse aponeurotic arch when the the hernia repair. However, their median repaired hernias using the tension-free transverse abdominal and internal oblique follow-up was only 11.4 months, and as we technique described by Lichtenstein et al. [21], muscles are tense) to contain the peritoneum show in the present report, the hernia can and reported their initial experience with 15 and its contents will produce a groin hernia recur after this period, as in two of the patients, who had no complications or [4]. present patients, at 18 and 24 months. recurrences with a mean follow-up of 5.5 months. However, the technique seems to McDonald and Huggins [8] were the first to The repair introduced by Stoppa et al. [9] be more laborious, as it requires further report an inguinal hernia repair concomitant remains one of the most reliable methods of dissection of the subcutaneous plane along with prostatectomy, but this was done with hernia repair [19]; they proposed that the the inferior aspect of the Pfannenstiel incision two separate incisions, with the hernia defect prosthetic mesh could replace the weakened to expose the external oblique aponeurosis, repaired through the inguinal approach. A transversalis fascia by eliminating any and an additional incision of this aponeurosis Pfannenstiel incision was subsequently potential protrusion of the abdominal before assessing the spermatic cord and proposed by others for the herniorrhaphy contents. This procedure has been the exploring the hernia sac. Also, the results of during prostatectomy, but also with and preferred method to correct hernial defects this technique need to be re-evaluated with inguinal approach to correct the hernia defect during prostate surgery for many authors. more patients and longer follow-up. [16]. Filiadis et al. [10] evaluated the results of hernia correction with a simultaneous Stoppa To date there are no prospective controlled The preperitoneal hernia repair was first procedure and open surgical prostatectomy trials comparing different techniques of reported by Annandale and subsequently for benign disease in 22 patients; with a herniorrhaphy during prostate surgery. The modified by Nyhus (cited in [4]). According to median follow-up of 20.4 months there was study by Choi et al. [4] was retrospective and the Nyhus technique, the transverses arch is one case of wound infection with urinary did not mention the types of inguinal hernia approximated to the iliopubic tract with fistula that required no treatment and one according to the Nyhus classification, creating interrupted polypropylene sutures and then recurrence that was clinically insignificant, a possible bias in the results. Perhaps it is these initial sutures are placed down to also treated conservatively. Patients with reasonable to avoid the use of prosthetic Cooper’s ligament to close the femoral canal, recurrent hernias were excluded from that mesh techniques only in patients with a high preventing potential recurrences in this area study. risk of wound infection, as in cases of [17]. preoperatively documented UTIs or rectal The Stoppa procedure was also described perforations during the procedure. The reported benefits of the preperitoneal simultaneously with RRP by Choi et al. [4], approach are the ease of exposing the hernial who retrospectively reviewed the results of In the present series there were two defects, which also allows an accurate 70 hernioplasties with the preperitoneal recurrences after the first year from surgery; identification of the vascular structures [3], approach (35 with and 35 without mesh) in these failures may have resulted from an the possibility to discover additional hernias 48 patients. In the prosthetic group they used inadequate size of prosthesis, insufficient to not detected on the initial physical a 12-cm mesh that was tapered to avoid cover the entire myopectinal orifice, or from examination, and in cases of previous inguinal approximation with the anastomosis, and migration of the mesh, as we did not use stay hernia corrections (common in patients with a fixed with one or two stay sutures to stabilize sutures. According to the Stoppa principle, history of prostatic symptoms, and 23% in the the mesh. The group with no mesh had the the prosthesis is held in place mainly by intra- present study), the area is free of the preperitoneal Nyhus technique, as described abdominal pressure, and no stay sutures are adhesions usually encountered when another by Schlegel and Walsh [3]. The mean (range) necessary, but when simultaneous with RRP inguinal approach is used [11]. age of the patients was 60.9 (43–73) years. much more dead space is left after dissecting
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the prostate, seminal vesicles and lymph retropubic prostatectomy. J Urol 1999; 14 Nyhus LM, Klein MS, Rogers FB. nodes, and this might influence recurrence. 161: 840–3 Inguinal hernia. Curr Probl Surg 1991; 28: The use of immobilising sutures could prevent 5 Drachenberg DE, Bell DG. Preperitoneal 401–50 mesh migration and reduce the present 4% mesh-plug herniorraphy during radical 15 Walsh PC. Radical retropubic recurrence rate. retropubic prostatectomy. Can J Urol prostatectomy. In Walsh PC, Retik AB, 2002; 9: 1602–6 Stamey TA, Vaughan ED eds. Campbell’s In conclusion, preperitoneal hernia repair with 6 Rutkow IM. Demographic and Urology, Vol. 3. Philadelphia: WB polypropylene mesh is safe, effective and socioeconomic aspects of hernia repair in Saunders, 1992: 2865 practical; the simultaneous approach gave the United States in 2003. Surg Clin North 16 Maluf NS, Tauber AS. Combined excellent results (success rate of 96%) with no Am 2003; 83: 1045–51 prostatectomy and herniorrhaphy significant increase in operative duration or 7 Regan TC, Mordkin RM, Constantinople through the Pfannenstiel incision. Urol Int additional complications. We therefore NL, Spence IJ, Dejter SW Jr. Incidence 1961; 11: 51–77 advocate this method in patients undergoing of inguinal hernias following radical 17 Nyhus LM, Condon RE, Harkins HN. RRP who have concomitant inguinal hernias, retropubic prostatectomy. Urology 1996; Clinical experiences with preperitoneal to avoid future surgery and potential 47: 536–7 hernial repair for all types of hernia of the complications from these unrepaired defects. 8 McDonald DF, Huggins C. Simultaneous groin, with particular reference to the prostatectomy and inguinal importance of transversalis fascia herniorrhaphy. Surg Gynecol Obstet 1949; analogues. Am J Surg 1960; 100: 234–44 CONFLICT OF INTEREST 89: 621 18 Read RC. Recurrence after preperitoneal 9 Stoppa RE, Rives JL, Warlaumont CR, herniorrhaphy in the adult. Arch Surg None declared. Palot JP, Verhaeghe PJ, Delattre JF. The 1975; 110: 666–71 use of Dacron in the repair of hernias of 19 Champault GG, Rizk N, Catheline JM, REFERENCES the groin. Surg Clin North Am 1984; 64: Turner R, Boutelier P. Inguinal hernia 269–85 repair: totally preperitoneal laparoscopic 1 Partin AW, Mangold LA, Lamm DM, 10 Filiadis I, Hastazeris K, Tsimaris I, approach versus Stoppa operation. Walsh PC, Epstein JI, Pearson JD. Papadopoulos A, Kakoulidis S, randomized trial of 100 cases. Surg Contemporary update of prostate cancer Stavropoulos NE. Simultaneous Laparosc Endosc 1997; 7: 445–50 staging nomograms (Partin Tables) for the adenomectomy and preperitoneal repair 20 Allaf ME, Hsu TH, Sullivan W, Su LM. new millennium. Urology 2001; 58: 843– of inguinal hernias by a single incision Simultaneous laparoscopic prosthetic 8 with the application of polypropylene mesh inguinal herniorrhaphy during 2 Cooperberg MR, Broering JM, Litwin mesh. Int Urol Nephrol 2003; 35: 19–24 transperitoneal laparoscopic radical MS et al. The contemporary management 11 Abarbanel J, Kimche D. Combined prostatectomy. Urology 2003; 62: 1121 of prostate cancer in the United States: retropubic prostatectomy and 21 Lichtenstein IL, Shulman AG, Amid PK, lessons from the cancer of the prostate preperitoneal inguinal herniorrhaphy. Montllor MM. The tension-free strategic urologic research endeavor J Urol 1988; 140: 1442–4 hernioplasty. Am J Surg 1989; 157: 188– (CapSURE), a national disease registry. 12 Kursh ED, Persky L. Preperitoneal 93 J Urol 2004; 171: 1393–401 herniorrhaphy. Adjunct to prostatic 3 Schlegel PN, Walsh PC. Simultaneous surgery. Urology 1975; 05: 322–5 Correspondence: Miguel Srougi, Rua Peixoto preperitoneal hernia repair during radical 13 Manoharan M, Gomez P, Soloway Gomide, 2055/81, Sao Paulo – SP, Brazil. pelvic surgery. J Urol 1987; 137: 1180–3 MS. Concurrent radical retropubic e-mail: [email protected] 4 Choi BB, Steckel J, Denoto G, Vaughan prostatectomy and inguinal hernia repair ED, Schlegel PN. Preperitoneal prosthetic through a modified Pfannenstiel incision. Abbreviations: RRP, radical retropubic mesh hernioplasty during radical BJU Int 2004; 93: 1203–6 prostatectomy.
© 2005 BJU INTERNATIONAL 333 Original Article IMMUNODIAGNOSTIC ASSAY FOR URINARY NMP-52 IN BLADDER CANCER ATTALLAH et al.
An office-based immunodiagnostic assay for detecting urinary nuclear matrix protein 52 in patients with bladder cancer
ABDELFATTAH M. ATTALLAH, HANEM A. SAKR*, HISHAM ISMAIL, EL-SAYED K. ABDEL-HADY† and IBRAHIM EL-DOSOKY‡ R & D Department, Biotechnology Research Center, New Damietta City, *Nuclear Medicine Department, Mansoura University Hospitals, †Faculty of Science, and ‡Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt Accepted for publication 10 March 2005
OBJECTIVE initial responses of 43 patients treated by tumour marker was not detected in the urine irradiation were followed using the assay. of patients who showed a response after To report the rapid (5 min) and simple radiotherapy. detection of a nuclear matrix protein (NMP) in RESULTS the urine of patients with bladder cancer, CONCLUSION using a newly developed office-based dot- The NMP marker was identified in the urine of enzyme-linked immunosorbent assay (ELISA). patients with bladder cancer at 52 kDa (NMP- Detecting the urinary NMP-52 marker using 52) by Western blot. The dot-ELISA detected dot-ELISA would be helpful in the rapid the urinary NMP-52 marker in 92% of diagnosis and follow-up of patients with PATIENTS AND METHODS patients with squamous cell carcinoma, 98% bladder cancer. with transitional cell carcinoma, and all six of Western blot and specific immunoglobulin-G those with adenocarcinoma of the bladder, antibody were used to identify the urinary with a specificity of 94%. The positive and KEYWORDS NMP marker. Urine samples from 149 patients negative predictive values (97% and 94%, with bladder cancer and 72 controls were respectively) and efficiency (96%) of the dot- bladder, tumour, marker, NMP, 52-kDa, urine, evaluated using the developed dot-ELISA. The ELISA were high. In addition, the NMP-52 diagnosis, follow-up, dot-ELISA
INTRODUCTION During the last few years, several urinary the rapid diagnosis and monitoring of markers of bladder cancer have been patients with bladder cancer after The highest incidence rates of bladder cancer introduced and evaluated for the noninvasive radiotherapy. are generally found in industrially developed detection of bladder cancer [6,7]. However, countries, particularly North America and most of the currently available urinary PATIENTS AND METHODS Western Europe, and areas associated with markers have lower specificity than urinary endemic schistosomiasis, including parts of cytology, particularly when the markers are Urine samples were collected from 149 Africa and the Middle East [1]. The appropriate used singly [8]. The nuclear matrix is central in patients with histopathologically diagnosed treatment of patients with bladder cancer regulating important cellular processes such bladder cancer (126 men and 23 women, mandates early detection and regular follow- as DNA replication and transcription [9]. The mean age 62.6 years, range 40–88) of up for recurrences [2]. Currently, cystoscopy is protein composition of the nuclear matrix is different types and grades. The patients were the standard method for diagnosing and tissue-specific and can serve as a ‘fingerprint’ subdivided according to the types of tumour monitoring bladder cancer recurrence, but it of each cell and/or tissue type [10,11]. into 25 with squamous cell carcinoma is an invasive and relatively costly technique, Differences in nuclear matrix protein (NMP) (SCC) type, 118 with TCC and six with and may sometimes be inconclusive, composition are found in several human adenocarcinoma. They were also subdivided particularly in cases of cystitis [3,4]. Also, tumours, including prostate [12], renal [13], according to the stages of tumour into two routine urinary cytology commonly used in breast [14], colon [15], cervical [16], and head with Ta, three with T1, two with T2, 29 with conjunction with cystoscopy is costly, requires and neck [17]. Thus, identifying nuclear matrix T3a, 59 with T3b, 33 with T4a and 21 with T4b. an experienced cytopathologist and offers biomarkers has potential in the diagnosis and Urine samples from 57 apparently healthy poor sensitivity for low-grade tumours [5]. prognosis of cancer [18]. In the present study volunteers (47 men and 10 women, aged These characteristics have prompted the we identified a urinary NMP marker and 25–65 years) and 15 patients with search for more reliable noninvasive markers evaluated a newly developed, reliable and malignancy other than bladder cancer (five of bladder cancer. more convenient office-based dot-ELISA for men and 10 women, aged 30–65 years) were
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used as controls. The collected urine samples malignancy other than bladder cancer NBT in 0.1 mol/L Tris buffer, pH 9.6; ABC were centrifuged at 2100 g to remove any including colorectal cancer (three), Diagnostics, New Damietta, Egypt). The colour cellular debris and tested fresh or stored at - hepatocellular carcinoma (four), breast cancer reaction was observed within 15 min, and 20 ∞C with no additions or treatment until (four) and prostate cancer (four) using the dipping the blots in distilled water then tested. The Ethical Committee of the dot-ELISA. stopped the reaction. Mansoura University Hospitals approved the study. Informed consent was obtained from SDS-PAGE AND GEL ELECTRO-ELUTION The purity of the purified antigen was all participants and they were fully informed assessed using analytical SDS-PAGE [19] and about the diagnostic procedures involved and Urine samples were subjected to analytical capillary zone electrophoresis (CZE) in a nature of the disease. SDS-PAGE, at 100 mg/lane, using vertical slabs modification of the method described by of 16% polyacrylamide [19]. Molecular- Gordon et al. [21], an autosampler (model In a follow-up study, 43 patients with weight standards (Sigma Chem Co., St Louis, 1-LIFT; Prince Technologies, Emmen, the histopathologically diagnosed bladder cancer MO) were run in parallel. In preparative slab Netherlands), a 65-cm fused silica capillary (38 men and five women, mean age gel electrophoresis, the running condition was (75 mm inner diameter) coated with polyimide 63.5 years, range 40–82; 27 stage T3 and 16 adapted to reduce smear of proteins and to film (Prince Technologies), a variable ultra- stage T4) received radiotherapy at a dose of enable a long migration distance between violet-visible detector (Lambda 1010; 65 Gy, using a linear accelerator, in two bands in the 52-kDa region, according to the Metrhom, Herisau, Switzerland) and phases. In Phase I the patient received a total pre-stained molecular weight marker. In each WinPrince software (Version 5; Prince treatment dosage of 45 Gy over 5 weeks (five run, 250-mL of urine per preparative gel Technologies). For the CZE run, 10 mL of a daily fractions a week, 1.8 Gy/day), and in was electrophoresed, and a lane from dilution of the purified antigen (50 mg/mL phase II, after 2 weeks interruption, the electrophoresed preparative gel stained with distilled water) was injected through the patients received 20 Gy over 2 weeks (five Coomassie blue and immunoblotted to capillary at high voltage (30 kV) and low daily fractions a week, 2 Gy/day). The status of identify the 52-kDa band. In the unstained pressure (2.5 kPa) for 10 s before the sample the tumour size, lymph nodes metastasis and preparative gel, the adjacent band was then was eluted with borate buffer (pH 8.3) at high distant metastasis were followed using CT to cut and the 52-kDa antigen electro-eluted voltage (30 kV) for 15 min while the internal evaluate the initial response to radiotherapy. from polyacrylamide gel at 200 V for 3 h in a capillary temperature was kept at 20 ∞C. Urine samples were collected from all treated dialysis bag (Sigma). Forty runs were Eluents were detected by their ultraviolet patients before and at the end of each phase completed to obtain 1 mg of the 52-kDa absorption at 200 nm and signals analysed (i.e. at 5 and 9 weeks) of radiotherapy and antigen. After dialysis, the electro-eluted using Dax software (Version 5; Prince then 4 weeks after stopping radiotherapy. antigen was concentrated using polyethylene Technologies). glycol and 40% trichloroacetic acid (TCA), PRODUCTION OF ANTI-NMP-52 then centrifuged at 6500 g for 15 min. The To create a simple and rapid assay, a IGG ANTIBODIES precipitate was washed twice using diethyl previously described dot-ELISA [22] was ether to remove excess TCA. The excess diethyl adapted to detect the target urinary NMP-52 Specific IgG antibodies were produced in four ether was removed by gentle drying and the marker. All the steps of the dot-ELISA were New Zealand white rabbits immunized pellet reconstituted in PBS (pH 7.2). The carried out on the surface of a nitrocellulose subcutaneously in three different inoculation protein content of a sample of electro-eluted membrane fixed in a plastic cartridge, and sites with the 52-kDa purified marker (see antigen was determined before the remainder each reagent completely absorbed into the below). In brief, equal volumes (500 mL) of the was stored at -20∞C. nitrocellulose membrane within 30 s antigen (500 mg/mL) and complete Freund’s (incubation time). After optimizing the adjuvant (CFA) or incomplete Freund’s WESTERN BLOT reaction conditions, 200 mL of urine sample adjuvant (IFA) were homogenized together were added per dot. Different concentrations using two Luer-lock syringes connected to a Urine samples separated on SDS-PAGE (50, 100 and 250 mg) of the NMP antigen and three-way stainless-steel valve. Each rabbit (as above) were electrotransferred onto an irrelevant protein (e.g. BSA) were used as was immunized subcutaneously three times, nitrocellulose membrane (0.45 mm pore size, positive and negative controls, respectively. once with antigen in CFA (on day 0) and twice Sigma) in a protein transfer unit [20]. The The nonspecific binding sites on the with antigen in IFA (on days 15 and 28) before nitrocellulose filter was blocked using 5% nitrocellulose membrane were blocked with being killed on day 32. Blood samples were (w/v) nonfat dry milk dissolved in 5% (w/v) BSA in PBS, pH 7.2. After washing collected from all rabbits at 0, 28 and 32 days 0.05 mol/L Tris-buffered saline (TBS) three times using 100 mL/wash of PBS, 200 mL of immunization. The sera were separated, containing 200 mmol/L NaCl (pH 7.4), rinsed of the specific anti-NMP-52 antibody diluted purified and stored at -20 ∞C until used. in TBS and incubated with the anti-NMP-52 1 : 100 in PBS was added. After washing, The reactivity of the collected rabbit sera antibody diluted in blocking buffer with 200 mL of the diluted antirabbit IgG alkaline was tested against urine samples of constant shaking. The blots were washed phosphatase conjugate was added; after more histopathologically diagnosed patients with three times (30 min each) in TBS, followed by washing, 200 mL of premixed NBT/BCIP bladder cancer, the purified 52-kDa antigen, incubation for 2 h with goat antirabbit IgG alkaline phosphatase substrate in 0.1 mol/L and the NMP-22 antigen (Matritech, Newton, alkaline phosphatase conjugate (Sigma) Tris buffer (ABC Diagnostics) was added; MA, USA). The specificity of the rabbit sera diluted 1: 500 in TBS. After washing three 2 min later the reaction stopped by distilled was tested against urine samples of 16 more times with TBS (15 min each), the blots water and the development of colour healthy individuals and patients with were soaked in substrate (premixed BCIP and observed. The colour of the tested urine
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FIG. 1. Western blot based on the anti-NMP-52 FIG. 2. Isolation and purification of the target NMP-52 from the urine of a patient with bladder cancer. A, antibody of urine samples from patients with Coomassie blue-stained SDS-PAGE showing a single band at 52 kDa. Lane 1, urine of a patient with bladder bladder cancer and from controls. Lanes 1–2, urine cancer; and lane 2, the purified 52-kDa fraction. Molecular weight standards (St) included: human transferrin of two controls; lane 3, urine of a patient with (76 kDa), BSA (66 kDa), egg albumin (45 kDa), a-lactoglobulin (36.6 kDa), a-chemotrypsinogen (25.7 kDa), bladder cancer and SCC; lane 4. urine of a patient myoglobin (17.2 kDa), cytochrome-c (12.7 kDa). B, Western blot showing reactivity of the NMP antibody. Lane with TCC; lane 5, urine of a patient with 1, urine of a patient with bladder cancer, and lane 2, the purified 52-kDa fraction. C, CZE electropherogram, adenocarcinoma. Repetitive epitopes at 52 and showing a single peak at 6.3 min, confirming the purity of the 52-kDa purified fraction. 40 kDa were identified only in the urine of patients with bladder cancer. Molecular weight markers (Mr) A B were not shown but indicated by arrows. Mr. St. 1 2 Mr. 12 (kDa) (kDa) Mr. 76.0 76.0 (kDa) 123 45 66.0 97.4 66.0 52-kDa 52-kDa 66.2 55.0 52-kDa 45.0 45.0 42.7 36.6 40.0 40-kDa 36.6 25.7 25.7 31.0 17.2 17.2 21.5 12.7 12.7 sample was compared and related to one of the positive control levels (low, +, moderate C ++, and high +++ or ++++) by one observer unaware of sample origin. 0.020 nm
To determine some of the biochemical 0.015 characteristics of the purified marker, samples of the target NMP-52 marker were treated 0.010 with protease and one of several other chemical reagents being tested in dot-ELISA,
Absorbance, at 200 0.005 to see if these treatments affected the reactive epitope. The purified marker (at 200 mg/mL) was incubated for 1 h either with 0.000 40% TCA (v/v) at 4 ∞C or with 0.2 mol/L NaOH 0.00 5.00 10.00 15.00 or 0.2 mol/L HCl (v/v) at room temperature. A Time, min periodate oxidation was carried out overnight with 20 mmol/L sodium meta-periodate at room temperature and the reaction then types of bladder cancer (Fig. 1). The 52-kDa peak at 6.3 min (Fig. 2C). Specific antibodies inhibited by adding an equal volume of antigen was identified in all 32 urine samples, developed in rabbits to human p53 (53-kDa) 130 mmol/L glycerol. In another series of while the 40-kDa antigen was identified only or IgG fraction (ª 50 kDa) showed no experiments, a sample of the purified marker in 19. To ensure that the 52-kDa marker was a reactivity to the target NMP using indirect was mixed with an equal volume of 20, 60 or feature of bladder carcinoma, 16 selected ELISA (data not shown). Partial biochemical 180 mmol/L b-mercaptoethanol. In the test urine samples from normal volunteers and 15 characterization of the reactive epitope with protease, purified antigen was incubated from patients with malignancy other than confirmed its protein moiety. The reactivity of at 37 ∞C with pepsin (1 mg/mL; Sigma) for 5, bladder carcinoma were assessed using the anti-NMP-52 antibody was lost (i.e. a 10, 15 or 20 min. Urine samples from patients Western blot. Neither the target 52-kDa nor negative result using dot-ELISA) towards the with bladder cancer and a healthy control the 40-kDa degradation product was purified antigen treated either with acid or were tested in parallel, as positive and identified in all blots of the 31 control urine alkali. However, antibody reactivity towards negative controls, respectively. samples. The high molecular weight reactive purified antigen was maintained after meta- epitope purified from urine was analysed by periodate oxidization and reduction with a- SDS-PAGE. A single polypeptide band was mercaptoethanol. The TCA precipitate fraction RESULTS stained with Coomassie blue, at 52-kDa was reactive with the anti-NMP-52 antibody (Fig. 2A). The reactivity of the isolated antigen as the purified antigen, but the TCA The anti-NMP-52 antibody identified two was confirmed using Western blot (Fig. 2B). supernatant fraction showed no reactivity. reactive epitopes at 52 and 40 kDa in the The purity of the eluted 52-kDa antigen was The reactivity of anti-NMP-52 antibody urine of 32 selected patients with different also confirmed using CZE; there was a single decreased by increasing the incubation time
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FIG. 3. Rapid and office-based detection of NMP-52 Dot-ELISA TABLE 1 marker in urine samples of patients with bladder Status N positive negative % positivity Detection of target NMP-52 cancer using the dot-ELISA. A and B represent urine in the urine of 149 samples from healthy individuals showing no Bladder cancer 149 145 (TP) 4 (FN) 97 SCC 25 23 2 92 histopathologically detection of the target NMP-52 (negative), C diagnosed patients with represents a urine sample from a patient with Grade I 16 15 1 94 bladder cancer, using dot- bladder cancer, showing a low level (+) of the target Grade II 2 2 0 – Grade III 7 6 1 – ELISA, and categorized by NMP-52 marker, and D another urine sample from a tumour stage patient with bladder cancer showing a high level TCC 118 116 2 98 (+++) of the target NMP-52 marker. Grade I 11 11 0 – Grade II 64 62 2 97 Grade III 43 43 0 100 Adenocarcinoma 6 6 0 – Grade I 2 2 0 – Grade II 1 1 0 – Grade III 3 3 0 – Controls 72 4 (FP) 68 (TN) 6 Ta 2 2 0 – T1 3 3 0 – T2 2 2 0 – T3a 29 29 0 100 T3b 59 57 2 97 T4a 33 31 2 94 T4b 21 21 0 100
TP, true positive (urine sample from a patient with confirmed bladder carcinoma with a positive dot-ELISA); FP, false positive (urine sample from a control with no bladder carcinoma and a positive dot-ELISA); TN, true negative (urine sample from a control with no bladder carcinoma and a negative dot-ELISA); FN, false negative (urine sample from a patient with confirmed bladder carcinoma with a negative = + = + ¥ = of the antigen with pepsin enzyme and it was dot-ELISA). Sensitivity TP/(TP FN) 145/(145 4) 100 97%; = + = + ¥ = completely lost at 20 min. specificity TN/(TN FP) 68/(68 4) 100 94%; positive predictive value = TP/(TP + FP) = 145/(145 + 4) ¥ 100 = 97%; Negative = + = + ¥ = We developed a simple noninvasive dot-ELISA predictive value TN/(TN FN) 68/(68 4) 100 94%; efficiency = + = + ¥ = format based on the anti-NMP-52 IgG of test (TP TN)/total (145 68)/221 100 96%. antibody for rapid detection (within 5 min) of the target marker in urine samples of patients with bladder cancer. The dot-ELISA allows a semiquantitative reading of the resulting coloured dot if the marker is detected (i.e. a and moderate dot-ELISA colour endpoints compared with standard histopathology are positive test). A colourless dot was produced if and stored frozen at -20∞C, the reactivity shown in Table 1. The dot-ELISA assay was no marker was detected (i.e. a negative test; of the target marker was maintained with no able to detect the urinary NMP-52 marker Fig. 3). To assess the reproducibility of these changes for long periods (ª18 months). with high sensitivity in the different types and endpoints, the dot-blot assay was performed grades of bladder tumour (Table 1), in the on five separate occasions for a selected To evaluate the diagnostic performance of the early stages of bladder tumour (pTa, pT1 group of urine samples of patients with developed test for clinical use, urine samples and pT2), and late stages (T3 and T4; bladder cancer, showing low (+), moderate from 149 patients with histopathologically Table 1). (++) and high (+++) colour endpoints (four diagnosed bladder cancer and 72 controls samples each). The urine sample was tested in were evaluated. The results were negative in Urine samples collected from all 43 patients triplicate on each occasion. The percentage four patients, low in 57, moderate in 48 and before, during and after radiotherapy were intra-assay and interassay coefficients of high in 40. The dot-ELISA assay showed only tested for the target urinary marker using variation were <10%, ascertaining the one false-positive result among 15 patients dot-ELISA (Table 2). Before radiotherapy the reproducibility of these colour endpoints. In with malignancy other than bladder cancer, dot-ELISA result of these patients were low in addition, the reactivity of the target NMP-52 and three false-positive results among 57 18, moderate in 17 and high in eight. During marker in urine samples with low dot-ELISA apparently healthy controls, giving an overall radiotherapy, reduced tumour size, no colour endpoints was maintained with no specificity of 94%. The sensitivity, specificity, regional lymph node metastasis and no change for at least as year after being stored efficiency and predictive values of a positive evidence of distant metastasis were frozen at -20∞C. In urine samples with high and a negative result for the dot-ELISA characteristics for all 22 patients showing a
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response to treatment. The intensities of the dot-ELISA TABLE 2 dot blots were significantly (P < 0.05) Sample time (week) N positive negative % negative The detection of NMP-52 in decreased in the urine of all those responding the urine of patients with and were unchanged (P > 0.05) in 21 treated Before radiotherapy (0) 43 43 0 0 bladder cancer using patients in whom the disease progressed. Four During radiotherapy: the dot-ELISA after weeks after radiotherapy the urinary NMP end of phase I (5) 43 37 6 14 radiotherapy; CT was used was not detected using dot-ELISA in all those end of phase II (9) 43 25 18 42 as the reference standard responding but was detected in all those not After radiotherapy (13) 43 21 22 51 responding to radiotherapy.
shown). The target NMP-52 is probably the NMP-52 test, further emphasising the DISCUSSION released from the nuclei of the tumour cells bladder cancer-specific nature of NMP-52. It during apoptosis. Partial biochemical would be wiser to compare NMP-52 results Bladder tumour markers are potentially useful characterization experiments indicated the with established urinary markers of bladder in screening for cancer, monitoring the course characteristic polypeptide nature of the cancer. However, this approach is beyond the of the disease, and detecting relapse or reactive epitope isolated from urine. scope and limited financial resources of the recurrence after treatment [7]. Studies aim to Interestingly, this NMP-52 has not been present work. develop easily applicable, noninvasive, described previously in bladder cancer, but inexpensive and reliable tools with high further molecular studies are required to The integration of urinary markers in follow- specificity and sensitivity to a certain tumour. confirm its identity. Attallah et al. [22] used a up protocols is another potential field of use. However, no tumour marker of high dot-ELISA based on a specific monoclonal The good sensitivity and negative predictive specificity and sensitivity has become a antibody to detect a target cytokeratin in values can reduce the need for follow-up routine diagnostic or screening tool for urine samples from patients with bladder cystoscopy. However, an apparent limitation bladder carcinoma [23]. Several NMPs were cancer, with high sensitivity, specificity and of the available urine-based markers in the identified and evaluated as markers of bladder efficiency (90%). The dot-ELISA format does follow-up of bladder cancer appears to be the cancer [24,25]; the one most widely not require sophisticated equipment nor high rate of false-positive results [27]. evaluated, NMP-22, is a nuclear mitotic highly trained technical staff, and can be Treatment selection is based on the extent or apparatus that is involved in the distribution completed in ª30 min. In the present study, stage of disease [28]. External beam of chromatin to daughter cells during cellular we developed a more convenient, reliable, radiotherapy is considered the standard in replication, and its concentration is at least 25 inexpensive and easily applicable dot-ELISA some countries, and recommended for times greater in bladder cancer than the mean format for the rapid detection (5 min) of the patients deemed unfit for cystectomy [29]. levels isolated from normal bladder [7]. A target NMP marker in the urine of patients Here, the initial responses of 43 patients urine-based test for NMPs has been used for with bladder cancer. The newly developed treated with irradiation were followed using detecting bladder cancer, with variable results. office-based format is suitable for the clinic the dot-ELISA. Other studies reported that The sensitivity of the NMP-22 test is and field use. We evaluated the performance NMPs could be useful in monitoring relapse 68.5–88.5% and the specificity 65.2–91.3%, characteristics of the developed assay for the and the patient’s response to treatment. In a depending on the thresholds used. However, rapid diagnosis and monitoring of bladder multicentre trial, urine was analysed in 1000 this assay is usually not a point-of-care cancer after radiotherapy. The dot-ELISA patients treated previously for bladder cancer test and needs a laboratory with trained detected the target NMP-52 marker in all who were being monitored for recurrence of technicians [25]. In the present study we types of bladder cancer with a sensitivity of their disease [30]. The NMP-22 test was able identified highly reactive epitopes at 52 and 92–100% and a specificity of 94%. In to detect all of the cases subsequently 40 kDa in the urine of patients with different addition, the assay had a high predictive identified as having invasive disease, and 70% types of bladder cancer, using specific anti- values, positive (98%) and negative (93%), with localized recurrence. It is obvious that NMP IgG antibody. Based on the presence of with an efficiency of 97%. An accurate rapid monitoring the NMP-52 marker after proteolytic enzymes in urine, we speculated test for detecting bladder cancer in the radiotherapy would have provided more that the 40-kDa antigen might be a stable follow-up must have high accuracy in valuable data about the reliability of this urinary degradation product of the 52-kDa patients with tumour stage pTa or pT1. The marker. The target marker was not detected in antigen. In addition, the 40-kDa protein was assay identified the target marker in patients the urine of responders 4 weeks after not detected alone in urine samples from with stage pTa, pT1 and pT2 disease. However, radiotherapy. patients with bladder cancer tested using more patients with early stages of bladder western immunoblotting. However, further tumour should be assessed before drawing In conclusion, the sensitive and specific characterization studies are required to final conclusions. In patients with no previous detection of urinary NMP-52 using the confirm our assumption that it might diagnosis of bladder cancer, the NMP-22 test simplified dot-ELISA would be helpful in the represent a degradation product. An intense had a greater sensitivity (80.9% vs 40%) but a rapid diagnosis and follow-up of patients and diffuse nuclear and cytoplasmic lower specificity (64.3% vs 100%) than voided with bladder cancer. Further studies are immunoperoxidase reaction was shown in urine cytology [26]. However, these values needed to confirm the efficacy of NMP-52 for formalin-fixed paraffin-embedded sections of for sensitivity and specificity are still monitoring the responses to surgery and different types of bladder carcinoma (data not significantly lower than those obtained using detecting recurrence.
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ACKNOWLEDGEMENTS matrix protein patterns. Mol Endo 1990; 23 Simon MA, Lokeshwar VB, Soloway MS. 4: 1336–42 Current bladder cancer tests: unnecessary The authors thank F. Abdelhameed, A. Sobh 11 Berezney RH, Coffey DS. Identification or beneficial? Crit Rev Oncol Hematol and M. Mostafa at Biotechnology Research of a nuclear protein matrix. Biochem 2003; 74: 91–107 Center, New Damietta for their kind help. Biophys Res Commun 1974; 60: 1410–7 24 Getzenberg RH, Konety BR, Oeler TA 12 Partin AW, Getzenberg RH, Carmichael et al. Bladder cancer associated nuclear MJ et al. Nuclear matrix protein patterns matrix proteins. Cancer Res 1996; 56: CONFLICT OF INTEREST in human benign prostatic hyperplasia 1690–4 and prostate cancer. Cancer Res 1993; 53: 25 Konety BR, Nguyen TT, Dhir R et al. None declared. Source of funding: 744–6 Detection of bladder cancer using a novel Biotechnology Research Center and 13 Konety BR, Nangia AK, Nguyen T-ST nuclear matrix protein, BLCA-4. 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Original Article LONG-TERM RESULTS OF DETRUSOR MYECTOMY
KUMAR and ABRAMS
Detrusor myectomy was Detrusor myectomy: long-term results introduced as an alternative to enterocystoplasty for refractory with a minimum follow-up of 2 years detrusor overactivity. The early SUNIL P.V. KUMAR and PAUL H. ABRAMS results of this procedure were Bristol Urological Institute, Southmead Hospital, Westbury-on-Trym, Bristol, UK described by the authors from Accepted for publication 7 April 2005 Bristol as encouraging, and they now present their long-term follow-up with a median of 79 OBJECTIVES CONCLUSIONS months. They found that the To assess the long-term results of detrusor Detrusor myectomy is successful in ≈80% of results were sustained in a myectomy, which has obvious theoretical patients with idiopathic DO, although significant group of these patients. advantages over enterocystoplasty for detrusor contractility is affected in most and refractory detrusor overactivity (DO), and for almost half of the patients required clean The value of frequency-volume which the early results have been intermittent self-catheterization afterward. encouraging. This procedure should be offered as an urinary diaries is undoubted in alternative to enterocystoplasty as it is less patients of either sex who have morbid and does not preclude subsequent LUTS, particularly in those with PATIENTS AND METHODS surgery if required. However, further symptoms suggestive of overactive evaluation of this technique is required in The medical records were reviewed of 30 neuropathic patients. bladder. Authors from Chicago consecutive patients (median age 33 years, compare such diaries between range 10–62) who had a detrusor myectomy asymptomatic controls and women between November 1992 and April 2002 in KEYWORDS our unit. Twenty-four patients (80%) had with symptoms of overactive idiopathic DO (six males and 18 females) and detrusor myectomy, detrusor overactivity, bladder. A whole range of diary six (20%) had neurogenic DO (four males and overactive bladder variables was compared, and the two females). The median (range) follow-up interesting findings used as a was 79 (28–142) months. All patients were confirmed to have DO on urodynamics before potential method to define surgery and 26 (87%) had urodynamics INTRODUCTION important outcome goals in afterward. therapeutic trials. In patients with refractory detrusor overactivity (DO), enterocystoplasty has the RESULTS highest overall rate of success, but with a much higher likelihood of early and delayed Nineteen (79%) of those with idiopathic DO complications [1,2]. Detrusor myectomy (DM) and two with neurogenic DO showed a is a surgical technique that attempts to bridge continued overall improvement. The the gap between the medical and the surgical cystometric capacity improved in 80% of treatment alternatives for refractory DO. patients after surgery, whilst the detrusor Since its original description by Cartwright pressure at maximum flow and the bladder and Snow in 1989 [3], there have been few contractility index decreased in 60% and 78% reports of this procedure. of the patients, respectively. Ten patients (45%) had to start clean intermittent self- One-year follow-up data were published from catheterization after surgery. the authors’ institution in 1998 [4]; the
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present report is a longer-term follow-up of FIG. 1. Video-urodynamics showing the mucosal diverticulum. that data. Published results have been variable, with some reporting good outcomes in patients with neurogenic DO (NDO) whilst others have been unable to duplicate these results [5,6]. There have been few published reports of children who have had DM, although the results appear poor [7,8]. Laparoscopic bladder autoaugmentation has also been reported, with reasonable short- term results [9,10]. Thus the aim of the present study was to assess the long-term results of DM.
PATIENTS AND METHODS
Thirty patients with troublesome overactive the voiding pressures were measured. Video TABLE 1 The correlation between mucosal tears bladder symptoms had DM between X-ray screening was used routinely in all and final outcomes November 1992 and April 2002; the patients. underlying cause was idiopathic DO (IDO) Mucosal n (%) n (%) in 24 (80%) and NDO in six (20%). All For the DM, an extraperitoneal approach was tears improvement no change patients were refractory to conventional used via a Pfannenstiel incision. The bladder Yes 10 (33) 5 (17) anticholinergic treatment and were keen to was distended with 250 mL of saline mixed No 11 (37) 4 (13) explore surgical treatment options. DM was with methylene blue. The peritoneum was offered to them as an alternative to dissected off the dome and the supero- enterocystoplasty. Patients were counselled posterior aspect of the bladder and a disk of about the relative novelty of the procedure detrusor muscle of 8–12 cm was excised. The and that long-term data as to the mucosa was left intact to develop into a performed after DM in 26 (87%) of the effectiveness of the technique were broad-based superiorly situated diverticulum. patients (Fig. 1). The main urodynamic unavailable. The possible need for clean After excising the detrusor muscle, the variables assessed before and after DM intermittent self-catheterization (CISC) and peritoneum was opened and the omentum were the cystometric capacity, maximum the likelihood of further surgery was brought down and sutured anteriorly and detrusor pressure at maximum flow (pdetQmax) discussed. As early results showed that a high laterally to the detrusor edge. and the bladder contractility index (BCI; proportion of patients would need to use pdetQmax + 5Qmax) [11]. CISC, all later patients were taught to use the When the mucosa was torn the defects were technique before surgery, to ensure repaired immediately with six ‘0’ absorbable compliance after surgery if CISC proved polyglactin sutures. In later cases a small RESULTS necessary. All patients had undergone piece of the excised detrusor muscle was used urodynamics before surgical intervention. as a buttress over which six ‘0’ sutures were The median (range) follow-up was 79 tied. This appeared to improve the closure of (28–142) months; the mucosa was breached For urodynamics, initial free urinary flow rates the defects, which were usually tears of during DM in 15 patients (50%) and this was and residuals were measured in all patients. <0.5 cm in maximum diameter. If there was sutured immediately. There was no correlation After counselling the patient, bladder and no leak at the end of the procedure when the between mucosal breach and the final rectal lines were inserted and the initial bladder was distended carefully, then bladder outcome (Table 1). There was one major residual urine usually drained and recorded. cycling was started on the evening of the complication, a bowel perforation that All patients had their urethral pressure operation. Bladder distension was started probably occurred during mobilization of the profiles measured and bladder filling 2 days after surgery if there was leakage after omentum. This patient required a laparotomy commenced at 50 mL/min. Quality control the mucosal tears were repaired. and closure of the perforation, with a was checked throughout the test by asking significant stay in intensive care. She did not the patient to cough, to ensure that both The urethral catheter was removed after 24 or have a good result from the DM and pressure lines were working properly. If the 48 h depending on the patients’ mobility and ultimately went on to have an ileal conduit. patients had severe DO the filling rate was according to whether or not the mucosa had slowed to ≈20 mL/min. Urodynamics were been intact during surgery. If the mucosa had Twenty-one patients (70%) had a continued usually conducted with the males standing been torn then a drain was left in situ and improvement, of whom 19 had IDO and two and the females sitting. The filling line was gentle bladder cycling continued until a NDO. One of the latter patients had an removed when the patients’ bladder was full cystogram was taken 7 days after DM. artificial urinary sphincter (AUS) inserted or when the patient reported a severe urge to Patients were then followed up at 3-, 6- and because of stress incontinence on void. The patient was then asked to void and 12-monthly intervals. Urodynamics were urodynamics (Table 2). Amongst the patients
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of this procedure in children with NDO have TABLE 2 Secondary procedures been poor [7,8]. The fate of the mucosal diverticulum is unknown, but it was Urodynamics Time after speculated that ultimately the diverticulum Diagnosis before DM after DM Secondary procedures DM, months will undergo fibrosis, or that muscular re- Spina bifida USI/No NDO Insertion of AUS 29 growth may occur [14]. However, we showed Spina bifida Persisting NDO Ileocystoplasty 14 that in patients with IDO the symptomatic Spina bifida Persisting NDO Sling + ileocystoplasty 26 improvement was maintained even in the Spina bifida Persisting NDO Colocystoplasty 11 long term; 45% of the patients had to use Spinal cord injury Persisting NDO Ileocystoplasty + AUS 13 CISC after DM, often because of recurrent IDO USI/No IDO Colposuspension 3 UTIs. IDO Persisting IDO Ileal conduit 62 IDO Persisting IDO Ileal conduit 50 The use of sterile intermittent catheterization in the management of spinal cord injury was USI, urodynamic stress incontinence. introduced by Guttman and Frankel [15] in 1947, and was slow to gain acceptance. Lapides et al. [16] went on to develop the concept of clean rather than sterile TABLE 3 Urodynamic variables before and after surgery intermittent catheterization. Although the improvement in continence rates was >90% % showing after CISC in all groups of patients [17,18], Variable Before After change P 41–48% were infection-free after starting Mean (range): CISC [17,18] and >95% were satisfied with Cystometric capacity, mL 228 (41–555) 405 (120–1040) +80 <0.001 CISC [18].
pdetQmax 38 (15–110) 26 (0–49) −60 <0.25 BCI 122 (50–241) 89 (0–185) −78 <0.06 Patients with NDO had a high failure rate in the present series. Initial published reports were encouraging in patients with NDO [5] and these results were further supplemented with an improvement, only 14 (67%) had no has not replaced enterocystoplasty as a by a longer-term follow-up by Stohrer et al. evidence of DO on cystometry after DM. The standard treatment for refractory DO. In [6]. The present initial results did not support values assessed before and after DM are addition, several variations of DM have been this and suggested that the outcome of this shown in Table 3. Overall, the cystometric described which aim to achieve better results. procedure was better in patients with IDO capacity increased in 80% of the patients by a Animal models have shown that bladder [4]. However, most patients in the study mean of 165 mL (P < 0.001). The change in capacity could be maintained if a graft (e.g. by Stohrer et al. had neurogenic voiding pdetQmax was not significant, even though it omentum, synthetic membrane or lyophilized dysfunction secondary to spinal cord injuries, decreased in 60% of the patients, whilst the dura) is inserted at the time of intervention, and were likely to have had associated BCI decreased in 78% (P < 0.06) after DM. Ten either in place of the removed detrusor detrusor sphincter dyssynergia (DSD). The one patients (45%) had to start CISC after surgery. muscle disk or between the muscle edges neurogenic patient in the present series who The mean (range) volume obtained on CISC where the muscle has been split, allowing the had had a spinal cord injury had associated was 325 (200–500) mL. The main indications exposed mucosa to bulge through. In either urethral sphincter weakness, subsequently for CISC were UTI in seven patients, persisting case the aim was to prevent adhesion of the necessitating the insertion of an AUS. symptoms in two and large postvoid residuals muscle edges and/or the mucosa either to the in one patient. Eight patients (27%) required surrounding tissues or, in the case of the Autoaugmentation with detrusor myotomy secondary procedures, five of whom had NDO, incised (rather than removed) detrusor, to rather than myectomy has also been reported, the indications and types of which are listed prevent the edges from re-uniting [12]. with encouraging early results in patients in Table 2. Two patients had no symptomatic Bladder autoaugmentation with rectus with myelomeningocele [19]. The long-term benefit from the procedure but desired no muscle backing was also described, where results in one published series of 21 patients further interventions, and one patient was both recti are dissected from the anterior and with a mean follow-up of 6 years showed an lost to follow-up. posterior sheaths and sutured to the detrusor effective reduction in intravesical pressure, edges [13]. All patients in the rectus muscle with a significant increase in bladder capacity study showed better compliance and [20]. However, the results have been poor, and DISCUSSION increased cystometric capacity, but there in one series the authors conclude that this were few patients and the follow-up was procedure cannot be recommended for DM or bladder autoaugmentation is an short. managing congenital neuropathic bladder alternative surgical option described by [21]. Autoaugmentation was also reported Cartwright and Snow for refractory DO [3]. Laparoscopic bladder augmentation was with variable results using demucosalized This procedure has produced mixed results in reported in children and in patients with gastric flaps, peritoneal flaps and different groups of patients, and therefore spinal cord injury [9,10]. The long-term results seromuscular colonic flaps to cover the
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urothelium after excising the detrusor muscle 3 Cartwright PC, Snow BW. Bladder 16 Lapides J, Diokno AC, Silber SJ, Lowe [22–24]. autoaugmentation: early clinical BS. Clean intermittent self- experience. J Urol 1989; 142: 505–8 catheterisation in the treatment of After DM there will still be persistent 4 Swami KS, Feneley RCL, Hammonds JC, urinary tract disease. J Urol 1972; 107: involuntary detrusor contractions. In a patient Abrams P. Detrusor myectomy for 458–61 with an incompetent urethra or no awareness detrusor overactivity: a minimum 1-year 17 Lapides J, Diokno AC, Gould FR, of detrusor contractions, leakage will occur follow up. Br J Urol 1998; 81: 68–72 Lowe BS. Further observations on self- and the mucosal segment will not expand. We 5 Stohrer M, Kramer G, Goepel M, catheterisation. J Urol 1976; 116: 169–71 hypothesise that DM requires an effective Lochner-Ernst D, Kruse D, Rubben H. 18 Webb RJ, Lawson AL, Neal DE. Clean urethral sphincter so that the defect resulting Bladder autoaugmentation in adult intermittent self-catheterisation in 172 from the excision of the detrusor disk can patients with neurogenic voiding adults. Br J Urol 1990; 65: 20–3 develop into a superiorly based diverticulum. dysfunction. Spinal Cord 1997; 35: 456–62 19 Stothers L, Johnson H, Arnold W, In patients with IDO and a competent urethra, 6 Stohrer M, Kramer G, Goepel M et al. Coleman G, Tearle H. Bladder and in those with spinal cord injury with DSD, Bladder auto-augmentation in adult autoaugmentation by vesicomyotomy in the involuntary detrusor contractions will be neurogenic bladder: long term follow-up. the paediatric neurogenic bladder. resisted by a voluntary sphincter and pelvic J Urol 2000; 163: 224A Urology 1994; 44: 110–3 floor contraction, or by DSD, and therefore 7 Potter JM, Duffy PG, Gordon EM, 20 Skobejko-Wlodarska L, Strulak K, the mucosal diverticulum will develop, so that Malone PR. Detrusor myotomy. A 5-year Nachulewicz P, Szymkiewicz C. Bladder there will be a gradual increase in bladder review in unstable and non-compliant autoaugmentation in myelodysplastic capacity. We cannot support this hypothesis bladders. BJU Int 2002; 89: 932–5 children. Br J Urol 1998; 81: 114–6 in the present series, as there were only a few 8 Marte A, Di-Meglio D, Cotrufo AM, 21 MacNeily AE, Afshar K, Coleman GU, patients with NDO. Di-Lorio G, De-Pasquale M, Vessella Johnson HW. Autoaugmentation by A. A long-term follow-up of detrusor myotomy: its lack of DM is simple, although rather tedious to autoaugmentation in myelodysplastic effectiveness in the management of perform, and gives satisfactory results with children. BJU Int 2002; 89: 928–31 congenital neuropathic bladder. J Urol minimal complications in patients with IDO. 9 Braren V, Bishop MR. Laparoscopic 2003; 170: 1643–6 We recommend this procedure as one of the bladder autoaugmentation in children. 22 Nguyen DH, Mitchell ME, Horowitz M, first-line options in patients with IDO, before Urol Clin North Am 1998; 25: 533–40 Bagli DJ, Carr MC. Demucosalised enterocystoplasty. It is less morbid than 10 Siracusano S, Trombetta C, Ligouri augmentation gastrocystoplasty with enterocystoplasty and less expensive than G et al. Laparoscopic bladder auto- bladder autoaugmentation in paediatric neuromodulation [25]. It does not preclude augmentation in an incomplete traumatic patients. J Urol 1996; 156: 206–9 subsequent surgery if required. Careful spinal cord injury. Spinal Cord 2000; 38: 23 Oge O, Tegkul S, Ergen A, Kendi S. patient selection and further evaluation of 59–61 Urothelium-preserving augmentation this technique is required in patients with 11 Abrams P. Bladder outlet obstruction cystoplasty covered with a peritoneal flap. NDO. The management algorithm may have to index, bladder contractility index and BJU Int 2000; 85: 802–5 be altered again if intravesical botulinum bladder voiding efficiency: three simple 24 Gonzalez R, Buson H, Reid C, Reinberg toxin injections are shown to have long-term indices to define bladder voiding function. Y. Seromuscular colocystoplasty lined efficacy and cost-effectiveness. BJU Int 1999; 84: 14–5 with urothelium: experience with 16 12 Taneli C, Genc A. Long-term follow-up patients. Urology 1995; 45: 124–9 CONFLICT OF INTEREST and evaluation of autoaugmentation 25 Abrams P, Blaivas JG, Fowler CJ et al. cystoplasty (detrusorotomy) in an animal The role of neuromodulation in the None declared. model. Int Urol Nephrol 1999; 31: 55–9 management of urinary urge 13 Perovic SV, Djordjevic MLJ, Kekic incontinence. BJU Int 2003; 91: 355–9 REFERENCES ZK, Vukadinovic VM. Bladder autoaugmentation with rectus muscle Correspondence: Sunil P.V. Kumar, Bristol 1 Quek ML, Ginsberg DA. Long term backing. J Urol 2002; 168: 1877–80 Urological Institute, Southmead Hospital, urodynamics follow up of bladder 14 Donald HN, Mitchell ME, Mark H, Westbury-on-Trym, Bristol BS10 5NB, UK. augmentation for neurogenic bladder. Darius JB, Can CG. Demucosalised e-mail: [email protected] J Urol 2003; 169: 195–8 augmentation gastrocystoplasty with 2 Hasan ST, Marshall C, Robson WA, bladder autoaugmentation in paediatric Abbreviations: DM, detrusor myectomy; Neal DE. Clinical outcome and quality patients. J Urol 1996; 156: 206–9 (N)(I)DO, (neurogenic) (idiopathic) detrusor of life following enterocystoplasty for 15 Guttman L, Frankel H. The value of overactivity; BCI, bladder contractility index; detrusor instability and neuropathic intermittent catheterisation in the early AUS, artificial urinary sphincter; CISC, clean bladder dysfunction. Br J Urol 1995; 76: management of neuropathic bladder intermittent self-catheterization; DSD, 551–7 dysfunction. Paraplegia 1966; 4: 63–78 detrusor sphincter dyssynergia.
344 © 2005 BJU INTERNATIONAL Original Article FILLED VOLUME IN PRESSURE FLOW STUDIES SAHADEVAN et al.
Are conventional pressure-flow measurements dependent upon filled volume?
KANAGASABAI SAHADEVAN, ANN S. LEONARD and ROBERT S. PICKARD* Department of Urology, Freeman Hospital and *School of Surgical and Reproductive Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, UK Accepted for publication 9 March 2005
OBJECTIVE adequately completed 3-day frequency- pdet.Qmax, at -1 (13) cmH2O (P = 0.91), obtained volume chart were recruited. Each underwent within each patient. For men there was 91% To determine, in a prospective study, whether two consecutive PFS with filling to MCC and agreement (32 of 35) in the classification of detrusor pressure (pdet.Qmax) and maximum average Vvoid in a random order, and obstruction. urinary flow rate (Qmax) measurements measurements of pdet.Qmax and Qmax were obtained after filling to maximum cystometric compared. For men, the agreement for a CONCLUSIONS capacity (MCC) differ from those obtained diagnosis of obstruction between the tests with filling restricted to average voided was also assessed. Restriction of filling to the average Vvoid volume (Vvoid), as standard protocols for during PFS allows a closer approximation to pressure flow studies (PFS) mandate bladder normal voiding and results in no clinically filling until the subject has a strong desire to RESULTS relevant change to the value of standard void, which aids standardization but further pressure-flow measurements or alters divorces the test from real-life experience. Complete data were obtained from 76 (90%) individual classification of obstruction. of the patients, with a mean (range) age of 64 (20–94) years. The mean (SD) difference KEYWORDS
PATIENTS AND METHODS between MCC and average Vvoid was 134 (113) mL (P < 0.01). There were no urodynamics, bladder outlet obstruction, After calculating the appropriate sample size, significant differences between estimates of pressure-flow study, frequency-volume chart,
84 patients attending for PFS with an Qmax, at -0.1 (3) mL/s (P = 0.75), and of voided volume
INTRODUCTION leading to reduced force of contraction [4] was required to detect clinically relevant
and hence reduced Qmax [5]. differences of 15 cmH2O or 2 mL/s in pdet.Qmax
Voiding dysfunction in patients with and Qmax, respectively, at 5% significance [6]. bothersome LUTS is currently diagnosed by As the role of PFS is to provide diagnostic All adult patients with no neurological disease plotting on a nomogram simultaneous measurements in the context of symptoms who attended our urodynamic laboratory for readings of maximum urinary flow rate (Qmax) experienced by an individual, it would seem conventional PFS and with an adequately and detrusor pressure at Qmax (pdet.Qmax) reasonable to recreate real-life conditions as completed 3-day frequency-volume chart obtained from a conventional pressure-flow far as possible within the clinical environment (FVC) were invited to participate in the study. study (PFS), allowing urodynamic of the urodynamic laboratory. As part of After a careful explanation of the aims and categorization into obstructed, equivocal or this aim, restricting filling to an individually methods of the study, and obtaining of unobstructed groups [1]. The reliability of comfortable bladder volume might be informed consent, we recruited 84 patients such categorization depends on several advantageous, provided the diagnostic over a 5-month period. factors, which may include the filled volume reliability was not compromised. We therefore of the bladder [2]. Based on recommendations carried out a prospective study to test the For each patient the average Vvoid was of the ICS, standard practice for PFS is to following hypotheses: (i) There is no difference calculated by summing the volumes of all continue bladder filling until the subject in simultaneous measurements of Qmax and voids recorded during three consecutive 24-h experiences a strong desire to void, this being pdet.Qmax made during voids initiated at MCC periods and dividing the total by the number defined as maximum cystometric capacity and average voided volume (Vvoid); (ii) the of voids. The patients then had two (MCC) [3]. The main reasons for this practice classification of obstruction is not changed by consecutive PFS with filling to both MCC, are the increased likelihood of detecting restricting bladder filling to the average Vvoid. indicated by a strong desire to void, and to detrusor overactivity (DO) during an extended average Vvoid, the sequence being determined filling phase, and to encourage the ability to PATIENTS AND METHODS by previous randomization. A standard void in an atypical setting. However, a possible technique for PFS was used which conformed disadvantage of filling beyond the functional A preliminary calculation of sample size to ICS good practice [2]. Briefly, after a private capacity is over-stretching the detrusor, showed that the recruitment of ≥75 subjects void and under aseptic conditions, the bladder
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was catheterized with a 10 F filling line and a Paired data Mean (SD) [95% CI] difference P TABLE 1 4 F bladder pressure line, whilst a 6 F catheter Random (76 patients): Comparison of Q , p covered with a vented finger cot was inserted max det.Qmax value at MCC - value at average V for and V measured during into the rectum for abdominal pressure void fill Q , mL -0.1 (3.2) [-0.9 to 0.6] 0.75 PFS after filling to MCC and recording. The water-filled lines were max p , cmH O -0.2 (12.6) [-3.0 to 2.7] 0.91 V , with randomized connected to pressure transducers placed at det.Qmax 2 void.mean A–G number 0.08 (11.8) [-2.6 to 2.8] 0.95 order of filling, with the level of the pubic symphysis and zeroed to V , mL 134 (114) [108–160] <0.01 sequential filling, and as a atmospheric pressure. The initial fill was with fill Sequential, value at 1 - value at 2 (76 patients) comparison between the the patient supine before changing to Q , mL 1.3 (3.0) [0.6–2.0] <0.01 two fills for patients whose standing or seated for voiding, whilst the max p , cmH O 5.3 (11.4) [2.7–7.9] <0.01 residual urine was >150 mL second fill was with the patient standing det.Qmax 2 AG number 2.7 (11.5) [0.1–5.3] <0.04 (men) or seated on a commode (women). Both V , mL 13 (179) [-27 to 54] 0.5 voids were therefore in the same position for fill Residual volume > 150 mL (12 patients) each patient. Non-physiological filling at a value at MCC - value at average V for rate of 100 mL/min was used throughout. void Q , mL -1.4 (2.6) [-3.0 to 0.2] 0.08 Intravesical pressure (p ), abdominal max ves p , cmH O -5.7 (12.7) [-13 to 2.4] 0.15 pressure (p ), subtracted detrusor pressure det.Qmax 2 abd AG no. -2.8 (11.8) [-10 to 4.7] 0.42 (p ), flow rate (Q) together with filled and det V , mL 188 (153) [91–286] <0.01 V were continuously recorded at a fill void at MCC sampling frequency of 10 Hz. Residual urine V - V , mL 135 (220) [-5.0 to 274] 0.06 was estimated at the end of the second void fill void at average V by abdominal ultrasonography. void Vfill - Vvoid, mL -27 (100) [-90 to 37] 0.37
Values for filled volume, Qmax and pdet.Qmax for each PFS were recorded and expressed as the mean (SD). Values for residual volume obtained at the end of the second void were noted but not added to the measured filled who completed the study, 38 were TABLE 2 Comparison of diagnostic volumes during PFS. The Abrams-Griffiths randomized to filling to MCC first, whilst 38 categorization of men, using the provisional ICS (AG) number (p - 2Q ) was calculated were initially filled to average V . det.Qmax max void nomogram, according to V and fill sequence for each void and men were categorized as fill being obstructed, equivocally obstructed or The mean (SD) infused volume required for Diagnosis unobstructed by plotting the values of Qmax MCC, at 327 (135) mL, was 134 (114) mL Fill at BOO Equivocal Unobstructed and pdet.Qmax from each void on the provisional (70%) higher than that of average Vvoid, at ICS nomogram [1]. Cystometry traces 193 (78) mL, calculated from the FVC MCC 35 18 6 Average 33 20 6 recorded for the two fills were examined by (P < 0.001). Overall, measurements of Qmax Vvoid two experienced urologists for the presence and pdet.Qmax obtained after filling to MCC and P 0.85 0.84 of DO, defined according to current ICS average Vvoid showed no statistical or clinically First 36 17 6 criteria [3]. Differences in paired values of Qmax relevant differences (Table 1, Fig. 1a,b). In all, Second 32 21 6 and pdet.Qmax within each patient were assessed 30 (39%) patients had a difference in Qmax of P 0.57 0.55 using Student’s t-test and the Bland-Altman >2 mL/s and 16 (21%) had a >15 cmH2O analysis to estimate bias and measurement difference in pdet.Qmax. There were systematic error [7]. The 95% CI for the mean was differences between voiding variables calculated when appropriate and statistical recorded from the first and second fills, significance assessed at the 5% level. irrespective of filled volume, with both Qmax of BOO using filling to average Vvoid in the
and pdet.Qmax being significantly greater on the subgroup of 59 men was 91%. All those with first fill (Table 1). The residual urine volume no BOO were correctly identified by filling to
RESULTS after the second void was >150 mL for 12 average Vvoid. There were phasic pressure rises (16%) patients, with a mean (range) of indicative of DO in 24 (32%) patients (Table 3). In all, 84 patients were recruited (63 men and 290 (170–500) mL. Analysis of the data from Statistical analysis of the detection rates for 21 women, mean age 65 years, range 20–94); this group showed no significant differences DO according to filled volume and order of of these, 76 (90%; 59 men and 17 women) from those with more complete bladder filling, assuming all cases of DO were completed the study, whilst eight were emptying (Table 1). identified, showed significantly more cases excluded because of expulsion of the bladder during the second fill, irrespective of the filled pressure line during voiding (two), failure to For men the diagnostic category for volume used (P < 0.001, Fisher’s exact test), void into the uroflowmeter (two), or failure to obstruction was changed for four (5%), with whilst the increased detection rate after filling void (four). Two of those who failed to void three moving from obstructed to equivocal to MCC compared to average Vvoid was of only did so on both the fills, and another two failed and one from equivocal to obstructed marginal significance (P < 0.041, Fisher’s after filling to the average Vvoid alone. Of those (Table 2). The reproducibility of the diagnosis exact test).
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FIG. 1. Bland-Altman analyses of: a, Qmax (MCC) and Qmax (Vvoid.mean); and b, pdet.Qmax (MCC) and pdet.Qmax (Vvoid.mean). constant fill rate, Groen et al. [12] compared
values of Qmax and pdet.Qmax obtained by a conventional PFS after filling to both MCC 10 and modal functional capacity in young 8 + 2 SD female volunteers. They found that flow rate 6 was lower and voiding pressure unchanged max 4
Q during voids initiated at functional capacity. ), mL/s
- 2 mean
void These findings were an advance on existing 0 -2 knowledge, but the quality of their data was (MCC) -4 compromised by a high exclusion rate, use of max - SD Q 2 (average V -6 unpaired data and lack of randomization of -8 voiding sequence. The effect of void sequence -10 is illustrated by findings from most studies 0 5 10 15 20 25 30 investigating the test/re-test reliability of + conventional PFS, which have shown Qmax (MCC) Qmax (average Vvoid)/2, mL/s sequence bias with values of both Qmax and b p being higher on the first fill [6,13], 50 det.Qmax changing the urodynamic classification of
40 obstruction for ª30% of cases [13,14], as also O 2 in the present study. These changes are 30 + 2 SD det.Qmax thought to reflect variation in contraction P - ), cmH 20 strength and outlet status rather than void 10 measurement error [13]. The design of the
(MCC) mean 0 present adequately powered study using a constant fill rate, identical voiding conditions
(average V -10 det.Qmax and randomization to nullify the effect of void P - 20 - 2 SD sequence, allows a more robust conclusion -30 that pressure-flow variables are unchanged by restricting filling, despite this being partly 0 50 100 150 200 contrary to previous work [12]. + Pdet.Qmax (MCC) Pdet.Qmax (average Vvoid)/2, cmH2O The relationship between bladder sensation and filled volume during natural bladder The effect of filled volume on measurements filling and nonphysiological filling for the TABLE 3 Comparison of the rate of diagnosis of obtained during conventional PFS has not purposes of conventional PFS was elegantly phasic DO during filling cystometry according to been systematically characterized to date. assessed by DeWachter and Wyndaele [15]. filled volume and sequence of fill for 24 patients Studies examining the volume-dependency of They found that although volume at strong who had DO on at least one fill free urinary flow rate showed an increase desire to void (MCC) was similar for both fill with V , particularly at 0–200 mL [8]. rates, >90% of natural voids occurred at or Fill at DO No DO void Theoretical modelling and experimental before an initial desire to void, with volumes MCC 17 7 studies suggest that over-stretching can ª60% of MCC. The present results are in Average V 915 void impair detrusor contraction strength and keeping with these data and suggest that P 0.041 hence reduce Q [4,5]. Further information average V is a valid, individually First 7 17 max void was provided by studies comparing standardized variable that provides a fair Second 19 5 ambulatory natural-fill urodynamics with reflection of normal micturition. P 0.001 conventional PFS, which showed that the
40–50% reduction in Vvoid after natural-fill The present data showed no overall bias in
was associated with increases in both measurement of Qmax and pdet.Qmax when filling
Qmax and pdet.Qmax compared to sequential was restricted to average Vvoid, but there was a DISCUSSION conventional PFS [9,10]. A subsequent degree of random variation. Analysis of this
comparative study where nonphysiological variation using pre-set limits (Qmax < 2 mL/s,
The present results suggest that for the filling during conventional PFS was restricted pdet.Qmax < 15 cmH2O) showed clinically purposes of a conventional PFS used to to ‘normal desire to void’ found that the significant changes for flow rate in 39% of investigate the urodynamic cause of voiding increase in Qmax recorded after ambulatory patients and for pressure measurement in dysfunction, restriction of bladder filling to filling was less pronounced and voiding 21%, compared to values of 20% and 15%, average Vvoid allows a valid estimation of pressure was similar, suggesting a respectively, in a recent reliability study [13].
Qmax and pdetQmax, and does not alter the dependency on filled volume rather than fill In contrast, Bland-Altman analysis, where classification of BOO for >90% of rate [11]. In an attempt to characterize more random variation is expressed by the SD of patients. precisely the effect of filled volume with a differences, showed similar findings to
© 2005 BJU INTERNATIONAL 347 SAHADEVAN ET AL.
previous studies [6,12]. On balance, it more important factor rather than filled studies. Neurourol Urodyn 2002; 21: 261– therefore appears reasonable to conclude that volume. This may have been influenced by 74 our methods caused no substantial increase performing the second fill standing or sitting, 3 Abrams P, Cardozo L, Fall M et al. The in random variation of standard pressure- a known provocative factor for DO [20]. standardisation of terminology of lower flow measurements. Another reason for filling to MCC is to urinary tract function: report from the encourage the subject to void in the Standardisation Sub-committee of the The FVC is now well established as a useful laboratory environment. This has not been International Continence Society. tool for evaluating patients with LUTS but for tested before, but in the present study only Neurourol Urodyn 2002; 21: 167–78 the purpose of informing the conduct of PFS, 2% of patients failed to void only when filling 4 Griffiths DJ, Rollema HJ. Urine flow a representative standard Vvoid for an was restricted to functional capacity. The curves of healthy males: a mathematical individual must be defined [16]. Previous patient experience during cystometry has not model of bladder and urethral function authors suggested the maximum Vvoid been well documented. A recent study during micturition. Med Biol Eng Comput (previously defined as functional capacity), suggested that men in particular find the 1979; 17: 291–300 modal Vvoid and average Vvoid over 24 h or procedure uncomfortable, whilst women 5 Griffiths DJ, van Mastrigt R, van Duyl during daytime alone. A review of relevant experience more shame and embarrassment WA, Coolsaet BL. Active mechanical reports suggests that the average Vvoid over [21]. Whether this discomfort was lessened by properties of the smooth muscle of the three or four consecutive 24-h periods is best, restricting filling to a functional capacity was urinary bladder. Med Biol Eng Comput a measure that has consistently been shown not assessed in the current study, but it may 1979; 17: 281–90 to be ª60% of MCC [15,17–19]. The precise benefit those who experience urge at higher 6 Rosier PF, de la Rosette JJ, Koldewijn volume within the bladder just before voiding volumes. EL, Debruyne FM, Wijkstra H. Variability will be the sum of filled volume, urine of pressure-flow analysis parameters in production during the test and residual In conclusion, in men with LUTS and no repeated cystometry in patients with volume. We decided to measure filled volume significant urge component who solely benign prostatic hyperplasia. J Urol 1995; only, as this represents the major component require diagnosis of possible BOO, a PFS with 153: 1520–5 of bladder capacity during conventional PFS, filling restricted to average Vvoid calculated 7 Bland JM, Altman DG. Statistical can be accurately measured and can be from the FVC allows valid pressure-flow methods for assessing agreement related directly to data from the FVC. It is measurements. Those patients with mixed between two methods of clinical possible that high residual urine volumes may symptoms, particularly involving urgency measurement. Lancet 1986; 1: 307–10 affect the reliability of pressure-flow or urge incontinence, require further 8 Drach GW, Layton TN, Binard WJ. Male measurements, but in the few present provocation by extended filling, change to peak urinary flow rate. relationships to patients with residuals of >150 mL the results upright position or a second fill, to reliably volume voided and age. J Urol 1979; 122: were unchanged. document DO. It may be possible therefore to 210–4 better tailor invasive urodynamic evaluation 9 Robertson AS, Griffiths CJ, Ramsden Given the lack of bias found in measurements to individual requirements provided the PD, Neal DE. Bladder function in healthy of Qmax and pdet.Qmax it is not surprising that rationale and conduct of the examination is volunteers: ambulatory monitoring and there were no clinically significant changes in fully documented in the report. conventional urodynamic studies. Br J classification of obstruction using either the Urol 1994; 73: 242–9 AG number or position on the provisional ICS 10 Heslington K, Hilton P. Ambulatory nomogram. Although such classification has urodynamic monitoring. Br J Obstet only been validated for men with LUTS, we felt CONFLICTS OF INTERESTS Gynaecol 1996; 103: 393–9 it appropriate to include women in the overall 11 Rosario DJ, MacDiarmid SA, Radley SC, study, to give a wide range of pressure and None declared. Chapple CR. A comparison of ambulatory flow readings and hence widen the and conventional urodynamic studies in applicability of the findings. men with borderline outlet obstruction. REFERENCES BJU Int 1999; 83: 400–9 The present results, together with previous 12 Groen J, van Mastrigt R, Bosch R. published work, suggest that pressure-flow 1 Griffiths D, Hofner K, van Mastrigt R, Factors causing differences in voiding measurements are consistent irrespective of Rollema HJ, Spangberg A, Gleason D. parameters between conventional and whether the void was initiated at functional Standardization of terminology of lower ambulatory urodynamics. Urol Res 2000; or maximum capacity, indicating that reduced urinary tract function: pressure-flow 28: 128–31 contraction strength caused by overfilling studies of voiding, urethral resistance, 13 Kranse R, van Mastrigt R. Causes for is not of practical importance during and urethral obstruction. International variability in repeated pressure-flow conventional PFS. Part of the rationale for Continence Society Subcommittee on measurements. Urology 2003; 61: 930–4 filling to MCC is to detect DO, although filled Standardization of Terminology of 14 Sonke GS, Kortmann BB, Verbeek AL, volume is only one of many factors that Pressure-Flow Studies. Neurourol Urodyn Kiemeney LA, Debruyne FM, de La influence this diagnosis [20]. The present 1997; 16: 1–18 Rosette JJ. Variability of pressure-flow study was not designed to answer this 2 Schafer W, Abrams P, Liao L et al. Good studies in men with lower urinary tract question, but there were marked variations in urodynamic practices. uroflowmetry, symptoms. Neurourol Urodyn 2000; 19: detecting DO, with fill sequence appearing the filling cystometry, and pressure-flow 637–51
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15 De Wachter S, Wyndaele JJ. Frequency- volume charts versus filling cystometric H, Oh SJ. Patient experience with a volume charts: a tool to evaluate bladder estimated capacities and prevalence of urodynamic study: a prospective study sensation. Neurourol Urodyn 2003; 22: instability in men with lower urinary tract in 208 patients. J Urol 2004; 171: 2307– 638–42 symptoms suggestive of benign prostatic 10 16 Siltberg H, Larsson G, Victor A. hyperplasia. Neurourol Urodyn 2002; 21: Frequency/Volume chart: the basic tool 106–11 Correspondence: Robert Pickard, Freeman for investigating urinary symptoms. Acta 19 Yoon E, Swift S. A comparison of Hospital, Newcastle upon Tyne, NE7 7 DN, UK. Obstet Gynecol Scand Suppl 1997; 166: maximum cystometric bladder capacity e-mail: [email protected] 24–7 with maximum environmental voided
17 Schick E, Jolivet-Tremblay M, Dupont Volumes. Int Urogynecol J Pelvic Floor Abbreviations: Qmax, maximum urinary flow
C, Bertrand PE, Tessier J. Frequency- Dysfunct 1998; 9: 78–82 rate; pdet.Qmax, detrusor pressure at Qmax; PFS, volume chart. The minimum number of 20 Flisser AJ, Blaivas JG. Role of cystometry pressure-flow study; MCC, maximum days required to obtain reliable results. in evaluating patients with overactive cystometric capacity; DO, detrusor
Neurourol Urodyn 2003; 22: 92–6 bladder. Urology 2002; 60 (Suppl. 1): 33– overactivity; Vvoid, fill, voided or filling volume; 18 van Venrooij GE, Eckhardt MD, Gisolf 42 FVC, frequency-volume chart; AG, Abrams- KW, Boon TA. Data from frequency- 21 Ku JH, Kim SW, Kim HH, Paick JS, Son Griffiths (number).
© 2005 BJU INTERNATIONAL 349 Original Article VALIDATION OF THE UTI SYMPTOM ASSESSMENT QUESTIONNAIRE CLAYSON et al.
Validation of a patient-administered questionnaire to measure the severity and bothersomeness of lower urinary tract symptoms in uncomplicated urinary tract infection (UTI): the UTI Symptom Assessment questionnaire
DARREN CLAYSON, DIANE WILD, HELEN DOLL*, KAREN KEATING† and KATHLEEN GONDEK† Oxford Outcomes Ltd, *Department of Public Health, University of Oxford, Oxford, UK, †Bayer HealthCare Pharmaceuticals Global Health Economics and Outcomes Research, West Haven CT, USA Accepted for publication 21 February 2005
OBJECTIVE Questionnaire (KHQ) were used to assess domains showed excellent discriminant convergent and divergent validity; responses validity, with scores on selected domains To develop and validate a self-administered to the Global Rating of Change (GRC) were discriminating between women with different questionnaire to assess the ‘severity’ and used to assess both responsiveness and the clinical evaluations. The responsiveness of ‘bothersomeness’ of the most frequently ‘minimally important difference’. Discriminant the UTISA was also excellent, with high reported signs and symptoms of validity and responsiveness were assessed by correlations between changes in domain uncomplicated urinary tract infection (uUTI). comparing UTISA scores with a clinical scores and the clinical evaluation and GRC evaluation of UTI symptoms performed by the items. Symptom improvement was highest in SUBJECTS AND METHODS investigator at baseline and at the test-of- the first 3 h, leading to greater responsiveness cure visit. and minimally important difference during The UTI Symptoms Assessment questionnaire this period. However, the UTISA could detect (UTISA) is a 14-item instrument asking about RESULTS even small subsequent changes. the severity and bothersomeness of seven key uUTI symptoms. It was developed after The UTISA was found to comprise three four- CONCLUSION comprehensive literature and data review and item domains named ‘urination regularity’, administration in draft form to a sample of 30 ‘problems with urination’, and ‘pain The three-domain UTISA has excellent women with uUTI. The final questionnaire was associated with UTI’. Two questions asking psychometric properties and it is likely to completed by 276 women with uUTI who about haematuria loaded on a fourth factor. prove an excellent tool for assessing uUTI participated in a noncomparative clinical trial The three domains were homogeneous (with outcome from a patient’s perspective, both in of ciprofloxacin. The women completed the high inter-item correlations) and internally research and clinical settings. questionnaire in electronic format at baseline consistent. Convergent validity was shown by (before the first dose of ciprofloxacin once- high correlations between similar UTISA and KEYWORDS
daily), at 3-h and 8-h intervals until all UTI KHQ domains (all rs > 0.40), and divergent symptoms were resolved, and at the test-of- validity by small correlations between unlike urinary tract infection, urinary symptoms,
cure visit. Baseline scores on the King’s Health domains (all rs < 0.15). In general, the UTISA questionnaire, validity, reliability.
INTRODUCTION An acute uncomplicated UTI (uUTI; also intercourse and a history of recurrent referred to as cystitis, acute cystitis or infection are risk factors for UTIs in women UTIs are considered to be the most common dysuria-frequency syndrome) has been [6,7]. bacterial infection, with an estimated seven defined in several ways. In women, it includes million physician visits and one million a clinical syndrome characterized by various While there has been some research on the emergency department visits each year in the combinations of dysuria (painful urination), impact of uUTI on everyday activities, with USA alone. Half of all women have at least frequency, urgency, gross haematuria, one study reporting that each episode of UTI one UTI in their lifetime [1,2]. However, the lower back and/or abdominal/suprapubic results in an average of 6.1 symptomatic days incidence of UTI is difficult to assess discomfort with pyuria and bacteriuria [3]. and 2.4 restricted-activity days, as well as accurately, as UTI is not well reported. Usually there is no identified underlying renal time lost from work [8], there has been Moreover, although diagnosis ideally involves or urological dysfunction or obstruction, and little research on symptom duration, confirmation of the presence of symptoms up to half of patients with uUTI do not have bothersomeness, or the impact of symptoms and a positive urine culture, in practice, a bacteriuria according to established criteria on patients’ quality of life (QoL) [9], although diagnosis is frequently made without the [4,5]. Frequent sexual intercourse, diaphragm an association is recognized [10]. Generalized benefit of culture results. use, the use of a spermicide, not voiding after symptoms of feeling ‘out of sorts’, especially
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feeling unwell, weak and tired, or irritable and rated bothersomeness on a 10-point Likert- and was clinically evaluated. Otherwise, these restless, are common [11], while women in type scale and indicated the time to symptom assessments were taken at the second test- one study described the dominant feeling as a resolution. Focus on ‘bothersomeness’ arose of-cure visit 5–9 days after treatment, at burning and scorching pain: ‘It feels like from research in BPH, which suggested that which point the patient-reported measures peeing barbed wire.’ [12]. the perceived bother from urinary symptoms were also completed. is a stronger predictor of healthcare-seeking One recent study examined the impact of uUTI behaviour for urinary dysfunction than is the Clinical evaluation involved the investigator on QoL [13] using the Medical Outcome Study absolute frequency of symptom occurrence. assessing five UTI symptoms (dysuria, Short-Form 36 Health Survey (SF-36) [14] to frequency, urgency, suprapubic pain, gross assess QoL, and found that women with uUTI The questionnaire was administered to 33 haematuria) rated either as ‘none’, ‘mild’, reported significantly poorer QoL in all SF-36 women aged 18–55 years who had been ‘moderate’, ‘severe’, and scored as 0–3. The domains, both emotional and physical. diagnosed with uUTI. The women were drawn clinical evaluations took place at the first visit, However, no validated instrument exists to from two ethnically and socio-economically at any premature discontinuation (day 1–3), measure symptoms in uUTI. diverse USA communities, and 30 of the 33 and at the test-of-cure visit. Bacteriological women completed the questionnaire. The assessments were also made, but the data The present study was designed to develop responses of these 30 women were reviewed were not used for validation as it was and validate a questionnaire, the UTI to finalise the UTISA questionnaire. The considered that the validity of the instrument Symptom Assessment questionnaire (UTISA), questionnaire was modified to make it self- would be related primarily to symptom to assess the ‘severity’ and ‘bothersomeness’ administered and to capture symptom severity and bothersomeness. Of the 273 of the most frequently reported symptoms severity as well as bothersomeness. The Likert women with culture data, those with (189, and signs of uUTI. The questionnaire was scales for each item were changed from 10- 69%) and those without positive cultures developed on the basis of the results of a point to 4-point scales, and the symptom of (defined as > 103 colony-forming units/mL at series of comprehensive reviews to identify urine leakage was replaced with haematuria first visit) did not differ significantly in terms the key symptoms associated with uUTI. The (blood in urine/dark urine), primarily for of any baseline demographic or clinical data. data for the validation study came from a clinical diagnostic value rather than for noncomparative clinical trial of the treatment symptomatic importance. The questionnaire Patient-reported outcomes were recorded of women with uUTI. The trial was specifically (baseline and follow-up versions) is shown in electronically (using ‘palm pilot’ computers designed to validate the new instrument, and Figs 1 and 2. For permission to use it, please with information downloaded to a host incorporated validated measures as well as contact the Bayer Pharmaceuticals Corp., computer) at the first visit (just before the clinical and patient evaluations of symptoms Global Health Economics and Outcomes first dose of ciprofloxacin once-daily), and at for the purposes of psychometric validation. Research Department, West Haven, CT. 3-h and then 8-h intervals until the The psychometric properties of the symptoms had resolved, or at the test-of-cure questionnaire were assessed primarily by the The assessment of reliability and validity was visit, whichever came first. The palm pilots pattern of associations between UTISA scores conducted in the context of a prospective, prompted the patients to complete the and scores on the King’s Health Questionnaire open-label, noncomparative, multicentre questionnaires at the correct times. (KHQ) and Global Rating of Change (GRC) clinical trial of ciprofloxacin once-daily scores. The assessed properties included 500 mg for 3 days. Women with uUTI were The UTISA is a self-administered, 14-item internal consistency, convergent and recruited for entry to this trial between 18 questionnaire that assesses, for each of the divergent reliability, discriminant validity, and June 2003 and 14 January 2004. At their seven most frequently reported symptoms responsiveness. The Minimally Important first visit, just before their first dose of and signs of UTI (frequency, urgency, Difference (MID) of the UTISA was also ciprofloxacin once-daily, the women gave pain/burning on urination, incomplete assessed. written informed consent, and gave a urine voiding, pain in pelvic area, low back pain, sample for dipstick biochemical analysis for blood in urine), levels of ‘severity’ and SUBJECTS AND METHODS nitrites or leukocyte esterase, and a clean- ‘bothersomeness’. Each item has a Likert-type catch midstream urine specimen for culture response scale, the ‘severity’ item response The UTISA was developed as a means of and sensitivity. The women also provided options being ‘did not have’, ‘mild’, ‘moderate’, assessing symptoms in uUTI and its demographic and medical history details (age, ‘severe’, scored 0–3; and the bothersomeness development has been reported in full ethnicity, years of education, employment item response options being ‘not at all’, ‘a elsewhere [7]. In brief, key clinical signs/ status, previous history of uUTI, number of little’, ‘moderately’, ‘a lot’, scored 0–3. The symptoms of uUTI were identified from days since onset of uUTI before seeing UTISA was administered at the first visit, every comprehensive literature and data reviews. physician), and completed the patient- 3 h for the first 24 h while awake, then every Seven key symptoms were identified: reported questionnaires. The clinical 8 h until all UTI symptoms were resolved (for frequency of urination, urgency of urination, evaluation was performed and the at least 24 h or three data capture points, pain and burning during urination (dysuria), ciprofloxacin once-daily dispensed. During whichever was longer), and finally at the test- inability to empty the bladder completely, treatment (days 1–3), the women completed of-cure visit. pain or discomfort in the lower abdomen, low the UTISA, the KHQ and the GRC. If the patient back pain, and urine leakage. A questionnaire discontinued the treatment prematurely The KHQ is a self-administered questionnaire to assess these seven symptoms was then during this time (days 1–3) a further clean- designed to assess the impact of urinary developed. For each symptom, the patient catch midstream urine specimen was taken incontinence on QoL. The measure was
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FIG. 1. The UTISA questionnaire (for use at baseline).
About Your Symptoms and Their Impact on Your Life (for use at visit 1) Please indicate whether you have had the If you have experienced these symptoms/problems in following symptoms/problems in the past 24 the past 24 hours, please indicate how bothersome hours and how severe they were: (Please circle SYMPTOMS they were? (Please circle one number for each one number for each symptom) symptom) Did not have Mild Moderate Severe Not at all A little Moderately A lot
Frequency of urination (going to the 0 1 2 3 toilet very often) 0 1 2 3 Urgency of urination (a strong and 0 1 2 3 uncontrollable urge to pass urine) 0 1 2 3
0 1 2 3 Pain or burning when passing urine 0 1 2 3 Not being able to empty your bladder 0 1 2 3 completely/passing only small 0 1 2 3 amounts of urine 0 1 2 3 Pain or uncomfortable pressure in the 0 1 2 3 lower abdomen/pelvic area caused by your urinary tract infection Low back pain caused by your urinary 0 1 2 3 tract infection 0 1 2 3
0 1 2 3 Blood in your urine 0 1 2 3
8. Please give an overall rating of the severity of your urinary tract infection symptoms as they are at this moment (Please circle the number of your answer)
0 No symptoms at all 1 Mild 2 Moderate 3 Severe
Copyright (c) 2003, 2004 by Bayer Pharmaceutical Corporation. All rights reserved. originally designed for use in women and for this study, item 1 asks women to rate the extracted if their eigenvalue was > 1. Domain contains 21 questions, which are scored in severity of their UTI symptoms (‘no symptoms scores of any resulting factors were nine domains (general health perception, at all’, ‘mild’, ‘moderate’, ‘severe’), item 2 asks calculated as a sum of the component item incontinence impact, role limitations, physical whether there have been any changes in their scores, where the higher the score the greater limitations, social limitations, personal UTI since last completing the questionnaire the symptoms. The normality of the relationships, emotions, sleep/energy, severity (‘about the same’, ‘better’, ‘worse’), and item 3 distribution of the resulting domain scores of urinary symptoms) [15]. Weighted asks women to rate the level of any symptom was assessed using Kolmogorov-Smirnov summary scores in each domain range from 0 improvement (‘a very great deal better’, ‘a statistics. Where data were not normally to 100, with higher scores indicating greater great deal better’, ‘a good deal better’, distributed, nonparametric tests were used. impairment. Part III of the questionnaire is a ‘moderately better’, ‘somewhat better’, ‘a little list of 10 individual bladder problems plus an better’). The GRC was administered at the first A correlation matrix was calculated for the 14 ‘other’ category. The KHQ was chosen as the visit (item 1 only) and at all subsequent UTISA items to assess domain homogeneity, primary instrument in the validation of the administrations of the UTISA. and Cronbach’s a statistics calculated to UTISA as it has been validated for use in assess the internal consistency reliability. assessing women with urinary problems such Data were analysed by ANOVA with post hoc Convergent validity was assessed in terms of as overactive bladder [16,17]; it contains Tukey tests (or nonparametric Kruskal–Wallis the strength of the associations between questions on bladder problems (frequency, test with Bonferroni-corrected post hoc UTISA domain scores and similar individual urgency, bladder pain, etc.), and how much Mann–Whitney tests to compare group symptom and domain scores of the KHQ. For these problems affect the woman at present. scores. Associations between continuous example, the UTISA ‘urination regularity’ The KHQ was administered at visit 1, on day 3, variables (absolute or change scores) were domain was expected to be strongly when the patient indicated that the UTI assessed using Pearson’s r or Spearman’s rs associated with the KHQ ‘frequency’ and symptoms had resolved (no symptoms for correlation coefficients. Throughout the ‘urgency’ items; the UTISA ‘pain associated 24 h, or over three data capture points, analysis, missing values were dealt with by with UTI domain’ with the KHQ ‘bladder pain’ whichever was longer), and at the test-of- excluding cases pairwise, and P < 0.05 was item; and the UTISA ‘problems with urination’ cure visit. considered to indicate statistical significance. domain with the KHQ ‘difficulty urinating’ Exploratory factor analysis using principle- item. As short-term UTI is not expected The GRC is a three-item measure used to components extraction and varimax rotation to have a major impact on personal assess symptom improvement. As formulated was used on the 14 UTISA items. Factors were relationships, divergent validity was assessed
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FIG. 2. The UTISA questionnaire (for use at follow-up).
About Your Symptoms and Their Impact on Your Life (for use after visit 1) Since you last completed this questionnaire Since you last completed this questionnaire, if you please indicate whether you have had the have experienced these symptoms/problems, please following symptoms/problems and how severe indicate how bothersome they were? (Please circle SYMPTOMS they were: (Please circle one number for each one number for each symptom) symptom) Did not have Mild Moderate Severe Not at all A little Moderately A lot
Frequency of urination (going to the 0 1 2 3 toilet very often) 0 1 2 3 Urgency of urination (a strong and 0 1 2 3 uncontrollable urge to pass urine) 0 1 2 3
0 1 2 3 Pain or burning when passing urine 0 1 2 3 Not being able to empty your bladder 0 1 2 3 completely/passing only small 0 1 2 3 amounts of urine 0 1 2 3 Pain or uncomfortable pressure in the 0 1 2 3 lower abdomen/pelvic area caused by your urinary tract infection Low back pain caused by your urinary 0 1 2 3 tract infection 0 1 2 3
0 1 2 3 Blood in your urine 0 1 2 3
8. Please give an overall rating of the severity of your urinary tract infection symptoms as they are at this moment (Please circle the number of your answer)
0 No symptoms at all 1 Mild 2 Moderate 3 Severe
9. Since you last completed this questionnaire, have there been any changes in your urinary tract infection symptoms? (Please circle the number of your answer)
0 about the same 1 better 2 worse
(Note – if the patient responded 1 – better) to question 9, go on question 10 below)
10. Please indicate how much better (circle the number of your answer)
6 a very great deal better 5 a great deal better 4 a good deal better 3 moderately better 2 somewhat better 1 a little better
Copyright (c) 2003, 2004 by Bayer Pharmaceutical Corporation. All rights reserved. by calculating the degree of association (at first administration) between the initial the ‘problems with urination’ domain would between the UTISA domains and the KHQ clinical ratings for dysuria, frequency, discriminate between the evaluations of ‘personal relationships’ domain; only small urgency, suprapubic pain and gross ‘dysuria’; that the ‘pain associated with UTI’ correlations were expected. haematuria. It was hypothesized that the domain would discriminate between the UTISA ‘urination regularity’ domain would different clinical evaluations of ‘suprapubic The discriminant validity of the UTISA was discriminate between different clinical pain’; and the ‘blood in urine’ domain between assessed by comparing UTISA domain scores evaluations of ‘frequency’ and ‘urgency’; that evaluations of ‘gross haematuria’. In addition,
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the responses to the GRC item 1 were TABLE 1 Factor loadings (loadings >0.4) on the four extracted components showing the structure of the examined in relation to the UTISA scores. UTISA Those reporting more severe symptoms on the GRC were expected to have higher UTISA Component scores. Item 1234 Responsiveness was assessed by comparing 1. Frequency – severity 0.770 the improvement in UTISA domain scores 2. Frequency – bothersomeness 0.794 (from the first visit to when symptoms were 3. Urgency – severity 0.821 no longer present) to the improvement in the 4. Urgency – bothersomeness 0.818 clinical evaluation of UTI; the greater the 5. Pain – severity 0.831 improvement in clinical severity, the greater 6. Pain – bothersomeness 0.839 the expected improvement in domain scores. 7. Empty – severity 0.508 0.585 To explore the responsiveness of the UTISA 8. Empty – bothersomeness 0.527 0.599 domains to patient-reported changes, 9. Discomfort – severity 0.461 0.657 changes in domain scores were compared 10. Discomfort – bothersomeness 0.414 0.696 among the three categories of responses to 11. Low back pain – severity 0.889 GRC item 2 (on the categories recorded as 12. Low back pain – bothersomeness 0.860 worse = -1, about the same = 0, better = 1). 13. Blood in urine- severity 0.890 The analyses were repeated at the second, 14. Blood in urine – bothersomeness 0.847 third fourth and fifth assessments (i.e. in the % of variance explained 37.8 15.1 11.5 8.2 first 1–2 days of the study after the initial administration of ciprofloxacin once-daily). In addition, the responsiveness of the UTISA domains to the level of patient-reported mean (SD, range) age of the women was and urgency (237, 85.9%). Suprapubic pain improvement was assessed by correlating 33.0 (11.46, 18–78) years. Although the was less common, with most women (179, changes in domain scores at the second, third, sample was ethnically diverse, 12% (34) were 64.9%) rated as having either mild or fourth and fifth assessments with changes in Black, 4% (12) American Indian, 2% (five) moderate suprapubic pain. Haematuria was GRC item 3. A responsiveness index was Hispanic, and most of the women (70%, 193) reported as absent in 151 women (54.7%). calculated for the UTISA domains by dividing were White. Overall, 175 women (64.5%) were Colony counts (colony-forming units/mL) for the mean change in score for patients who working full time, 65 (23.8%) were working the 273 women with culture data were as report feeling ‘a little better’ (GRC item 3) by part time, 107 (39.2%) women reported that follows: £103, 84 (30.8%); >103-104, nine the SD for those patients who feel ‘about the they were looking after the house and/or (3.3%); >104-105, 28 (10.3%); >105, 152 same’ (GRC item 2). Index of responsiveness children full time, 53 (19.4%) women were (55.7%). scores of 0.2 are regarded as small, 0.5 as studying at university either full or part time, moderate and 0.8 as large [18]. To assess and 46 (6.8%) reported that they were On exploratory-factor analysis of the baseline whether the responsiveness of the UTISA is engaged in some other role. UTISA scores, four components were consistent across time, these analyses were extracted which explained 72.6% of the conducted for assessments 1–5 of the UTISA Most of the women reported that their variance (Table 1). For each symptom, the and GRC questionnaires. present overall health was either very good severity and bothersomeness items loaded (110, 40.3%) or good (136, 49.8%), and that onto the same factor. Four items (items The MID is the difference in the measure their bladder problem affected their life either relating to inability to completely empty associated with the smallest detectable a little (108, 39.6%) or moderately (83, 30.4%). bladder and pain/discomfort in the lower symptom improvement. The MID was Most of the women (171, 62.0%) reported no abdomen) loaded on to two components. The calculated by selecting patients who reported previous episode of uUTI, although 26.4% (73) items were allocated to the component on that they felt ‘better’ on GRC item 2 and ‘a reported one previous episode, 11.2% (31) two which the loading was highest. The four little better’ on GRC item 3. The change scores previous episodes and 0.4% (one) three components were termed ‘urination for the UTISA were then calculated (e.g. time 1 previous episodes. In terms of the duration of regularity’, ‘problems with urination’, ‘pain minus time 2). This analysis was repeated at the current episode, 14.1% (39) reported that associated with UTI’, and ‘blood in urine’. The assessments 2–5. it had been present for 1 day, 38.4% (106) for last component contained only two items and 2 days, 44.2% (122) for 3 days, and 3.3% it was retained in the UTISA for clinical (nine) for 4 days. There was no association diagnostic value rather than symptomatic between number of previous episodes and importance. RESULTS duration of the current episode. The domains were internally homogeneous In all, 276 women were recruited to the In terms of the investigator-reported clinical with average intra-item correlations being ciprofloxacin once-daily trial and thus to the evaluations at baseline, most of the women notably higher than average inter-item validation study; 267 women (96.7%) were were considered to have moderate or severe correlations: urination regularity (0.644 vs followed up to the test-of-cure visit. The dysuria (208, 75.4%), frequency (238, 86.2%) 0.284); problems with urination (0.610 vs
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(all P < 0.01), with scores increasing with TABLE 2 Spearman correlation coefficients between UTISA domains and selected KHQ items and increasing clinical severity. The blood in urine domains for the assessment of the convergent and divergent validity of the UTISA domain discriminated mainly between the clinical evaluations of ‘gross haematuria’, UTISA domains with domain scores increasing with Problems with Pain associated increasing clinical severity (P < 0.01). KHQ domain/item Urination regularity urination with UTI Convergent validity Spearman correlations between the change in Sleep/energy domain 0.33† NA 0.33† UTISA domain scores and change in the Role limitations domain 0.43† NA 0.31† clinical evaluation of UTI (both assessed at the Social limitations domain 0.37† NA 0.31† test-of-cure visit) are shown in Table 4. The Physical limitations domain 0.45† NA 0.29† UTISA domains of urination regularity, Frequency item 0.69† NA NA problems with urination, and pain associated Urgency item 0.71† NA NA with UTI were responsive to changes in the Bladder pain item NA NA 0.58† clinical evaluation of ‘dysuria’, ‘frequency’, Difficulty urinating item NA 0.46† NA and ‘urgency’, with all correlation coefficients Divergent validity being at least moderate and statistically Personal relationships domain 0.04 0.01 0.13* significant. In addition, the domain pain associated with UTI was responsive to *P < 0.05, †P < 0.01; NA, not assessed changes in the clinical evaluation of ‘suprapubic pain’, and the domain blood in urine to changes in ‘gross haematuria’. All other correlations, even if significant, were 0.290); pain associated with UTI (0.616 vs While there was no association between small (<0.20). Mean change scores in the 0.210); and blood in urine (0.830 vs 0.108). UTISA scores and number of previous UTISA domains at the first five assessments by episodes, the ‘pain associated with UTI’ and patient-reported level of change are shown in The Cronbach’s a coefficients for the three ‘blood in urine’ scores differed significantly Table 5, with the Spearman’s correlation four-item domains were >0.8 (0.87, 0.85, and between those with different duration coefficients between the UTISA change scores 0.83 for urination regularity, problems with (Kruskal–Wallis c2 = 12.14, P = 0.007, and and the GRC items 2 and 3. At assessments urination, and pain associated with UTI, 11.31, P = 0.010, respectively). Pain associated two and three, change in each UTISA domain respectively), showing high internal with UTI scores tended to increase with (from the previous assessment) was highly consistency. The coefficient for the two-item increasing duration of the episode (rs = 0.185, responsive to patient-reported change with blood in urine domain was 0.72. P = 0.002) and ‘blood in urine’ scores to mean scores differing at P < 0.001 between
decrease (rs = -0.177, P = 0.003). the patient-reported change categories, and Mean (SD, median) scores for the four Spearman’s correlation coefficients being domains were: urination regularity, 9.01 (2.63, The Spearman’s correlation coefficients moderate and also significant at P < 0.001. 9); problems with urination, 7.98 (2.97, 8); between the UTISA and KHQ domains and Patients who reported that they felt worse pain associated with urination, 5.69 (3.41, 6); selected KHQ items are shown in Table 2. The generally reported deterioration in UTISA and blood in urine, 1.52 (1.87, 1). Respondents correlation coefficients for the assessment of domain score, while those who reported that used the full range of scores for each domain convergent validity were all positive (i.e. the they felt better reported an improvement. The (0–12 for the four-item domains and 0–6 for higher the UTISA score the higher the KHQ associations were weaker at assessments four the two-item domain). score) and statistically significant. In and five, and the blood in urine domain scores particular, the correlation coefficients were not significantly associated with The only statistically significant correlation between the UTISA domain scores and the patient-reported change. However, in terms between domain scores and age was between corresponding KHQ items were all > 0.4. In of the degree of improvement (GRC item 3), the ‘problems with urination’ score and age terms of divergent validity, although there only at the second assessment (3 h) were any
(rs = -0.13, P < 0.05), indicating that younger was a statistically significant association of the UTISA domains responsive. The women reported more of these problems between the KHQ ‘personal relationships’ responsiveness indices of the UTISA domains (pain/burning when urinating and a feeling of domain and the UTISA ‘pain associated with during the first 1-2 days of treatment in incomplete emptying). In terms of association UTI’ domain, the correlation coefficient was relation to the GRC responses are shown in with ethnicity, ‘pain associated with UTI’ small, and neither of the other domains Table 6. The largest changes in domain scores scores differed significantly between the showed a significant association. were during the first two assessments. For ethnic groups (c2 = 9.397, d.f. 3, P < 0.05), example, the mean (SD) urination regularity with White women reporting significantly less The mean UTISA domain scores by clinical scores at baseline, and the second, third, pain than Black women, at a mean (SD) of score rating for each of the five symptoms are fourth and fifth assessments were 9.01 (2.63), 5.34 (3.30) vs 7.03 (3.26); z = -2.53, P < 0.05). shown in Table 3. The urination regularity 6.43 (3.09), 4.86 (3.03), and 3.81 (2.86), Scores for each item were consistent with and problems with urination domains respectively (Table 7). The responsiveness of Black women scoring higher than White discriminated between ratings of ‘dysuria’, the UTISA domains was also higher at these women. ‘frequency’, ‘urgency’, and ‘suprapubic pain’ first two assessments than at the subsequent
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assessments, although most indices indicated TABLE 3 Mean UTISA domain scores by clinical rating scale scores for the assessment of discriminant moderate (>0.50) or high (>0.80) validity responsiveness [18]. In other words, the change in UTISA scores associated with a UTISA Mean domain score by clinical evaluation response of ‘a little better’ to the GRC was Symptoms domains None Milda Moderateb Severec Kruskal–Wallis c2 greater at the early stages than at the later stages of treatment. Thus, the UTISA is Dysuria UR 2.00 8.07§ 8.65 10.98‡ 55.01‡ responsive to this difference in pattern of PWU 2.00 5.45§ 8.06‡ 10.67‡ 102.71‡ improvement. PAU 8.00 5.03§ 5.53 6.77* 10.55* BIU 0.00 1.34§ 1.49 1.84 1.98 As the degree of improvement in UTISA scores Frequency UR 3.71 5.58§ 8.89‡ 10.62‡ 103.49‡ was higher at the first two assessments after PWU 5.43 5.00§ 8.13‡ 8.89* 41.47‡ treatment than at subsequent assessments, PAU 4.43 3.26§ 6.04‡ 6.07 19.69‡ the estimated MID for each domain tended to BIU 0.86 0.87§ 1.53 1.77 4.31 be larger in the early stages of treatment than Urgency UR 4.67 7.04* 8.57† 10.54‡ 82.04‡ in later stages (Table 8). This means that the PWU 4.33 6.44* 7.94* 8.85† 32.86‡ smaller levels of improvement in scores in PAU 3.58 4.78 5.56 6.33* 11.11* the later stages of treatment are indeed BIU 1.17 1.22 1.50 1.68 0.93 detectable by the patients. However, these Suprapubic pain UR 9.39 8.24* 8.95* 10.20* 17.18† analyses are based on relatively few patients, PWU 7.50 7.22 8.34* 9.34* 16.68† so to obtain an overall MID for each scale, a PAU 3.44 4.51* 6.66‡ 8.80‡ 72.34‡ mean was taken of the estimated MIDs at BIU 1.13 1.33 1.60 2.27 10.01* each assessment. The mean scores were Gross haematuria UR 8.93 8.96 8.97 9.50 2.81 rounded for ease of use, giving MIDs of 1.75, PWU 7.57 8.02 8.38 9.34 10.88* 1.50, 1.25, and 0.50 for the urination PAU 5.34 6.55* 5.10 6.63* 8.96* regularity, problems with urination, pain BIU 0.61 1.87‡ 2.87† 3.56 98.67† associated with UTI, and blood in urine domains, respectively. UR, urination regularity; PWU, problems with urination; PAU: pain associated with UTI; BIU, blood in urine; Mann–Whitney U-tests used to test differences between clinical evaluations anone and mild, bmild and moderate, cmoderate and severe (§ not tested due to small N in the ‘None’ group); *P < 0.05, †P < 0.01, ‡P < 0.001. DISCUSSION
This study reports the development and validation of a new instrument, the UTISA questionnaire, to measure the severity and TABLE 4 Spearman’s correlation coefficients between change in UTISA domain scores and change in bothersomeness of the most frequently clinical evaluation of five symptoms for the evaluation of responsiveness reported symptoms and signs of uncomplicated uUTI. Strengths of the study UTISA domains include comprehensive reviews of published Urination Problems with Pain associated Blood material in the questionnaire-development Clinical evaluation regularity urination with UTI in urine stage, combined with administration of a Dysuria 0.42† 0.59† 0.18† 0.11 draft measure. The validity of the revised Frequency 0.56† 0.35† 0.22† 0.15* questionnaire was tested in a large sample of Urgency 0.49† 0.31† 0.24† 0.09 276 ethnically and socio-economically diverse Suprapubic pain 0.10 0.19† 0.47† 0.17† women with uUTI in the context of a Gross haematuria 0.09 0.18† 0.14* 0.58† noncomparative clinical trial. *P < 0.05, †P < 0.01. One interesting feature of the trial was its use of electronic recording devices. Palm pilot devices are inexpensive, small, light, and well suited for collecting patient-reported several measures over frequent and varying The UTISA is a 14-item questionnaire that asks outcomes. Alarms can be set to trigger data periods. Electronic methods of data collection about the ‘severity’ and ‘bothersomeness’ of collection at specific intervals and, as the have been used successfully in other studies seven key symptoms and signs of uUTI, and patient responses are time-stamped, the time [19–21] showing that such methods are includes three principal domains of urination at which the data were gathered is more reliable and valid [21], and can yield a regularity (frequency and urgency), problems accurate than with paper diaries. The devices more complete and accurate profile of signs with urination (pain/burning on urination and worked well in the present study, which and symptoms than paper questionnaires a feeling of incomplete emptying), and pain involved repeated collection of data for [19,20]. associated with UTI (pain/pressure in lower
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TABLE 5 Mean (SD) UTISA domain scores by change in UTI symptoms (GRC item 2) and Spearman’s correlation coefficients between UTISA change scores and GRC item 2 (scored as worse, same, better) and item 3 during the first five assessments for evaluation of responsiveness
GRC item UTISA 2: Changes in UTI 2: Changes in 3: How much Change score domain symptoms same better worse K-W P UTI symptoms better Time 1–2 UR 1.81 (2.46) 4.33 (2.73) 0.39 (2.64) <0.001 0.460‡ 0.439‡ PWU 1.75 (2.55) 3.73 (2.97) -0.72 (2.65) <0.001 0.396‡ 0.390‡ PAU 0.89 (2.11) 2.23 (3.03) -0.78 (1.73) <0.001 0.316‡ 0.217* BIU 0.41 (1.30) 1.03 (1.68) -0.39 (1.58) <0.001 0.281‡ 0.088 Time 2–3 UR 0.63 (1.83) 2.45 (2.41) -1.50 (2.98) <0.001 0.421‡ 0.055 PWU 0.52 (1.93) 2.05 (2.32) -1.13 (2.17) <0.001 0.357‡ 0.092 PAU 0.45 (1.70) 1.56 (2.09) -2.00 (1.07) <0.001 0.355‡ -0.005 BIU 0.12 (0.73) 0.52 (1.07) -1.00 (1.20) <0.001 0.246‡ -0.026 Time 3–4 UR 0.52 (1.49) 1.36 (2.16) -0.75 (1.50) 0.001 0.218‡ 0.068 PWU 0.63 (1.58) 1.55 (2.18) -2.50 (3.42) <0.001 0.258‡ -0.045 PAU -0.11 (3.55) 0.59 (2.74) -5.50 (2.52) 0.004 0.129* 0.112 BIU 0.17 (0.68) 0.30 (0.90) -0.50 (1.00) 0.111 0.101 0.106 Time 4–5 UR 0.17 (1.50) 1.18 (1.92) -1.00 (1.73) <0.001 0.281‡ -0.133 PWU 0.39 (1.83) 0.90 (1.86) 1.33 (1.15) 0.029 0.138* -0.077 PAU 0.68 (3.21) 1.41 (2.51) -0.67 (2.31) 0.024 0.161† -0.077 BIU 0.14 (0.58) 0.20 (0.74) -0.33 (0.58) 0.135 0.032 -0.006
UR, urination regularity; PWU, problems with urination; PAU: pain associated with UTI; BIU, blood in urine; K-W, Kruskal–Wallis; *P < 0.05, †P < 0.01, ‡P < 0.001.
psychometric properties, and was retained for TABLE 6 Responsiveness indices for each UTISA domain at each assessment clinical diagnostic value only.
UTISA GRC item and response The mean domain scores indicated that items Change score domain 3: ‘A little better’ 2: ‘No change’ Responsiveness index related to urination regularity are the most Time 1–2 UR 2.75 2.46 1.12 troublesome symptoms in acute uUTI. PWU 2.40 2.55 0.94 Interestingly, Black women reported more PAU 1.65 2.11 0.78 problems with pain than White women, BIU 0.70 1.30 0.54 having significantly higher scores on the Time 2–3 UR 2.15 1.83 1.17 UTISA pain associated with UTI domain PWU 0.96 1.93 0.50 (P < 0.05). This is consistent with other PAU 1.59 1.70 0.94 reports of different experiences of pain across BIU 0.67 0.73 0.92 racial and ethnic groups, with African- Time 3–4 UR 0.78 1.49 0.52 Americans reporting higher levels of pain PWU 1.11 1.58 0.70 than White Americans in a variety of different PAU 0.44 1.52 0.29 conditions [24]. BIU 0.11 0.68 0.16 Time 4–5 UR 1.22 1.50 0.81 All three UTISA domains had excellent PWU 1.17 1.83 0.64 psychometric properties. Convergent validity PAU 1.22 1.40 0.87 was indicated by high and significant BIU 0.39 0.58 0.67 correlations between the UTISA domains and related KHQ items and domains. Divergent UR, urination regularity; PWU, problems with urination; PAU: pain associated with UTI; BIU, blood in validity was indicated by the small and urine. generally non-significant correlations between the UTISA domains and the KHQ personal relationships domain. The small but statistically significant correlation between abdomen and low back pain, both caused optimum range of 0.8–0.9. A Cronbach a of the UTISA pain associated with UTI domain by UTI). The domains were internally >0.9 is considered to indicate that the scale and the KHQ personal relationships domain homogeneous and had good internal items are too similar [22,23]. The blood in (rs = 0.13, P < 0.05) might be explained in consistency, with a Cronbach a in the urine domain had two items and weaker that one of the KHQ items within this
© 2005 BJU INTERNATIONAL 357 CLAYSON ET AL.
domain is ‘Does your bladder problem TABLE 7 Mean (SD) changes in UTISA domain scores over the first five assessments affect your sex life?’ It is possible that a woman’s sex life might be affected more UTISA Domains by pain associated with UTI than by any other Problems with Pain associated symptom. Change score Urination regularity urination with UTI Blood in urine The three UTISA domains generally had Time 1–2 2.58 (2.87) 2.26 (2.96) 1.24 (2.57) 0.57 (1.50) excellent discriminant validity in relation to Time 2–3 1.58 (2.43) 1.31 (2.32) 0.99 (2.05) 0.31 (0.99) the clinical evaluation. They also had very Time 3–4 1.07 (2.01) 1.20 (2.12) 0.28 (3.10) 0.25 (0.84) high levels of responsiveness, with strong Time 4–5 0.80 (1.85) 0.72 (1.85) 1.13 (2.80) 0.17 (0.68) associations between changes in domain scores and changes in clinical evaluation. Responsiveness was also shown by the strong associations between UTISA domain change Assessment TABLE 8 scores and GRC items, particularly GRC item 2, UTISA domain time point N Mean (SD) Mean (SD) scores for which asks whether the patient felt their Urination regularity 2 20 2.8 (1.9) patients who reported that condition had worsened, stayed about 3 27 2.1 (2.3) they felt ‘better’ on GRC the same, or improved since the last 4 18 0.8 (1.9) item 2 and ‘a little better’ on assessment. 5 18 1.2 (2.2) GRC item 3 for the Mean, MID 1.73, 1.75 estimation of MID scores In terms of the calculated responsiveness Problems with urination 2 20 2.4 (2.5) for the UTISA domains. The indices, these were generally at least 3 27 1.0 (2.2) MID is taken as the rounded moderate and mirrored the reported changes 4 18 1.1 (2.2) mean score over the four in UTISA domain scores, which were greatest 5 18 1.2 (2.6) assessments in the two assessments immediately after Mean, MID 1.43, 1.50 treatment. Thus the UTISA is responsive to this Pain associated with UTI 2 20 1.7 (2.2) difference in pattern of improvement, with 3 27 1.6 (1.8) the responsiveness indices at the first two 4 18 0.4 (1.5) assessments generally being greater than 5 18 1.2 (1.8) those at the subsequent assessments. Mean, MID 1.23, 1.25 Blood in urine 2 20 0.7 (1.3) The estimated MID values also reflected 3 27 0.7 (1.3) the greater improvement in symptoms 4 18 0.1 (0.5) immediately after treatment, being greater 5 18 0.4 (1.1) initially than after a few hours of treatment. Mean, MID 0.48, 0.50 This probably reflects that, as the improvement in symptoms is initially rapid, the symptom improvement (as measured by improvement in the UTISA domain scores) associated with patient reports that they felt CONFLICT OF INTEREST Equal symptomatic outcome after ‘a little better’ is likely to be greater than the antibacterial treatment of acute lower associated improvement at a time when None declared. Source of funding: Bayer urinary tract infection and the acute symptom resolution is less rapid. To take Healthcare Pharmaceuticals. urethral syndrome in adult women. Scand account of this, the estimated MID was taken J Prim Health Care 1999; 17: 170–3 as the rounded mean value of all MIDs 5 Brumfitt W, Hamilton-Miller JM, calculated over the four assessments 2–5. REFERENCES Gillespie WA. The mysterious ‘urethral syndrome’. BMJ 1991; 303: 719–20 In conclusion, the UTISA questionnaire 1 Nicolle L. Epidemiology of urinary tract 6 Hooton TM, Scholes D, Hughes JP et al. measures the severity and bothersomeness of infections. Infect Med 2001; 18: 153–62 A prospective study of risk factors for key signs and symptoms associated with uUTI. 2 Foxman B. Epidemiology of urinary tract symptomatic urinary tract infection in The questionnaire comprises three four-item infections: incidence, morbidity, and young women. N Engl J Med 1996; 335: domains (urination regularity, problems with economic costs. Dis Mon 2003; 49: 53– 468–74 urination, and pain associated with UTI), with 70 7 Colgan R, Keating K, Dougouih M. two additional items measuring haematuria. 3 Rubin RH, Beam TR Jr, Stamm WE. Survey of symptom burden in women The three domains have excellent An approach to evaluating antibacterial with uncomplicated urinary tract psychometric properties. The questionnaire agents in the treatment of urinary tract infections. Clin Drug Invest 2004; 24: 55– was designed for use in a clinical setting, but infection. Clin Infect Dis 1992; 14 (Suppl 60 is also likely to be suitable for use in an 2): S253–4 8 Foxman B, Frerichs RR. Epidemiology of epidemiological context. 4 Baerheim A, Digranes A, Hunskaar S. urinary tract infection: I. Diaphragm use
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and sexual intercourse. Am J Public Health Salvatore S. A new questionnaire to 21 Kreindler D, Levitt A, Woolridge N, 1985; 75: 1308–13 assess the quality of life of urinary Lumsden CJ. Portable mood mapping: 9 Foxman B, Barlow R, D’Arcy H, Gillespie incontinent women. Br J Obs Gynecol the validity and reliability of analog scale B, Sobel JD. Urinary tract infection: self- 1997; 104: 1374–9 displays for mood assessment via hand- reported incidence and associated costs. 16 Reese PR, Pleil AM, Okano GJ, Kelleher held computer. Psychiatry Res 2003; 120: Ann Epidemiol 2000; 10: 509–15 CJ. Multinational study of reliability and 165–77 10 Reid G, Bruce AW. Urogenital infections validity of the King’s Health Questionnaire 22 Nunnally JC, Bernstein IH. Psychometric in women: can probiotics help? Postgrad in patients with overactive bladder. Qual Theory, 3rd edn. New York: McGraw- Hill Med J 2003; 79: 428–32 Life Res 2003; 12: 427–42 Series in Psychology, 1978 11 Baerheim A, Digranes A, Jureen R, 17 Uemura S, Homma Y. Reliability and 23 Kline P. The Handbook of Psychological Malterud K. Generalised symptoms in validity of King’s Health Questionnaire in Testing. London: Routledge, 1993 adult women with acute uncomplicated patients with symptoms of overactive 24 Riley JL 3rd, Wade JB, Myers CD, lower urinary tract infection: an bladder with urge incontinence in Sheffield D, Papas RK, Price DD. observational study. MedGenMed 2003; Japan. Neurourol Urodyn 2004; 23: Racial/ethnic differences in the 5: http://www.medscape.com/viewarticle/ 94–100 experience of chronic pain. Pain 2002; 457337 18 Guyatt GH, Eagle DJ, Sackett B et al. 100: 291–8 12 Malterud K, Baerheim A. ‘Peeing barbed Measuring quality of life in the frail wire.’ Symptom experiences in women elderly. J Clin Epidemiol 1993; 46: 1433– Correspondence: Diane Wild, Director, Oxford with lower urinary tract infection. Scan J 44 Outcomes Ltd, Old Barn, Jericho Farm, Prim Health Care 1999; 17: 49–53 19 Robinson R, West R. A comparison of Cassington, Oxford OX29 4SZ, UK. 13 Ellis AK, Verma S. Quality of life in computer and questionnaire methods of e-mail: [email protected] women with urinary tract infections: is history-taking in a genito-urinary clinic. benign disease a misnomer? J Am Board Psychol Health 1992; 6: 77–84 Abbreviations: uUTI, uncomplicated urinary Fam Pract 2000; 13: 392–7 20 Peters ML, Sorbi MJ, Kruise DA, tract infection; UTISA, UTI Symptoms 14 Ware JE Jr, Sherbourne CD. The MOS 36- Kerssens JJ, Verhaak PF, Bensing JM. Assessment questionnaire; QoL, quality of item Short-Form Health Survey (SF-36). I. Electronic diary assessment of pain, life; SF-36, Medical Outcome Study Short- Conceptual framework and item selection. disability and psychological adaptation in Form 36 Health Survey ; KHQ, King’s Health Med Care 1992; 30: 473–83 patients differing in duration of pain. Pain questionnaire; GRC, Global Rating of Change; 15 Kelleher CJ, Cardoza LD, Khullar V, 2000; 84: 181–92 MID, Minimally-Important Difference.
© 2005 BJU INTERNATIONAL 359 Original Article UCD TO REDUCE CONTAMINATION RATES IN URINE CULTURES JACKSON et al.
A novel midstream urine-collection device reduces contamination rates in urine cultures amongst women
SIMON R. JACKSON, MATHEW DRYDEN*, PAUL GILLETT†, PADDY KEARNEY‡ and ROSEMARY WEATHERALL¶ Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford, *Department of Microbiology, Royal Hampshire County Hospital, Winchester, †Department of Microbiology, Stoke Mandeville Hospital, Aylesbury, ‡Department of Microbiology, United Hospitals Trust, Antrim, Northern Ireland and ¶Oxford Research Development Support Consortium, Health Services Research Unit, Oxford, UK Accepted for publication 22 March 2005
OBJECTIVE MSU collection and collection with a novel P = 0.005). Those using the UCD preferred it MSU UCD (the Whiz®, JBOL Ltd, Oxford, UK). to the conventional method (67.5%) and To evaluate a novel urine-collection device Semi-quantitative growth and user experienced significantly less spillage during (UCD) that automatically collects a midstream acceptability were compared between the sample collection (27% vs 46%, P = 0.001; urine (MSU) sample, and compare collection methods. relative reduction 41%). contamination rates to those of the conventional MSU sampling method, as the RESULTS CONCLUSION contamination of urine samples for microbiological analysis in women leads to MSU samples collected with the UCD had The UCD reduced contamination rates in urine diagnostic ambiguity and unnecessary costs, significantly fewer mixed growth samples (9% samples and improved the predictive value of and may result in part from an incorrect vs 14%, P = 0.001; 36% relative reduction), the urine culture in a manner acceptable to collection procedure. significantly fewer heavy mixed growth patients and staff. samples (1.2% vs 3.0%, P = 0.004; 60% PATIENTS AND METHODS relative reduction) and required significantly fewer re-tests (11% vs 16%, P = 0.002; 31% KEYWORDS In all, 2823 women from four centres, most relative reduction). There were more samples from antenatal clinics, were randomized to with clinically insignificant growth than the clean-catch, mid-stream, preterm labour, two urine-collection methods: conventional conventional MSU group (86% vs 82%, urine contamination, urine collection
INTRODUCTION of nonpathogenic commensals [2]. urinary stream and with no interruption of Contamination rates as high as 30% have urine flow, consistent with British Standard UTIs and symptoms mimicking UTI are been reported [2]. Such contamination Operating Procedure for urine testing [4]. We common in women. The diagnosis of UTI is obscures interpretation of the urine culture conducted a clinical trial to investigate based on urine sampling and testing with and may mask underlying bacteriuria. The whether the novel UCD reduced reagent sticks and/or laboratory culture, both importance of reducing contamination levels contamination rates when compared with of which require a high-quality specimen free in MSU samples is not limited to possible cost conventional MSU sampling methods, and to of perineal, fecal or vaginal contaminating savings to health services. The threshold for establish patient preference. organisms and inflammatory cells [1]. The treating bacteriuria is lower in some clinical interpretation of the urine culture uses settings, including pregnancy, dialysis and semiquantitative methods, including the those who are immunocompromised, where PATIENTS AND METHODS number of colony-forming units per unit bacteriuria may lead to complications, e.g. volume, the number of species of organism premature labour, or may indicate subclinical The MSU collection devices (Whiz® UCD, JBOL cultured and the identification of species as infections with slow-growing organisms [3]. Ltd, Oxford, UK) were donated by the supplier. likely pathogenic organisms. Urine can be Conventional MSU samples were collected sampled by suprapubic puncture, catheter To standardize the method of collecting a using methods and supplies usually available insertion or midstream urine (MSU) collection. MSU sample, to remove dependence on in the participating centres. Inherent in catheter insertion and MSU patients to produce an adequate specimen, to sampling is possible contamination by simplify the compliance required from Women attending outpatient clinics in four perineal, vaginal, fecal or skin flora. While patients and the need for time-consuming different centres, and who were required to suprapubic aspirate is free of contaminating instruction by clinical staff, a novel urine provide a urine sample for microbiological organisms, the procedure is invasive and collection device (UCD) was developed for analysis, were asked to participate in the trial. limited to a few specific clinical situations. urine sampling in women. The device Most women were recruited from antenatal MSU sampling is the commonest method, but automatically (i.e. independent of user clinics (85%), with a minority from general has a high inherent contamination rate, intervention) collects a MSU sample by practice (15%). The indication for urine defined by mixed-growth cultures and growth excluding the initial low-flow portion of the testing was recorded. Women at each centre
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FIG. 1. Diagrammatic representation of the UCD and instructions for use.
were randomized into two equal test groups to enable a comparative evaluation amongst culture, the results of 641 (315 conventional using serially numbered sealed envelopes. UCD users only between their use of the UCD and 326 UCD samples) were lost to the study Individual samples and the group sample and their previous conventional methods of through labelling errors and sample method were further identified by unique collection. Patients using the UCD were asked processing errors. This loss of laboratory data serial numbers, and thus laboratory staff were to indicate whether they had given a did not introduce a bias towards one or other unaware of the collection method for each conventional urine sample in the past. At the method (chi-square 0.446, one degree of sample when reading the culture plates. end of the trial the acceptability of the UCD to freedom, P = 0.504). clinical staff was assessed by an interview and The practice of collecting conventional MSU questionnaire to the clinical staff involved Microbiological culture results were obtained samples (group 1) was according the usual with the trial. In all, 2823 participants were on 2182 urine specimens; Table 1 shows how procedure of instruction in each particular recruited from four different centres and the laboratory results were interpreted setting, and this varied among the centres. randomized to either conventional MSU clinically, and Table 2 the results of Not all centres advised patients on perimeatal collection (1420) or collection with the UCD semiquantitative culture, the relative cleansing or labial separation for (1403). reduction or increase between the arms of the conventional MSU sample collection. trial and statistical values. In the study as a The results were assessed statistically using whole, 13.3% of samples required a re-test In group 2 (UCD), patients were given the pack Pearson chi-squared tests to compare the (see Table 1 for the criteria). However, samples including the device, and asked to read the percentages, and Mann–Whitney/Wilcoxon collected with the UCD were significantly less instructions provided on the side of the box tests where outcomes were in ordered likely to require re-testing than the (Fig. 1) and give a sample. No cleansing categories. ANOVA or logistic regression conventional MSU samples (UCD 11%, procedures or labial separation were advised. methods were used to investigate potential conventional 16%, P = 0.002; relative confounding factors. reduction 31%). The reason for the test, To determine the patient response to the UCD posture during sampling and the centre at and gauge opinions on the conventional which the sample was taken had no effect on methods, patients were asked to complete a RESULTS the significance of the results shown in questionnaire after giving a sample. Table 2 (Pearson chi-square P = 0.004, 0.364 Questionnaires provided details of age, The age distribution of the subjects was: and 0.916, respectively). posture during urine sampling, reason for the <20 years, 4.3%; 20–35, 72.1%); 36–49, urine test, spillage during sample collection 21.2%; 50–64, 1.7%; ≥65, 0.69%; the mean User acceptability data showed that half the and preference for MSU collection technique. (SD) age was 31 (8.1) years, using midpoints respondents experienced little difficulty in In addition, ease of use of the device and for the age categories, with most patients in collecting the urine sample with either conventional method was scored using a both trial groups aged 20–35 years (72.1%). method (score 1 or 2 from 10 on the numeric scale (1 to 10). The UCD user There was no difference in the age groupings numerical scale). There was no significant questionnaire contained an extra question, of the different arms of the trial (data not difference in ease-of-use scores between the ‘Have you ever given a urine sample before?’ shown). Of the 2823 samples collected for methods of collection (Wilcoxon/Mann–
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TABLE 1 Interpretation of and clinical response for semiquantitative MSU culture
Growth, CFU/mL N different organisms Clinical interpretation Action <10 000 Any number Not significant No further action if asymptomatic 10 000–100 000 1–2 Equivocal growth Retest Possible early infection or contamination 10 000–100 000 >2 Equivocal growth. Probable contamination Retest >100 000 >2 Heavy mixed growth. Frankly contaminated Retest >100 000 1–2 Significant growth indicating UTI Treat if clinically indicated
CFU, colony-forming units.
TABLE 2 Semi-quantitative culture results of 2182 urine specimens randomised to conventional MSU and UCD collection; chi square, P = 0.012
Culture result Total, n (%) Conventional UCD Change, % (95% CI) Relative change, % No significant growth 1829 (83.8) 902 (81.6) 927 (86.7) 4.4 (-1.4 to 7.5) +5.16 Equivocal single species 33 (1.51) 17 (1.54) 16 (1.49) 0.05 (-1.0 to 1.1) -3.25 Equivocal mixed growth 211 (9.67) 122 (11.0) 89 (8.26) 2.78 (0.3 to 5.3) -33.66 Heavy mixed growth 46 (2.11) 33 (2.99) 13 (1.21) 1.78 (0.6 to 3.0) -59.63 UTI 63 (2.89) 31 (2.81) 32 (2.97) 0.16 (-1.6 to 1.2) +5.69 Total 2182 (100) 1105 (100) 1077 (100)
Whitney test, P = 0.1286). Users of the UCD Both groups in all centres, except the GP the peri-meatal area and a small cup for urine had significantly less spillage during surgeries, use dipstick testing, and did this by collection, and users were instructed by staff collection (27% vs 46%, P < 0.001; relative pouring a small portion of the urine sample on how to collect the MSU sample, which reduction 41%); 67.5% of UCD users collected onto the dipstick, rather than included separating the labia and to void into preferred the UCD to the conventional dipping in the sample, and the remaining the toilet, then to stop, then to collect a methods (95% CI 65.0–70.1%). UTIs were urine in the collection bottle was sent to the sample and finish voiding into the toilet. The positively identified in 3.0% of patients in the laboratory. sample collected was then transferred to a UCD group and 2.8% of patients in the universal sample bottle. At Royal Hampshire conventional MSU group, although the The practice of collecting conventional MSU County Hospital group-1 patients were asked difference was not statistically significant samples (group 1) varied among centres; to give an MSU; some of the GP surgeries (P = 0.8; 6% relative increase). All patients in instructions to patients on collection varied. instructed on separating the labia and the the UCD group had, at some time in the past, At United Hospital Trust (Mid Ulster Hospital) need to give an MSU, but others did not. No provided urine specimens using the patients were instructed to catch the middle further instructions were given. conventional MSU method; 62% of patients part of the urine flow but they were not in both groups produced a sample while instructed on cleaning or separating the labia. All centres for group 2 were given the packet seated, 34% while squatting, and 4% while At the John Radcliffe Women’s Centre all containing the Whiz UCD, which contained standing. Use of the UCD did not influence patients in group 1 were given a sterile pack the instructions and device, and no further the posture adopted. containing a gauze and cotton wool to instructions were given. At Stoke Mandeville facilitate cleaning of the peri-meatal area, women were instructed to read the Acceptance of the device by clinical staff was and were instructed by staff on how to collect instructions and make sure the device was assessed through interview, and all 12 a MSU, which included separating the labia held against the perineum, i.e. not used as a interviewed indicated a preference for the and to urinate into the toilet, then to stop, funnel. UCD, citing time-saving and improved then to collect a sample and finish voiding hygiene as the main reasons for their into the toilet. It was reported by staff at the preference. John Radcliffe centre that several of these DISCUSSION peri-meatal cleaning packs were thrown away The indication for MSU testing in all patients unused, nor could staff verify that the The ability of clinicians to accurately diagnose from the hospital antenatal clinics (85% of instructions for giving an MSU, i.e. separating a UTI is impaired by high rates of patients) was ‘routine antenatal screening’. the labia, were carried out while in the privacy contamination, particularly in samples Indications for specimens collected in general of the sample areas. At Stoke Mandeville obtained from women [2], children [5], the practice (15% of patients) were ‘UTI’ in 1% of Hospital, those in group 1 were given a elderly [6] and in general practice [7]. In all patients, ‘other’ in 8%, and ‘routine’ in the specially designed sterilized pack which addition, clinical situations in which low levels remaining 6%. contained cotton wool to facilitate cleaning of bacteriuria may be clinically significant, e.g.
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in antenatal and urogynaecological patients, consequently more samples with no The trial samples were identified to the are complicated by bacterial contamination of significant growth. The lower levels of laboratory database by a unique trial samples. This may lead to a delay in the contamination resulted in fewer re-tests identification number, to ensure that diagnosis of a urinary infection, with required for these patients and improved the laboratory staff were unaware of the sample consequent adverse outcomes for the patient predictive value of the urine culture, i.e. more method. Several samples were excluded (e.g. pre-term labour) and consequent true-negative and fewer false-positive results. because of an administrative error while morbidity, mortality and healthcare costs. Taken together, the quality of urine sampling attaching labels to some of the specimens. was significantly improved. This mislabelling affected both groups equally The reasons for high levels of contamination and was not a source of bias to the primary in women include anatomical factors A urine culture is a frequently requested outcomes of the study. (proximity of urethral meatus to vulva and investigation; the present data suggest that covering by labia [8]) and compliance factors up to 15% of urine cultures collected by In conclusion, we show that the rate of in collecting the sample. Most samples in conventional MSU sampling cannot be contamination of urine specimens can be clinical practice are collected unsupervised, interpreted clinically. This finding is similar to reduced by using an automatic midstream and while careful instruction to patients on that of Valenstein and Meier [11], who found UCD with no need for perimeatal cleansing or technique may be beneficial in reducing that a median 18% of outpatient urine labial separation, and that such a device is contamination, this may be difficult to cultures were contaminated. Furthermore, as more acceptable to patients and staff than achieve in busy clinical environments and sample collection is a fraction of the cost of conventional MSU sampling. Use of this UCD may equally have an undesired negative the administrative, staffing and laboratory should be considered for collecting all MSU effect on contamination rates [9]. Physical costs of the urine culture, we assert that a samples in women, where the specimen is to constraints (e.g. old age, pregnancy) and significant portion of the microbiology be used for bacterial culture. This may be urinary pathology (e.g. stress incontinence) budget for urine culture is consumed by particularly important during pregnancy, may further limit compliance and good samples with little clinical worth. A greater where UTI may result in serious complications, technique. accuracy in diagnosis of urinary symptoms, including premature delivery and its including those that require exclusion of a associated morbidity [12]. Further studies are The collection of a MSU sample requires urinary infection, will positively affect patient needed in other clinical settings in which understanding and implementation by care and is likely to improve outcomes for urine culture poses a diagnostic difficulty or the patient, with little opportunity for patients, and reduce wastage of laboratory leads to additional complications. intervention by clinical staff. It has been and clinical resources. The trend towards found that conventional MSU sampling with detecting many UTIs using the UCD, while not additional cleansing procedures does not statistically significant in the present study of ACKNOWLEDGEMENTS significantly alter culture outcome or levels of asymptomatic patients, suggests further contamination [2,10]. This is attributed at study on different patient groups, e.g. those We thank the clinical staff of the centres least in part to the lack of supervision in who have symptoms suggestive of UTI. involved for their enthusiastic and competent sample collection. For this reason, we participation in the trial and thank all those hypothesized that removing the need for The present data indicate that the UCD is both who read and commented on the manuscript. patient intervention, and standardization of easy to use and more acceptable to the MSU sample collection, might reduce patients providing the samples. Reasons for contamination levels. The UCD used is not this may include the reduction of spillage CONFLICT OF INTEREST simply a funnel, but incorporates a flow- during collection, removal of the need to ‘aim’ sensitive sampling channel and diverter that, or control the urine stream, and improved None declared. Source of funding: R. using urodynamic principles, excludes the hygiene of sample collection. Clinical staff Weatherall was employed by the NHS initial low-flow portion of the urinary stream, supervising the use of the UCD preferred it to at the start of the research so was paid by thus discarding the contaminated early conventional MSU sampling because they JBOL. stream volume, and automatically collects the thought it reduced the time taken to collect midstream volume without interrupting the and process samples. They also considered stream. The British Standard Operating that the UCD improved hygiene for staff, REFERENCES Procedure for MSU testing states that ‘the because it removed the need to transfer the first part of voided urine is discarded and sample from a collection pot to a sample 1 Franz M, Horl WH. Common errors in without interrupting the flow, approximately container. diagnosis and management of urinary 10 mL is collected into a sterile container’ [4]. tract infection. I. pathophysiology and The new device is also used with no need for This study was limited to women diagnostic techniques. Nephrol Dial cleansing or separating the labia. predominantly aged 20–35 years. Further Transplant 1999; 14: 2746–53 studies are required to establish the possible 2 Lifshitz E, Kramer L. Outpatient urine The present data show that urine samples benefit of the UCD in other populations, culture: does collection technique matter? collected with the UCD had significantly lower particularly men, children and the elderly, or Arch Intern Med 2000; 160: 2537–40 contamination levels than conventional MSU where there are high rates of sample 3 Kunin CM, White LV, Hua TH. A samples. Use of the UCD resulted in a contamination and possibly lower rates of reassessment of the importance of reduction in mixed-growth samples and proper compliance with the MSU technique. ‘lowcount’ bacteriuria in young women
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with acute urinary symptoms. Ann Intern prospective cohort study. Fam Pract 2003; Pathologists Q-Probes study of Med 1993; 119: 454–60 20: 1–6 contaminated urine cultures in 906 4 Health Protection Agency. National 8 Baerheim A, Laerum E. Home-voided institutions. Arch Pathol Lab Med 1998; Standard Method. Investigation of Urine. urine specimens in women. Diagnostic 122: 123–9 In: Bsop41i4; 2003 agreement with clean-catch midstream 12 Spinillo A, Capuzzo E, Stronati M, 5 Schlager TA, Hendley JO, Dudley SM, specimens. Scand J Prim Health Care Ometto A, De Santolo A, Acciano S. Hayden GF, Lohr JA. Explanation for 1990; 8: 207–11 Obstetric risk factors for periventricular false-positive urine cultures obtained by 9 Lipsky BA, Inui TS. ‘The best laid plans’. leukomalacia among preterm infants. Br J bag technique. Arch Pediatr Adolesc Med An evaluation of a patient education Obstet Gynaecol 1998; 105: 865–71 1995; 149: 170–3 program. Med Care 1983; 21: 655–60 6 McMurdo ME, Gillespie ND. Urinary 10 Prandoni D, Boone MH, Larson E, Correspondence: Simon Jackson, Department tract infection in old age. Overdiagnosed Blane CG, Fitzpatrick H. Assessment of of Obstetrics and Gynaecology, John Radcliffe and over-treated. Age Ageing 2000; 29: urine collection technique for microbial Hospital, Oxford, UK. 297–8 culture. Am J Infect Control 1996; 24: e-mail: [email protected] 7 Fahey T, Webb E, Montgomery AA, 219–21 Heyderman RS. Clinical management of 11 Valenstein P, Meier F. Urine culture Abbreviations: MSU, midstream urine; UCD, urinary tract infection in women: a contamination. A College of American urine-collection device.
364 © 2005 BJU INTERNATIONAL Original Article URINARY DIARY VARIABLES IN WOMEN WITH OAB AND CONTROLS FITZGERALD et al.
How do urinary diaries of women with an overactive bladder differ from those of asymptomatic controls?
MARY P. FITZGERALD, DEBORAH AYUSTE and LINDA BRUBAKER Division of Female Pelvic Medicine and Reconstructive Surgery, Loyola University Medical Center, Maywood, IL, USA Accepted for publication 30 March 2005
OBJECTIVE RESULTS CONCLUSIONS
To quantify clinically important differences The 49 patients with OAB symptoms had This preliminary study suggests that a median in common diary variables between a median (range) age of 51 (20–85) years, reduction of three voids/24 h and an increase asymptomatic controls and women with a body mass index of 25 (17–46) kg/m2 of 70 mL in the mean voided volume might be symptoms of overactive bladder (OAB), and a parity of 2 (0–5). The median clinically important goals in therapeutic trials controlling for the effects of age and race. number of voids was significantly greater for treating OAB symptoms. This remains in women with OAB than asymptomatic to be confirmed by further studies linking controls (P < 0.001). The median value for improvements in quality of life and the overall PATIENTS, SUBJECTS AND METHODS mean voided volume was significantly impression of bladder health with these lower in women with OAB than quantitative diary variable changes. The 24-h urinary diaries of 49 women with asymptomatic controls (P = 0.014). There symptoms of OAB were compared to those of was no difference in the maximum voided KEYWORDS age- and race-matched asymptomatic volume, total voided volume, daytime or controls. Control subjects did not have a night-time diuresis rates, voids per litre urinary frequency, lower urinary tract, physical examination. intake, or total fluid intake. overactive bladder syndrome.
INTRODUCTION PATIENTS, SUBJECTS AND METHODS RESULTS
Treatments for overactive bladder (OAB) After Institutional Review Board approval, We collected complete 24-h diaries from 49 symptoms of urgency, frequency and/or 24-h urinary diaries were collected from women who presented to the centre with urge incontinence should restore normal consecutive women presenting to the Female symptoms of OAB, as determined by patient urinary tract function. As few studies Pelvic Medicine Center at Loyola University interview; these patients were age- and race- have documented the urinary habits of Medical Center as new patients with OAB matched to women from a contemporaneous asymptomatic women, there is little symptoms (urinary urgency, frequency and/or sample of 300 asymptomatic women. The 49 published information comparing normal urge incontinence). These diaries were patients had a median (range) age of 50 voiding habits to those of women with LUTS compared with the diaries of 300 age- (within (39–61) years, a body mass index of 25 [1,2], and therefore there are almost no data 5 years) and race-matched asymptomatic (23–30) kg/m2, and a parity of 2 (0–5). available on the likely magnitude of the women that were collected at the same time, Twenty-four women (49%) were treatment effect needed to restore normality. and which were reported previously [3]. premenopausal, 32 (65%) had concurrent This lack of information can impede clinical Patients with OAB symptoms completed a symptoms of stress urinary incontinence, and decision-making and the design of research single 24-h diary before their first clinic visit, 14 (33%) had concurrent symptoms of pelvic trials. and the presence of OAB symptoms was organ prolapse. The physical examination determined by patient interview. Control determined that there were pelvic organ In a previous study of the urinary diaries subjects did not have a physical examination. support defects to the hymen or beyond in 19 of 300 asymptomatic women [3] we Diary variables included daytime and night- patients with OAB symptoms (45%). The racial found that urinary diary variables, e.g. time urinary frequency, total urinary composition of the sample was 82% 24-h frequency and mean voided frequency, total intake and voided volumes Caucasian, 12% African-American and 6% volume, depended on the subject’s age (maximum and mean), and daytime and Hispanic. and race. The aim of the present study night-time diuresis rates were calculated. was to quantify clinically important Urinary diary definitions are detailed in Patients with OAB and controls had similar differences in diary variables between Table 1. Diary values were compared parity and body mass index. Results of the asymptomatic controls and women with between groups using nonparametric sign comparison of diary data are detailed in symptoms of OAB, controlling for the effects tests, with differences considered significant Table 2. As expected, the median number of of age and race. at P < 0.05. voids was significantly greater in women with
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OAB than asymptomatic controls (P < 0.001), TABLE 1 Diary formulae and the median value for mean voided volume was significantly lower in women Variable Formula with OAB than in controls (P = 0.045). There Daytime urine output Sum of total urine volume after the first morning void, through to the last was no difference in maximum voided void before retiring. volume, total voided volume, daytime or Daytime diuresis rate Daytime urine volume divided by the total number of minutes between the night-time diuresis rates, voids per litre first void of the day, and the last void before retiring. intake, or total fluid intake. Night-time urine output Sum of total urine volume voided during the night (after retiring with the intention of sleeping) plus the first void of the next morning. DISCUSSION Night-time diuresis rate Night-time urine volume divided by the number of minutes between the last void before retiring and the first void of the following morning The only published studies we are aware of that directly compare the diaries of symptomatic subjects with asymptomatic controls are those of Larsson et al. [4], who compared the diaries of 62 women with urge TABLE 2 Diary variable values in age- and race-matched women (49 in each group) with and without incontinence to those of 151 healthy controls, symptoms of OAB. Values are the median (range), with the sign test result (P) and found that women with urge incontinence had greater urinary frequency, Variable Patients with OAB Asymptomatic controls P smaller mean voided volumes and smaller Frequency of micturition/24 h, n 11 (9–16) 7 (4.5–9) <0.001 maximum voided volumes than controls, as Number of daytime voids, n 10 (8–13) 6.5 (4.5–8) 0.003 detailed in Table 3; the racial composition of Number of night-time voids, n 1 (0–3) 0.5 (0–1) 0.045 the study participants was not stated, but is Total voided volume, mL 1950 (1365–2760) 1218 (827–2499) 0.8 presumed to be predominantly Caucasian. Mean voided volume, mL 171 (145–205) 200 (171–266) 0.014 Maximum voided volume, mL 360 (300–480) 390 (357–560) 0.2 There are some striking similarities between Total fluid intake/24 h, mL 2040 (1470–2610) 1725 (979–3147) 0.7 the present results and those of Larsson et al. Daytime diuresis rate, mL/min 1.4 (1–2.1) 0.8 (0.4–1.7) 0.5 [4] of women with detrusor instability; the Night-time diuresis rate, mL/min 1 (0.7–1.4) 0.4 (0.3–1.6) 0.8 values for mean and maximum voided Voids per litre intake, n 5.6 (4.4–7.8) 4 (3.2–4.6) 0.3 volumes are essentially identical in the two studies, and the greater urinary frequency recorded in the present study is partly explicable by the greater total voided volumes recorded by the present subjects. It is likely TABLE 3 Comparison of results from present study and those by Larsson et al. [4] comparing urinary that the fluid intake was higher in the present habits of asymptomatic women to those with detrusor instability. Values represent medians sample, but this factor was not recorded in the report by Larsson et al. [4]. Present study: [4]: women with detrusor Variable women with OAB instability Published studies of the urinary habits of Total voided volume, mL 1890 1490 ‘normal’ adults [1,5–7] suggest that ‘normal’ Total voids/24 h, n 9.5 11 habits might depend on race, culture and/or Mean voided volume, mL 172 170 geography. In most areas of medicine it is Maximum voided volume, mL 330 360 appropriate to establish normative values before interpreting abnormal values. It seems appropriate to do this when interpreting urinary diary variables, to allow researchers to of this difference is understudied. The present recorded well in a urinary diary, reflect only recognise clinically important changes in preliminary study suggests that a median part of the clinical picture, e.g. urinary urinary function. Although quantifying reduction of three voids/24 h and an increase urgency might be far more troublesome to change is irresistible for researchers, the of 70 mL in mean voided volume might be patients with OAB than urinary frequency per change for the patient in terms of her life clinically important goals, apparently se, but it is not reflected in simple urinary impact, treatment goals, treatment distinguishing normal voiding patterns diaries. satisfaction and overall quality of life cannot from those clinically diagnosed with OAB. be replaced with arbitrary numerical Further research is needed to study the The present study is limited because we used thresholds. relationship between these quantitative a simple 1-day diary rather than a longer diary improvements and the quality-of-life record of urinary habits. However, we have The urinary diary is an excellent clinical and improvement and overall impression of found such 1-day records to be clinically research tool in women with OAB. Although bladder health. Clinicians are acutely aware useful, and a study by van Melick et al. [8] certain diary variables are known to be that lower urinary tract attributes such as suggested little difference in the value of different in patients with OAB, the magnitude bladder volume and urinary frequency, while voiding diary variables when a 1-day diary
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was compared to dairies of 2 or 3 days’ Yang Q, Abrams P. Female urinary reference values and analysing variables. duration in patients with motor urge symptoms; age prevalence in a BJU Int 2004; 93: 1257–61 incontinence. We were also limited by the community dwelling population using a 7 Mueller E, Latini J, Lux M et al. Gender relatively few matched pairs, but a strength of validated questionnaire. Neurourol differences in 24-hour urinary diaries of the present study is that we were able to Urodynam 1997; 16: 432–4 asymptomatic North American adults. control for race and age using this paired 3 Fitzgerald MP, Stablein U, Brubaker L. J Urol 2005; 173: 490–2 analysis. Urinary habits among asymptomatic 8 van Melick HH, Gisolf KW, Eckhardt women. Am J Obstet Gynecol 2002; 187: MD, van Venrooij GE, Boon TA. One 1384–8 24-hour frequency-volume chart in a CONFLICT OF INTEREST 4 Larsson G, Abrams P, Victor A. The woman with objective urinary motor urge frequency/volume chart in detrusor incontinence is sufficient. Urology 2001; None declared. instability. Neurourol Urodynam 1991; 10: 58: 188–92 533–43 5 Latini JM, Mueller E, Lux MM, Correspondence: Mary FitzGerald, Division of REFERENCES Fitzgerald MP, Kreder KJ. Voiding Female Pelvic Medicine and Reconstructive frequency in a sample of asymptomatic Surgery, Loyola University Medical Center, 1 Larsson G, Victor A. Micturition patterns American men. J Urol 2004; 172: 980–4 2160 South First Avenue, Bldg 103, Room in a healthy female population, studied 6 van Haarst EP, Heldeweg EA, Newling 1004, Maywood, IL 60153, USA. with a frequency/volume chart. Scand J DW, Schlatmann TJ. The 24-h e-mail: mfi[email protected] Urol Nephrol Suppl 1988; 114: 53–7 frequency-volume chart in adults 2 Swithinbank LV, Donovan J, James MC, reporting no voiding complaints: defining Abbreviations: OAB, overactive bladder.
© 2005 BJU INTERNATIONAL 367 Original Article TUR SYNDROME AND IRRIGANTS FOR TURP COLLINS et al.
A comparison of the effect of 1.5% glycine and 5% glucose irrigants on plasma serum physiology and the incidence of transurethral resection syndrome during prostate resection
JUSTIN W. COLLINS, SEAMUS MacDERMOTT*, RICHARD A. BRADBROOK*, FRANCIS X. KEELEY Jr and ANTHONY G. TIMONEY Bristol Urological Institute, Southmead Hospital, Bristol, *Torbay Hospital, Torquay, UK Accepted for publication 11 April 2005
OBJECTIVE ethanol measurements. Operative details were difference between the groups in levels of recorded, including the type of anaesthesia sodium, potassium, urea, creatinine, To examine changes in the pathophysiology (with or with no sedation), resection time and osmolality, calcium, haematocrit, albumin and frequency of the transurethral resection weight of resected tissue. Peri-operative serum levels or peri-operative blood loss (TUR) syndrome with two irrigation fluids, as symptoms were documented prospectively. (defined as a change from before to after variable amounts of irrigation fluid are TUR syndrome was defined as a serum sodium TURP in haemoglobin level, accounting for absorbed during TUR of the prostate (TURP), level of £125 mmol/L with two or more transfusions). and although polar solutes are required to associated symptoms or signs of TUR prevent an effect on diathermy, the solutes syndrome. CONCLUSIONS may have effects when absorbed. RESULTS An increase in serum glycine was associated PATIENTS AND METHODS with TUR syndrome; there were large Five (2%) patients had TUR syndrome; all five variations in the amounts of glycine absorbed, Between December 2001 and March 2003, were irrigated with glycine, although this reaching levels many times the upper limit 250 patients were included in a prospective difference was not statistically significant of normal. In other studies, glycine was randomized trial comparing glycine 1.5% with (P = 0.06). Of the five men, three had reportedly toxic, and that the levels recorded 5% glucose irrigation fluids. We measured hypotension, four were tired, one was were many times the upper limit of normal blood loss, fluid absorption, temperature nauseous, two had parasthesia, two had may have both immediate and long-term change, biochemistry including a glycine ‘uneasiness’, one had blurred vision and two effects. assay, and peri-operative symptoms. Blood were confused; none had chest pain. There samples were taken immediately before and was a large variation between the groups in KEYWORDS immediately, 5 and 24 h after TURP. Irrigating the level of glycine assayed immediately after fluid absorption during TURP was measured TURP; a high glycine level was associated with glycine toxicity, osmolar concentration, TURP, with 1% ethanol as a marker and breath the TUR syndrome (P = 0.01). There was no irrigation fluid, TUR syndrome, adverse events
INTRODUCTION used glycine at 1.1% and 2.1% to prevent the irrigant of choice, and their clinical experience haemolysis that occurred when sterile water lead them to think that 5% glucose solution is Since the introduction of TURP by McCarthy was used as an irrigant. TURP has several not toxic and is entirely satisfactory as an in 1926, the problem of which irrigation fluid recognized complications; one of the more irrigating fluid for use during endoscopic to use during the procedure has caused wide- serious and potentially fatal is the TUR surgery [10]. These urologists have apparently ranging debate, up to and including the syndrome. not been aware of problems with stickiness of present. For standard TURP the criteria for an the instruments or caramelization of the ideal irrigant are: it must irrigate the surgical Estimates of the incidence of TUR syndrome cutting loop diathermy during surgery, and field; not be an electrical conductor and not range from 0% [2], 1% [3], 2% [4], 7% [5] to consider 5% glucose to appear optically affect diathermy; have good visual acuity and 10% [6–8], but it is currently poorly defined identical to 1.5% glycine. be ‘user-friendly’; have similar osmolality to and many mild cases can be falsely attributed serum; minimal side-effects when absorbed; to old age, anaesthetic complications and and can be detectable by the surgeon when excessive blood loss. The symptoms arising PATIENTS AND METHODS excess volume is absorbed. might also differ depending on the choice of irrigating fluid [9]. Between December 2001 and March 2003, Glycine solution is the most commonly used 250 patients undergoing TURP in two irrigant and has been used in TURP for For over 20 years, urologists in one district hospitals (Southmead and Torbay) were >50 years. In 1948, Nesbitt and Glickman [1] general hospital used only 5% glucose as their recruited to a prospective randomized trial,
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FIG. 1. A plot of the sodium level the day after TURP against that before TURP in 244 patients, for 120 patients after TURP for the two treatment groups, irrigated with glucose (1) or 124 with glycine (2), with regression lines shown for both plots. adjusting for baseline (before TURP) values. Interactions between treatment group and 146 baseline values were examined and retained if significant at the 5% level. If the baseline 144 1 1 values did not influence the next-day values, 142 1 1 1 1 2 1 either a two-sample t-test or a Wilcoxon test 2 1 12 12 12 was used to assess the next-day values as 140 1122 21 1 1 12 2 12 21 21122212 21 2 appropriate. Model assumptions were also
, mmol/L 138 22212212 21 2211 21 2 1 assessed graphically. 1 12112121 12 12 12 12 12 1 1 136 2 2 222212 12 11112 21122 2 2112 2111 21 12 12 2 1 2 1 134 2 1 12 2 1 12 1 1 1 RESULTS 1 2 2 2 21 1 2 2 2 1 2 1 2 Next day sodium 132 In all, 124 patients were randomized to 2 1 2 1 2 130 1 1 2 1 receive 5% glucose and 126 to receive 1.5% 2 glycine; the mean (SD, range) age of the 128 2 1 1 1 patients was 74.3 (8.9, 48–96) years. There 2 was no significant difference between the 126 groups in sodium levels (Fig. 1) or for the 128 130 132 134 136 138 140 142 144 146 changes in potassium, urea, creatinine, Preoperative sodium, mmol/L osmolality, calcium, haemoglobin or haematocrit.
Five of the 233 patients for whom the TUR [12]; the total irrigation fluid absorbed by syndrome status could be determined had TABLE 1 TUR syndrome by treatment group and each patient was recorded. The duration of TUR syndrome (2.1%, 95% CI 0.7–5.0; the glycine level after TURP TURP, weight of resected tissue, volume of Table 1). Of the five patients who had TUR irrigant used and evidence of prostatic syndrome, one had bradycardia, three had TUR syndrome? capsule perforation were recorded. Blood hypotension, four were drowsy, one was Treatment No Yes Total transfusions were recorded and a standard nauseous, two had prickling, two experienced Glucose 115 0 115 protocol was for two 8-hourly bags of normal uneasiness, one had blurred vision and two Glycine 113 5 118 saline to be prescribed; no patient received i.v. were confused; none had chest pain. Total 228 5 233 dextrose or dextrose saline after undergoing Although all five patients with TUR syndrome Glycine after TURP, mmol/L TURP. were in the glycine group and none of the <400 138 0 138 patients in the glucose group developed TUR ≥400 88 5 93 After TURP, in recovery, blood samples were syndrome, this difference did not reach Total 226 5 231 taken to measure haemoglobin, haematocrit, statistical significance (Fisher’s exact test, sodium, potassium, urea, creatinine, glucose, P = 0.06, n = 233). osmolality, calcium and glycine. Glycine was analysed using anion-exchange All five patients with TUR syndrome (Table 1) chromatography with ninhydrin detection on had glycine levels above the normal range and randomly allocated to either irrigation an amino-acid analyser. Blood samples were (150–399 mmol/L), at a mean (range) of during TURP with glycine 1.5% or 5% glucose. rechecked at 5 and 24 h after TURP, and all 28 915 (16 686–36 800) mmol/L, a fluid All patients gave fully informed consent and results compared with values before TURP. absorption of 3.6 (2.6–4.1) L, and a resection were assessed with immediate preoperative time of 47.6 (35–58) min; four had prostate blood analysis and electrocardiograms [11]. The TUR syndrome was defined as a sodium capsule perforation noted during TURP. In the level after TURP of £125 mmol/L [4], with two glycine group overall, there was significant Only patients with spinal anaesthesia were or more symptoms or signs of TUR syndrome. variation in the glycine assay results, with included in the analysis and their operative Symptoms or signs attributed to TUR some values many times the upper limit of details recorded. The protocol requested that syndrome were nausea, vomiting, normal. sedation was not used, but if sedation was bradycardia, hypotension, hypertension, chest required then lethargy was not included as a pain, mental confusion, anxiety, parasthesia, There was evidence of an association between symptom of TUR syndrome. The irrigant and visual disturbances. Any symptoms or TUR syndrome and raised glycine levels at the selected was unknown to both the surgeon signs of TUR syndrome noted during TURP end of TURP (Fisher’s exact test, P = 0.01, 231 and anaesthetist, as the irrigants were put were also recorded. men). Patients with TUR syndrome were more into unmarked bags. The amount of irrigant likely to have a glycine level outside the absorbed was measured by breath ethanol Analysis of covariance was used to test for normal range than those who did not levels on an alcolmeter, using a nomogram differences between the blood values the day have TUR syndrome; the median level of
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glycine in the glucose, glycine, TUR syndrome 145 FIG. 2. group and non-TUR syndrome group groups A plot of the sodium and glycine 140 was (mmol/L) 241, 791, 29 665 and 317, levels at the end of TURP for 231 respectively. 135 patients; values from those men 130 with TUR syndrome are shown as In the glycine group there was no evidence to crosses. 125 suggest an association between glycine levels and osmolarity at the end of TURP 120 (Spearman’s rank correlation coefficient, 0.05, 115 119 men), but the sodium levels tended to
Sodium at end of operation, mmol/L 110 decrease with increasing glycine levels 0 5 10 15 20 25 30 35 40 (Spearman’s rank correlation coefficient Glycine at end of operation, mmol/L -0.57).
There were 124 patients in the glucose group, the venous sinuses were opened, meaning TABLE 2 Serum glucose values after TURP in the of whom 13 were diabetic; they were that most of the fluid was in the periprostatic glucose group (124 patients) managed peri-operatively with a standard area. Currently surgeons are more aware of protocol for diabetic patients, receiving i.v. the dangers of irrigant absorption and most Median (interquartile insulin infusion. Immediately after TURP in would attempt to limit the duration of TURP; Glucose, mmol/L range, range) [number] these 13 patients the median (interquartile however TUR syndrome still occurs. Immediately 6.1 (5.2–9.9, 4.2–40) [121] range, range) glucose level was 8.1 (5.6–10.3, after TURP 5.6–23.9) mmol/L, but by the second blood Several irrigant solutions are available, 5 h after TURP 6.5 (5.7–7.9, 3.8–15.8 [113] sample at 5 h after TURP all patients were including sorbitol-mannitol and glycine; the within the normal range. former is used in Europe but glycine is most common in the UK and North America. There None of the patients in the glucose group is now increasing evidence highlighting the this has also been associated with developed TUR syndrome, although one had a toxicity of 1.5% glycine solution when hyperammonaemia [12]. serum sodium value of <125 mmol/L after absorbed during TURP [14]. Glycine is an TURP (Fig. 2) but did not fulfil the criteria for amino acid present in humans at <400 mmol/ Alternatively, a direct toxic effect of glycine TUR syndrome, as he had no symptoms or L; at higher concentrations research has may be part of the mechanism of the cerebral signs of TUR syndrome. This patient, shown it has direct and indirect cardiotoxic side-effects of glycine absorption [24]. according to the breath ethanol nomogram effects in animal studies [15,16], and Glycine is an inhibitory neurotransmitter, and [7], had absorbed just under 3 L of 5% glucose pathophysiological action in stimulating, the visual disturbances in TUR syndrome are irrigation, and the glucose and sodium levels amongst other things, the release of atrial not the same as those expected in cortical immediately after TURP were 40 and natriuretic peptide, thereby enhancing oedema. The condition can proceed to 119 mmol/L, respectively; 5 h later the sodium loss and contributing to transient blindness and is sometimes the only respective levels had returned to normal, at hyponatraemia, which is part of the TUR sign of fluid absorption [25]. Light perception 5.9 and 135 mmol/L; Table 2 gives values for syndrome [17]. The amount of glycine is usually lost in cortical oedema, but not in all patients in the glucose group. absorbed seems to have an independent TUR syndrome [26]. Fundoscopy is normal contribution to cerebral effects in volunteers [25] and measurement of intraocular pressure DISCUSSION [18] and to mortality in mice [19]. is also unchanged in TUR syndrome, which would indicate that visual changes are not Endoscopic surgery of the genitourinary tract The metabolism of glycine gives rise to due to cerebral oedema secondary to requires the use of an irrigating fluid. The glycolic acid and ammonia, and high levels of hyponatraemia [27]. However, there is little absorption of some irrigant occurs during blood ammonia have also been suggested as a doubt that the hyponatraemia resulting from almost every TURP [12]. Volumes of irrigation possible cause of TUR syndrome [12]. Previous a dilutional effect of all irrigating fluids fluid absorbed can be difficult to predict, studies showed a correlation between eventually causes neurological symptoms although the volume tends to be greater in symptoms and hyperammonaemia after related to cerebral oedema. Istre et al. [28] extended and bloody operations [13]. In the infusion of glycine 2.2% [18] and TURP detected cerebral oedema by CT that 1950s, several studies were undertaken to [20]. correlated with nausea after the absorption of determine the amount of fluid absorbed as little as 1 L of glycine 1.5% in females during TURP. Hagstrom (1955) weighed Nausea, vomiting and confusion occur six to undergoing transcervical resection of patients before and after TURP, and calculated nine times more often when 1–2 L of glycine endometrium. Restlessness and epileptic that ª20 mL/min of fluid was absorbed by the solution is absorbed than when no absorption seizures are signs of massive absorption; they patient. However, there appeared to be a wide is detected [21]. Most patients with a are most likely caused by hyponatraemia, as variation among patients; Oester and Madsen, transient deterioration in mental status these symptoms have been associated with using a double-isotope technique, showed in after TURP have absorbed irrigant [22]. various irrigants, e.g. glycine [6], sorbitol 3% 1969 that the mean was ª1 L, and that a third Consciousness appears to be lowered when [29], sorbitol-mannitol [30] and sterile water of the fluid was absorbed intravenously, when even more glycine is absorbed [22,23], and [31].
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However, the hyponatraemia associated with diathermy [32–35]. This relatively new resection reaction. J Urol 1956; 75: 95– TUR syndrome is not simple dilutional development allows TURP using a familiar 110 hyponatraemia; there is a loss of sodium technique. Like 5% glucose, normal saline is a 7 Hahn RG. Early detection of the TUR during the osmotic diuresis associated with more physiological solution that can be given syndrome by marking the irrigating fluid irrigant absorption, therefore the urinary intravenously and with minimal known side- with 1% ethanol. Acta Anaesthesiol Scand excretion of sodium represents an absolute effects. However, there are as yet no large 1989; 33: 146–51 loss, as the irrigant contains no electrolytes scale randomized studies comparing the 8 Ghanem AN, Ward JP. Osmotic and [9]. Also, large amounts of glycine have been clinical effectiveness and cost-effectiveness metabolic sequelae of volumetric shown to increase the release of atrial of this technique compared to standard TURP; overload in relation to the TUR syndrome. natriuretic peptide in excess of that expected such studies are urgently needed. Br J Urol 1990; 66: 71–8 from the volume absorbed, which will further 9 Hahn RG. Irrigating fluids in endoscopic promote natriuresis [17]. This supports our In conclusion, hyponatraemia and the toxicity surgery. Br J Urol 1997; 79: 669–80 findings that an increase in glycine level is not of glycine and/or its metabolites explain the 10 Kirollos MMK, Campbell N. Factors associated with a change in osmolality caused clinical symptoms of TUR syndrome. Although influencing blood loss in transurethral by a simple dilutional effect, but still results in endoscopic procedures on the genitourinary resection of the prostate (TURP). Auditing a lower sodium level. system are currently limited to using TURP. Br J Urol 1997; 80: 111–5 irrigation fluids, the choice of irrigant is not 11 Hahn RG, Essen P. ECG and cardiac Serum osmolality usually remains normal or limited. We recommend that surgeons should enzymes after glycine absorption in decreases by £10 mosmol/kg when fluid is consider the use of alternative irrigants to transurethral prostatic resection. Acta absorbed. However, the change in osmolality glycine or alternative surgical techniques that Anaesthesiol Scand 1994; 34: 550–6 correctly indicates tissue oedema only when allow crystalloids such as normal saline to be 12 Hoeksta PT, Kahnoski R, McCamish MA, mannitol is absorbed. As glycine and glucose used as an irrigant. Bergen W, Heetderks DR. Transurethral enter the cells they will be accompanied by prostatic resection syndrome – A new water through osmosis, even when serum perspective: Encephalopathy with osmolality is normal. Tissue oedema will CONFLICT OF INTEREST associated hyperammonemia. J Urol 1983; therefore be greater than indicated by the 130: 704–7 serum osmolality. Thus, the terminology None declared. Source of funding: Southmead 13 Hahn RG, Ekengren J. Patterns of ‘isotonic hyponatraemia’ is not useful when Hospital Research Fund, Torbay Hospital irrigating fluid absorption during glycine or glucose is used. It is particularly Research Fund. transurethral resection of the prostate as irrelevant when ethanol is used to indicate indicated by ethanol. J Urol 1993; 149: fluid absorption, as this agent increases the 502–6 osmolality without redistributing water [9]. REFERENCES 14 Zhang W, Andersson BS, Hahn RG. Effect of irrigating fluids and A solution of 5% glucose is a standard 1 Nesbit RM, Glickman SI. The use of prostate tissue extracts on isolated crystalloid; because glucose is metabolized glycine solution as an irrigating medium cardiomyocytes. Urology 1995;46: throughout the body it requires 13 L to be during transurethral resection. J Urol 821–4 given/absorbed intravenously to expand the 1948; 59: 1212–6 15 Talman WT, Robertson SC, Cassell MD. intravascular compartment by 1 L. Normal 2 Goel CM, Badenoch DF, Fowler CG, Mechanisms of cardiovascular responses serum osmolality is ª290 mosmol/kg. The Blandy JP, Tiptaft RC. Transurethral to glycine injected into the dorsal vagal osmolality of 5% glucose is 285 mosmol/kg, resection syndrome. A prospective study. motor nucleus in the rat. Hypertension as opposed to the osmolality of 1.5% glycine, Eur Urol 1992; 21: 15–7 1992; 19: 187–92 which is 190 mosmol/kg. This higher 3 Weis N, Jorgensen PE, Bruun E. ‘TUR 16 Madorin WS, Calaresu FR. osmolality provided by 5% glucose solution syndrome’ after transurethral resection of Cardiovascular changes elicited by may be beneficial in reducing the possible the prostate using suprapubic drainage. microinjection of glycine or GABA into the side-effects of cerebral oedema, which can Int Urol Nephrol 1987; 19: 165–9 spinal intermediolateral nucleus in occur after inadvertent absorption of 4 Mebust WK, Holtgrewe HL, Cocked AT, urethane-anaesthetised rats. Brain Res irrigating fluids. Peters PC. Transurethral prostatectomy: 1994; 634: 13–9 immediate and postoperative 17 Hahn R, Stalberg H, Carlstrom K, In the present study, for glucose control, there complications. A cooperative study of Hjelmqvist H, Ullman J, Rundgn M. seemed to be no adverse effect of absorbing 13 participating institutions evaluating Plasma atrial natriuretic peptide large quantities of glucose. The largest 3,885 patients. J Urol 1989; 141: 243– concentration and renin activity during values were immediately after TURP (range 7 overhydration with 1.5% glycine solution 4.2–40 mmol/L), even in the patient whose 5 Rhymer JC, Bell TJ, Perry KC, Ward JP. in conscious sheep. Prostate 1994; 24: glucose level was 40 mmol/L after absorbing Hyponatraemia following transurethral 55–61 2.8 L of irrigant, who had a normal level of 5.9 resection of the prostate. Br J Urol 1985; 18 Hahn RG, Stalberg HP, Gustafsson SA. at 5 h and 6.3 mmol/L at 24 h after TURP. 57: 450–2 Intravenous infusion of irrigating fluids 6 Harrison RH, Boren JS, Robison JR. containing glycine or mannitol with Another potentially safer alternative to Dilutional hyponatraemic shock: another and without ethanol. J Urol 1989; 142: glycine irrigation is normal saline with bipolar concept of the transurethral prostatic 1102–5
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19 Zhang W, Hahn RG. ‘Double toxicity’ of 26 Ovassapian A, Joshi CW, Brinner EA. transurethral prostatectomy using glycine solution in the mouse. Br J Urol Visual disturbances: An unusual symptom distilled water as an irrigating medium. 1996; 77: 203–6 of transurethral prostatic resection J Urol 1966; 95: 396–406 20 Shepard RL, Kraus SE, Babayan RK, reaction. Anaesthesiology 1982; 57: 332– 32 Starkman JS, Santucci RA. Comparison Siroky MB. The role of ammonia toxicity 4 of bipolar transurethral resection of the in the post transurethral prostatectomy 27 Peters KR, Muir J, Wingard DW. prostate with standard transurethral syndrome. Br J Urol 1987; 60: 349–51 Intraocular pressure after transurethral prostatectomy: shorter stay, earlier 21 Olsson J, Nilsson A, Hahn RG. prostatic surgery. Anaesthesiology 1981; catheter removal and fewer Symptoms of the transurethral resection 55: 327–9 complications. BJU Int 2005; 95: 69–71 syndrome using glycine as the irrigant. 28 Istre O, Bjoennes J, Naess R, Hornbaek 33 Eaton AC, Francis RN. The provision of J Urol 1995; 154: 123–8 K, Forman A. Postoperative cerebral transurethral prostatectomy on a day- 22 Nilsson A, Hahn RG. Mental status after oedema after transcervical endometrial case basis using bipolar plasma kinetic transurethral resection of the prostate. resection and uterine irrigation with 1.5% technology. BJU Int 2002; 89: 534–7 Eur Urol 1994; 26: 1–5 glycine. Lancet 1994; 344: 1187–9 34 Issa MM, Young MR, Bullock AR, Bouet 23 Henderson DJ, Middleton RG. Coma 29 Baba T, Shibata Y, Ogata K et al. Isotonic R, Petros JA. Dilutional hyponatremia of from hyponatraemia following hyponatremia and cerebrospinal fluid TURP syndrome: a historical event in the transurethral resection of the prostate. sodium during and after transurethral 21st century. Urology 2004; 64: 298–301 Urology 1980; 15: 267–71 resection of the prostate. J Anesth 1995; 35 Botto H, Lebret T, Barre P, Orsoni 24 Roesch RP, Stoelting RK, Lingeman JE, 9: 135–41 JL, Herve JM, Lugagne PM. Kahnoski RJ, Backes DJ, Gephardt SA. 30 Akan H, Sargin S, Turkseven F, Electrovaporization of the prostate with Ammonia toxicity resulting from glycine Yazicioglu A, Cetin S. Comparison of the Gyrus device. J Endourol 2001; 15: absorption during a transurethral three different irrigation fluids used in 313–6 resection of the prostate. Anaesthesiology transurethral prostatectomy based on 1983; 58: 577–9 plasma Volume expansion and metabolic Correspondence: Justin W. Collins, Bristol 25 Russell D. Painless loss of vision after effects. Br J Urol 1996; 78: 224–7 Urological Institute, Southmead Hospital, transurethral resection of the prostate. 31 Lehman TH, Loomis RC, Moore RJ, Westbury on Trym, Bristol BS10 5NB. Anaesthesia 1990; 45: 218–21 Hodges CV. Intravenous mannitol during e-mail: [email protected]
372 © 2005 BJU INTERNATIONAL Original Article PENILE FRACTURE AND MRI FINDINGS ABOLYOSR et al.
Associate Editor The management of penile fracture Michael G. Wyllie based on clinical and magnetic Editorial Board resonance imaging findings Ian Eardley, UK Jean Fourcroy, USA AHMAD ABOLYOSR, ALAA E. ABDEL MONEIM, ATEF M. ABDELATIF, Sidney Glina, Brazil MEDHAT A. ABDALLA and HISHAM M.K. IMAM* Julia Heiman, USA Departments of Urology and *Radiology, Assiut University Hospital, Egypt Accepted for publication 10 March 2005 Chris McMahon, Australia Bob Millar, UK Alvaro Morales, Canada OBJECTIVE fracture, and it improves the management Michael Perelman, USA plan. Marcel Waldinger, Netherlands To present our experience with repairing penile fracture, based on clinical and KEYWORDS magnetic resonance imaging (MRI) findings. penis, fracture, MRI, tunica, tear PATIENTS AND METHODS
Between December 2002 and October 2004, INTRODUCTION 14 men (19–64 years old) presented to our centre with a penile fracture. Two patients Penile fracture is a urological emergency, had urethral bleeding. MRI was used before being the rupture of the tunica albuginea of surgery in all patients, and the repair the corpus cavernosum caused by trauma to comprised a localized longitudinal penile the erect penis [1]. The most common cases incision in 13 men. This incision was designed reported in the Western world occur during according to the tunical tear site and size sexual intercourse [2]. In Middle Eastern already depicted by MRI. One case was countries many of these injuries are self- managed conservatively, as MRI confirmed an inflicted during masturbation, as the patient intercavernosal haematoma with no tunical bends the erect penis abruptly in an attempt tear. The follow-up was 4–21 months. to achieve detumescence after prolonged erection [3]. Other causes of fracture are RESULTS variations of striking the erect penis, e.g. falling on the erected penis or even rolling The tear involved one corpus cavernosum in over on the erect penis in bed [4]. It is a rare 11 patients; two were associated with urethral event, which is why the best management injury. The course after repair was uneventful plan is not well defined [5]. in all men; the follow-up showed no erectile dysfunction in any. The patients reported Surgical intervention is generally neither pain nor penile curvature during recommended to preserve the tunical erection. integrity that is essential for erection. Beforehand an accurate assessment of the CONCLUSION location and size of the tunical tear, and whether there is associated urethral injury, is MRI is a simple and informative investigation important. For this purpose many authors for evaluating and documenting a penile have tried cavernosography [4,6] and
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TABLE 1 Patient demographic data, cause of injury and MRI findings
Site, cm from Tear Patient/age, years Cause coronal sulcus size, mm Laterality Associated injuries 1/23 Bending erect penis 5 13 R 2/39 Bending erect penis 6 9 R 3/21 Bending erect penis 4.5 12 L Urethral injury 4/25 Bending erect penis 6.5 10 L 5/19 Sexual intercourse 5.5 6 R 6/37 Bending erect penis 6 11 R 7/26 Bending erect penis 7 14 L 8/28 Sexual intercourse – – – Intracavernosal haematoma 9/33 Falling on the erect penis 6 12 R 10/29 Bending erect penis 6.5 11 L 11/35 Bending erect penis 5 14 R Urethral injury 12/64 Sexual intercourse 4 13 R 13/33 Trauma by axe while farming 5 11 L 14/49 Bending erect penis 5.5 8 R
urethrography [7]. However, these parameters. In some cases additional axial for 4–21 months and all reported subjectively investigations have their problems. Others and sagittal T1-weighted images (repetition good erectile function, with neither penile used ultrasonography [8–11] but it was time/echo time 400/10 ms) were obtained to curvature nor pain during erection. unhelpful [12]. MRI was used recently to confirm the penile haematoma. The field of evaluate penile fracture, and was found to be view of all sequences was 215–320 mm. All DISCUSSION effective [12–15]. In the present study we patients required surgical intervention except report our experience in managing penile one in whom MRI showed intercavernosal Penile fracture is a rare condition that is easy fracture, using MRI as a noninvasive haematoma with no tunical tear. This patient to diagnose clinically; immediate surgical documentary tool, in addition to its efficacy in was managed conservatively using analgesics, repair is recommended to avoid the depicting the anatomical details of the ice-packs and a pressure bandage. Surgical complications of conservative management, condition, which not only facilitates surgical exploration was by a longitudinal incision i.e. penile curvature and deformity, fibrosis intervention but also minimizes its morbidity. placed at the site of the tunical tear as and sexual dysfunction. Moreover determined by MRI. The haematoma was conservative treatment requires a prolonged evacuated and the tunical tear repaired using hospital stay [16–18]. PATIENTS AND METHODS interrupted 2–0 polyglactin sutures. The urethral injury was repaired on a urethral Locating the tunical tear site and associated Between December 2002 and October 2004, catheter using interrupted 4–0 polyglactin urethral injury before surgery is important to 14 patients with penile fracture were treated sutures and the catheter was left for 1 week. make a correct incision for the repair. in our centre. The delay in presentation was Patients were discharged from hospital 24 h Although the tear can be palpated manually, it 1–17 h from injury; all patients reported after surgery; all were instructed to avoid may be obscured by the swelling and hearing a cracking sound, followed by rapid sexual intercourse for 1 month. The patients’ haematoma even if the examination is under detumescence associated with pain and demographic data, cause of injury and MRI anaesthesia. penile swelling. Two patients had urethral findings are shown in Table 1. bleeding. On physical examination all patients Some authors advocated the use of had various degrees of penile swelling and cavernosography to locate the tear site [4,6], ecchymosis. Because of penile tenderness and RESULTS but this requires manipulation of the tender the associated swelling, the definite site of and swollen penis. Also, some patients with tunical tear could not be adequately palpated The most common mechanism of penile normal findings on cavernosography have a in 10 patients. All patients had emergency fracture in the patients was bending the erect rare related injury requiring open exploration, MRI, using a surface coil. With the patient penis (nine of 14). MRI detected that the i.e. deep dorsal vein rupture [19]. supine the penis was taped against the tunical tear involved the right corpus in eight Cavernosography also cannot be used in abdominal wall and the surface coil placed on men and the left in five. Other MRI data on patients allergic to contrast material. the penis. Sagittal T2-weighted spin-echo tear size, site and associated injuries are Moreover, it can give false-negative results images (repetition time/echo time, 3750/ shown in Table 1 and Figs 1–5. In no case were [16,20]. 100 ms) were used as a ‘scout’ for the the MRI findings refuted at operation. There subsequent axial and coronal T2-weighted were no significant complications during or Penile fracture is associated with urethral fast-spin echo images, with the same soon after surgery. The patients were followed injury in up to 38% of patients [1].
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FIG. 1. MRI findings of patient no. 1: Tear of the tunica albuginea. Coronal T2-weighted MR image shows a identifying the tunical tear and associated discontinuity of the low-signal-intensity tunica albuginea (arrow) and surrounding haematoma (*) in the urethral injury [12–15]. Thus we used MRI as a ventral aspect of the right corpus cavernosum. The tear was 5 cm from the coronal sulcus of the penis, non-contact investigation for such a tender confirmed by the scale on the images. and painful condition, to determine the site and size of the tear and associated urethral injury. According to the MRI findings we used a localized longitudinal incision centred over the tear. We think that this approach is minimally invasive and less morbid than the most commonly used exploratory subcoronal penile degloving incision. In the present series the tear site was 4–7 cm from the penile coronal sulcus. Accordingly, using penile degloving leads to unnecessary dissection of 4–7 cm of the penis to get access to the tear site. Moreover, penile degloving was reported to carry a high complication rate (14–25%) including infection, abscess formation and skin necrosis [23,24]. None of these complications occurred in the present patients. Our localized approach was easy and provided a ‘skin window’ directly over the tear, allowing an adequate repair of the tunica and the urethral injury. It decreased the hospital stay, as all of the patients were discharged 24 h after surgery, sooner than reported (1–4 days) by many authors using penile degloving [7,25,26].
Penile fracture carries a risk of erectile dysfunction; in our locality it is not infrequent FIG. 2. MRI findings in patient no. 3: A tunical tear with urethral rupture. Coronal T2-weighted MR image that the patient (after surgical repair) claims shows a tunical tear in the ventral aspect of the left corpus cavernosum 4.5 cm distal to the penile coronal that they have de novo erectile dysfunction as sulcus (arrowhead). A large haematoma adjacent to the tear (H) and disruption of the corpus spongiosum a result of faulty surgery. Thus before surgery and urethra (arrow) are also clear. MRI is an effective measure providing objective documentation of the condition for such medicolegal purposes. Moreover, MR images can be used for teaching purposes and for comparing results from different centres.
Notably, MRI saved one of the present patients from surgical intervention; in this patient, although presenting with typical findings of a penile fracture during sexual intercourse, MRI proved that there was an intercavernosal haematoma with no tunical tear (Figs 4 and 5).
In conclusion, MRI is an easy and informative investigation for evaluating and documenting Urethrography was used by some authors to evidence of urethral injury on exploration, penile fracture; it also improves the confirm associated urethral injury [7]. while others had urethral injuries with no management plan. However, MRI is expensive Moreover, a Consensus Group [21] blood at the meatus. Nevertheless, retrograde and needs available apparatus and an expert recommended retrograde urethrography as a urethrography is an invasive examination, operator. routine in suspected cases of penile fracture, needs contrast material, and carries the risk of as the presence of blood at the external extravasation and introduction of infection. ACKNOWLEDGEMENTS meatus is neither sensitive nor specific for urethral injury. Mydlo [22] reported that some Recently MRI was used to evaluate penile The authors acknowledge Salah El-Din Shaker, patients with blood at the meatus had no fractures, where it was highly accurate in MD (Urology Department, Assiut University
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FIG. 3. MRI findings in patient no. 13: A tear of the tunica albuginea. (a) Axial T1-weighted MR image shows Hospital, Egypt), and Ahmad Shehata, MD a discontinuity of the low-signal-intensity tunica albuginea (arrow) and surrounding haematoma (*) in the (Urology Department, Assiut University dorsal aspect of the left corpus cavernosum. Hospital, Egypt), for review.
CONFLICT OF INTEREST
None declared. Source of funding: Assiut University Hospital, Egypt.
REFERENCES
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resonance imaging in the diagnosis of conservative treatment. Urology 1984; penile fracture. J Urol 2001; 166: suspected penile fracture with atypical 24: 21–4 528–9 clinical findings. J Urol 1996; 155: 1924–7 18 Farah RN, Stiles R, Cerny JC. Surgical 23 Mansi MK, Emran M, el-Mahrouky A, 13 Maubon AJ, Roux JO, Faix A, Segui B, treatment of deformity and coital el-Mateet MS. Experience with penile Ferru JM, Rouanet JP. Penile fracture. difficulty in healed traumatic rupture of fractures in Egypt. long-term results of MRI demonstration of a urethral tear the corpora cavernosa. J Urol 1978; 120: immediate surgical repair. J Trauma 1993; associated with a rupture of the corpus 118–20 35: 67–70 cavernosum. Eur Radiol 1998; 8: 469–70 19 Nicely ER, Costabile RA, Moul JW. 24 Morris SB, Miller MA, Anson K. 14 Choi MH, Kim B, Ryu JA, Lee SW, Lee Rupture of the deep dorsal vein of the Management of penile fracture. J R Soc KS. MR imaging of acute penile fracture. penis during sexual intercourse. J Urol Med 1998; 91: 427 Radiographics 2000; 20: 1397–405 1992; 147: 150–2 25 Dincel C, Caskurlu T, Resim S, Bayraktar 15 Uder M, Gohl D, Takahashi M et al. 20 Grosman H, Gray RR, St Louis EL, Z, Tasci AI, Sevin G. Fracture of the MRI of penile fracture: diagnosis and Casey R, Keresteci AG, Elliott DS. The penis. Int Urol Nephrol 1998; 30: 761–5 therapeutic follow-up. Eur Radiol 2002; role of corpus cavernography in acute 26 Zargooshi J. Penile fracture in 12: 113–20 ‘fracture’ of the penis. Radiology 1982; Kermanshah, Iran. Report of 172 cases. 16 Dever DP, Saraf PG, Catanese RP, 144: 787–8 J Urol 2000; 164: 364–6 Feinstein MJ, Davis RS. Penile 21 Morey AF, Metro MJ, Carney KJ, Miller fracture. operative management and KS, McAninch JW. Consensus on Correspondence: Ahmad Abolyosr, cavernosography. Urology 1983; 22: 394 genitourinary trauma: external genitalia. Department of Urology, Assiut University 17 Kalash SS, Young JD Jr. Fracture of BJU Int 2004; 94: 507–15 Hospital, Egypt. penis: Controversy of surgical versus 22 Mydlo JH. Surgeon experience with e-mail: [email protected]
© 2005 BJU INTERNATIONAL 377 Original Article PERCUTANEOUS NEPHROLITHOTOMY IN PATIENTS WITH SPINAL CORD INJURY LAWRENTSCHUK et al.
The use of percutaneous Outcome from percutaneous nephrolithotomy to treat renal calculi in patients with spinal cord nephrolithotomy in patients with injury is described by authors from spinal cord injury, using a single-stage Melbourne. This is the first contemporary series reported for dilator for access over 13 years, and the authors describe various unique features NATHAN LAWRENTSCHUK, DAVID PAN, RICHARD GRILLS, JOHN ROGERSON, DAVID ANGUS, DAVID R. WEBB and DAMIEN M. BOLTON about their series and compare University of Melbourne, Department of Surgery and Department of Urology, Austin Hospital, their results to previously reported Heidelberg, Victoria, Australia studies. Accepted for publication 30 March 2005
Authors from London describe the largest single series of renal OBJECTIVE CONCLUSIONS transplant patients in adults and children with urolithiasis, study risk To present our experience of percutaneous PCNL has a high success rate and acceptable factors associated with this nephrolithotomy (PCNL) for treating complication rate compared to extracorporeal urolithiasis in patients with spinal cord injury shock-wave lithotripsy, and remains a valid condition in renal transplant (SCI) using a single-stage dilator for first-line treatment option for kidney stones recipients, and report on their percutaneous access. in patients with SCI. multimodal management by endourological and open KEYWORDS PATIENTS AND METHODS procedures. spinal cord injuries, percutaneous A prospective database of patients with SCI nephrostomy, lithotripsy, kidney calculi, having PCNL using the single-stage dilator surgical instruments was assessed, analysing patient data, stone- free rates, morbidity and the follow-up outcome. INTRODUCTION
Patients with spinal cord injury (SCI) have RESULTS impairment of sensory, motor or autonomic function. When their primary neurological In all, 26 patients had 54 PCNLs on 32 kidneys; lesion is coupled with the associated 20 had unilateral and six bilateral stone problems of immobilization, metabolic disease; there were many staghorn calculi alteration, and neurogenic bladder and bowel (24/54). Major complications occurred in dysfunction, they are predisposed to a variety three of 54 PCNLs (6%). The complete stone- of secondary complications [1]. Historically clearance rate was 87% for PCNL alone, rising neurogenic bladder dysfunction was often to 29 of 32 kidneys (91%) or 24 of 26 patients poorly managed, predisposing patients to (92%) with adjuvant procedures. A further extremely high detrusor pressures, VUR, three kidneys required no further treatment poor bladder emptying, detrusor muscle and were monitored, having residual deterioration, and chronic infection, which fragments of £2 mm. contributed to urolithiasis [2–4]. Urolithiasis
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FIG. 1. Radiograph of a complex left-sided kidney stone in a patient with SCI. The scoliosis in the spine of this TABLE 1 Patient characteristics, stone locations patient shows the difficulty in positioning such patients for PCNL. and results of PCNL
Variable N Total number of patients 26 Bacteriuria 22 Indwelling catheterization 11 Condom urinary drainage 7 Condom/CISC 4 CISC alone 2 Ileal conduit 2 Level of injury Quadriplegics 12 Paraplegics 14 Stones Kidneys with a solitary calculus 39 Staghorn calculi 24 Kidneys with multiple calculi 15 Location Renal pelvis 29 Upper ureter 7 Upper pole calyx 8 Lower pole calyx 10 Results Operated kidneys 32 Previously operated kidneys 3 PCNLs 54 PCNLs per patient 2.12 PCNLs per kidney 1.67 often involved large calculi, because of the and improved stone-clearance rates, has been Mean duration of operation, min 103 use of long-term catheter drainage considered a valid option for treating calculi Patients stone-free, n (%) predisposing them to chronic bacteriuria in patients with SCI [5]. This trend has been After one PCNL 37/44 (84) (Fig. 1) [5,6]. The stones that form are supported by some series that have found After two PCNLs 47/54 (87) primarily struvite (magnesium ammonium high morbidity when managing struvite phosphate), and often contributed to by stones, particularly in patients with SCI [2,11]. *CISC, clean intermittent self-catheterization. infections with urea-splitting organisms such We present a series of PCNLs for treating as Proteus, Ureaplasma or Klebsiella [3]. urolithiasis in patients with SCI from a Contemporary urodynamic evaluation and specialized spinal urology unit, using a single- management of detrusor and sphincter stage dilator for access, and compare it to function, combined with clean intermittent published series of PCNL with complete data, the complex nature of the stones. Urine catheterization, has resulted in most patients and those primarily using ESWL to treat cultures were also taken before surgery, and with SCI having low-pressure urinary similar stones. appropriate antibiotic cover began at least drainage systems and reduced rates of urinary 24 h before surgery and ceased 48 h after the infection [3]. Despite this, patients with procedure. Patients all received general SCI still have a significant incidence of PATIENTS AND METHODS anaesthesia and underwent cystoscopy with a urolithiasis, and a recent longitudinal study ureteric catheter placed under fluoroscopy found almost no change in the past 25 years A prospective database of patients with SCI whilst in the lithotomy position (except for a [1]. Furthermore, 34% of patients with SCI who had PCNL in the past 8 years was patient with an ileal conduit). The patients developing one stone will have a second stone examined, as were medical records where any were then placed prone on the operating episode within 5 years [7]. Effective stone data were inconclusive or incomplete. This table, with appropriate use of support to treatment is very important, as the presence yielded 26 consecutive patients who had had obtain the best position for percutaneous of stones is associated with decreasing renal 54 PCNLs (Table 1). The greatest length and access to the affected renal system. The most function [8]. width of solitary stones were measured by CT, appropriate calyx, based on preoperative and the values multiplied together to give a imaging and patient positioning (i.e. the calyx Percutaneous nephrolithotomy (PCNL) measure of stone area. giving the best access to the stone mass, or a revolutionized stone surgery over 20 years targeted calyx containing an isolated stone, ago, replacing open surgery as the treatment The surgical procedure of PCNL was e.g. parallel lie), was punctured under bi- of choice for large calculi [2,9,10]. However, in consistent throughout, with no patients planar C-arm fluoroscopic control and a the past decade ESWL, with its low morbidity excluded, and CT was undertaken because of ‘slippery’ guidewire inserted (0.97 mm, Cook
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FIG. 2. A single-stage (‘Webb’) fascial dilator FIG. 3. Example of the difficulty in accessing the collecting system in the patient from Fig. 1 with multiple consisting of a bevelled sheath (16 cm, top) and a punctures. The nephroscope is inside the dilator sheath with a second nephrostomy being used to access the tapered dilator (30 cm, below) that is solid apart superior portion of the collecting system now containing a 10 F nephrostomy tube. from its centre (inset) through which a wire may pass. The tapered dilator has a mark at 19 cm, allowing an accurate assessment of the depth of the tapered portion (3 cm) of the dilator (far right) and the sheath, so the sheath is not advanced independent of the dilator causing injury.
Urological Inc., Spencer, IN, USA). A single- stage renal and fascial dilator (‘Webb’ dilator, William A. Cook Australia Pty Ltd, Brisbane, Australia) of 28 F (Fig. 2) was used to create the track for the nephroscope sheath. This is a purpose-designed target dilator that dilates to 28 F with a single passage over a guidewire. A second universal or ‘safety’ guidewire was then placed once access was obtained. The nephroscope was then introduced (Fig. 3). A lithoclast or ultrasonic lithotripter (both Karl Storz GmbH & Co., Tuttlingen, Germany) was used to fracture and fragment the stones, Complication Patients, n (%) Procedures, n (%) TABLE 2 with forceps used to extract larger stone Major Complications of PCNL fragments that were not aspirated or flushed Mortality 0 0 among 26 patients (54 out. At the end of the procedure, a Pneumothorax 2 (8) 2 (4) PCNLs) nephrostomy tube (10 F Cope type, Cook Urosepsis 1 (4) 1 (2) Urological) was placed and only removed Total 3 (12) 3 (6) when a nephrostogram and ureterogram Minor showed clear and free drainage of the Fever (> 38.5∞C) 15 (58) 26 (48) operated system 2 days after surgery. Data Blood transfusion 3 (12) 3 (6) were analysed using the chi-square test for Calyceal perforation* 2 (8) 2 (4) categorical variables. Total 20 (77) 31 (57)
*calyceal perforation, entrance into and then out of the collecting RESULTS system as visible by extravasation of contrast medium on the image intensifier during surgery. In all, 26 patients with SCI had 54 PCNLs on 32 kidneys in during the past 8 years at our institution (Table 1), including 23 male and three female patients (12 quadriplegics, 14 Multiple calyceal punctures were required in ESWL (one with 2-mm fragments remaining), paraplegics) with a median age of 50 years. 13 of the 54 PCNLs, and 23 punctures were one had open pyelolithotomy, and two had Six patients had bilateral stone disease and 20 supracostal. ureteroscopic stone removal. In summary, the had unilateral stone disease. Of those with a stones were completely cleared in 29 of 32 single calculus (39/54), the mean (range) The overall success rate for complete stone kidneys (91%) with three kidneys being stone area was 480 (70–3500) mm2 and 24/54 clearance per kidney after one PCNL was 84% monitored as they had fragments £2 mm, PCNLs involved staghorn calculi (stone (37/44 PCNLs), increasing to 87% (47/54 because of the high risk of larger stones occupying all the calyces or 80% of the PCNLs) with two such procedures. Of the recurring. collecting system space). The stone was kidneys with residual stone fragments, two struvite in 50 of the 54 PCNLs, and calcium had 2-mm stone fragments after treatment Major complications occurred in three of 26 oxalate in the other four. The mean (range) that were monitored with no further patients (12%) or three of 54 PCNLs (6%) operation time was 103 (30–220) min. management. A further two kidneys had (Table 2); two were pneumothorax requiring
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TABLE 3 Comparison of series of PCNL and ESWL to treat renal calculi in patients with SCI
Variable Present [13] [2] [5] [14] [15] [16] [17] [18] Year of publication 2005 1990 1986 1988 1994 1986 1991 1988 1995 Patients, n 26 35 23 32 15 8 11 5 15 Procedures, n 54 42 47 46 16 18 18 10 63 Kidneys treated, n 32 42 28 41 24 10 13 8 16 Quadraplegic, n 12271827NA8458 Paraplegic, n 148557NA0707 Method PCNL PCNL PCNL ESWL ESWL ESWL ESWL ESWL ESWL Mean age, years 50 44 43 52 NA NA 30 39 39 Mean operation time, min 103 75 105 68 NA NA NA NA NA Procedure per kidney, n 1.66 1.44 1.67 1.44 1.5 1.8 1.5 1.25 2.74 % Stone-free after one procedure 84 54 NA NA 44 NA NA NA NA % or n/N Overall stone-free rate per kidney 87 89 83 76 67 5/10 5/13 4/8 53 Follow-up auxiliary procedure/kidney* 9 11 11 38 NA 25 10 88 27 Postoperative fever 58 74 44 13 20 2/8 2/10 NA 0 Blood transfusion 6 49 19 0 0 0000 Major complication† 12 20 17 0 3 1/8 0 1/8 0 Death 010000000
NA, not available; *Includes ESWL after PCNL, open pyelolithotomy, ureteroscopic stone removal, open drainage of perirenal abscesses, nephrostomy, open ureterolithotomy and PCNL after ESWL; †Perirenal abscess, respiratory arrest, aspiration pneumonia, fistula, hydrothorax, urosepsis requiring nephrostomy.
chest-tube drainage only, one urosepsis UTI, are immobile and often have poorly patients with SCI, who can have significant requiring antibiotics, and there were no draining urinary systems. The optimum spinal curvature and extremity contractures. deaths. Minor complications occurred in 20 of contemporary management in this group Inadequate positioning for ESWL reduces 26 patients (77%) with most (58%) being a should still be determined by the basic success rates [4]. Furthermore, because of postoperative fever (>38 ∞C) for <24 h that principles of stone evaluation, including stone positioning problems related to the potential resolved with no extension of routine size and site, drainage of the system, and the kyphoscoliosis and pelvic tilt, and consequent perioperative prophylactic antibiotic use. The presence of infection. difficulties in the accurate location of shock- blood transfusion rate was 6% for 54 PCNLs. waves on renal calculi for lithotripsy, these A review of series reporting stone treatment patients might be at greater risk of developing with PCNL, ESWL or combined treatments in renal parenchymal and vascular damage after DISCUSSION patients with SCI identifies overall success ESWL [19]. The potential long-term effects on rates of 38–89% (Table 3) [2,5,13–18]. In the renal parenchyma dictate strict control of its Conservative management of upper tract present series of 26 patients, the number repeated use [18]. Other common issues that calculi was abandoned 20 years ago, of PCNLs was 1.69 per kidney treated, arise with ESWL are the elimination of stone following advances in endourological remarkably similar to other series of PCNL fragments that can cause obstruction, and techniques and lithotripter technology, as (1.44 and 1.67) [2,13]. The major complication incomplete stone clearance permitting serious infection or significant deterioration rate of 12% (three of 26) was less than in ongoing infection and nephrolithiasis [18]. in renal infection often developed with no other series of PCNL (17% and 20%), but intervention [12]. Recent reviews concluded not significantly less (P > 0.06 and 0.39, Despite these limitations, acceptable results that there has been a relatively constant respectively) [2,13]. Success rates with PCNL (53–73%) have been obtained using ESWL in incidence of initial kidney stones in patients alone, including the present series, were all patients with SCI (Table 3). In the largest with SCI over this period, and the recurrence similar (81–89%). series, 32 patients had ESWL on 41 kidneys, rate of kidney stones has not been with a mean stone burden of 2.9 cm per significantly reduced despite advances in the ESWL has been suggested both as a primary kidney [5]. All stones were treated without management of patients with SCI [1,7]. and adjuvant treatment to PCNL for patients previous debulking on a HM-3 lithotripter Furthermore the stone-recurrence rate in with SCI [3,5,7]. Struvite stones in patients (Dornier Medizintechnik GMBH, Germering, patients with SCI (34% at 5 years) is higher with SCI are often soft and are easily Germany). A stone-free rate at 3 months of than in the general population and is not visualized with fluoroscopy or conventional 73% (26/41) was reported. ESWL has some influenced by the method of urinary drainage radiography, making them suitable targets for advantages in that it can be undertaken in [7]. Urolithiasis will continue to be a problem ESWL. However, difficulty in locating renal selected patients with SCI using either no or for patients with SCI, as they are still at risk of calculi for ESWL must be anticipated in local anaesthetic, without autonomic
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dysreflexia in some cases [14,18]. It also has advancing a sheath over an incompletely treatment of spinal cord injury patients. lower morbidity, with no deaths and fewer dilated balloon, might result in haemorrhage J Urol 1988; 140: 266–9 blood transfusions. [20]. 6 Webb DR, Fitzpatrick JM, O’Flynn JD. A 15-year follow-up of 406 consecutive Culkin et al. [13] found that major morbidity We agree with Chen et al. [7] that, when spinal cord injuries. Br J Urol 1984; 56: after PCNL was significantly higher in patients considering kidney stones in patients with 614–7 with SCI (20% per patient operated) than in SCI, choice of treatment should be 7 Chen Y, DeVivo MJ, Stover SL, Lloyd LK. ambulatory patients (1.4%). Minor morbidity determined by stone size, location, patient’s Recurrent kidney stone: a 25-year follow- such as blood transfusions per patient medical condition and the experience of the up study in persons with spinal cord operated was also higher in the SCI group urologist, rather than by a preconceived bias injury. Urology 2002; 60: 228–32 (49% vs 20%). However, these results must be that one procedure is better than another. 8 Sekar P, Wallace DD, Waites KB et al. interpreted with caution, as the patients were However, we would also consider specifically Comparison of long-term renal function not matched for stone size, age or other the presence of UTI and drainage of the after spinal cord injury using different morbidities. The SCI group had 31% of affected system, with the principle that PCNL urinary management methods. Arch Phys patients with staghorn or partial staghorn is more appropriate than ESWL for larger Med Rehabil 1997; 78: 992–7 calculi, compared to only 9% in the stones, in poorly draining systems or in the 9 Brannen GE, Bush WH, Correa RJ, ambulatory group. presence of UTI, where complete stone Gibbons RP, Elder JS. Kidney stone clearance is paramount. Furthermore, from removal: percutaneous versus surgical There are many reasons for patients with available evidence, PCNL has high success lithotomy. J Urol 1985; 133: 6–12 SCI to be at higher risk of postoperative rates and acceptable complication rates 10 Preminger GM, Clayman RV, Hardeman complications than ambulatory patients; they compared to ESWL, and remains a valid SW, Franklin J, Curry T, Peters PC. often have poor respiratory reserves, leading treatment option for patients with SCI. Percutaneous nephrostolithotomy vs to airway problems such as pulmonary Consideration should be given to using a open surgery for renal calculi. A atelectasis and pneumonia, their surgical single-stage dilating system, which was a comparative study. JAMA 1985; 254: wounds take longer to heal, and they are at reliable technique in the present series. Finally, 1054–8 higher risk of infection than the general we stress the importance of preventing calculi 11 Segura JW, Patterson DE, LeRoy AJ et al. population. Despite this perceived additional and detecting them when they are small, Percutaneous removal of kidney stones: morbidity, stone-free rates of >80% are which will improve treatment outcomes for review of 1,000 cases. J Urol 1985; 134: attainable [4]. upper tract calculi in all patients with SCI. 1077–81 12 Gardner BP, Parsons KF, Soni BM, Surgical technique is important, and the Krishnan KR. The management of upper benefits of using a single-stage dilator such CONFLICT OF INTEREST urinary tract calculi in spinal cord as the ‘Webb’ [20], can be applied to patients damaged patients. Paraplegia 1985; 23: with SCI. Single-stage dilatation offers more None declared. 371–8 accuracy, as repeated passage of multiple 13 Culkin DJ, Wheeler JS, Nemchausky BA, targeted sheaths is not required. Also, because Fruin RC, Canning JR. Percutaneous of the large stones in patients with SCI, there REFERENCES nephrolithotomy: spinal cord injury vs. is little room in the collecting system in which ambulatory patients. J Am Paraplegia Soc to dilate and place a wire. Repeated 1 Chen Y, DeVivo MJ, Roseman JM. 1990; 13: 4–6 movements in and out using multiple dilators Current trend and risk factors for kidney 14 Deliveliotis C, Picramenos D, can dislodge a wire, compromising the stones in persons with spinal cord injury: Kostakopoulos A, Stavropoulos NI, procedure and leading to further unnecessary a longitudinal study. Spinal Cord 2000; Alexopoulou K, Karagiotis E. punctures or resulting in haemorrhage [20]. A 38: 346–53 Extracorporeal shock wave lithotripsy in single-stage dilator with a marker indicating 2 Culkin DJ, Wheeler JS Jr, Nemchausky paraplegic and quadriplegic patients. Int where the sheath meets the tapering of the BA, Fruin RC, Canning JR. Percutaneous Urol Nephrol 1994; 26: 151–4 trocar (Fig. 2) prevents unnecessary nephrolithotomy in the spinal cord 15 Neuwirth H, Royce PL, Chaussy C. Use advancement of the sheath without the injury population. J Urol 1986; 136: 1181– of extracorporeal shock-wave lithotripsy trocar, minimizing parenchymal damage and 3 in quadriplegic patients. JAMA 1986; 256: reducing the reliance on an image intensifier 3 Donnellan SM, Bolton DM. The impact 1295 to gauge the position of the sheath. Finally, of contemporary bladder management 16 Niedrach WL, Davis RS, Tonetti FW, chronically infected kidneys also can bleed techniques on struvite calculi associated Cockett AT. Extracorporeal shock-wave with repeated trauma, and single dilatation with spinal cord injury. BJU Int 1999; 84: lithotripsy in patients with spinal cord might minimize this risk, and this might 280–5 dysfunction. Urology 1991; 38: 152–6 explain the lower haemorrhage rate in the 4 Levy DA, Resnick MI. Management of 17 Spirnak JP, Bodner D, Udayashankar S, present series than in other reported series urinary stones in the patient with spinal Resnick MI. Extracorporeal shock wave that used different methods of access cord injury. Urol Clin North Am 1993; 20: lithotripsy in traumatic quadriplegic (Table 3). Single-stage dilators might also be 435–42 patients: can it be safely performed better than balloon dilators because extruding 5 Lazare JN, Saltzman B, Sotolongo J. without anesthesia? J Urol 1988; 139: the balloon from the collecting system, or Extracorporeal shock wave lithotripsy 18–9
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18 Robert M, Bennani A, Ohanna F, Guiter corporeal shock wave lithotripsy of renal Correspondence: Associate Professor David R. J, Averous M, Grasset D. The calculus in a paraplegic patient with Webb, Freemasons Hospital Medical Centre, management of upper urinary tract marked spinal curvature. Spinal Cord Suite 103/320 Victoria Parade, East calculi by piezoelectric extracorporeal 2002; 40: 609–14 Melbourne, Vic 3002, Australia. shock wave lithotripsy in spinal cord 20 Goharderakhshan RZ, Schwartz BF, e-mail: [email protected] injury patients. Paraplegia 1995; 33: 132– Rudnick DM, Irby PB, Stoller ML. 5 Radially expanding single-step Abbreviations: SCI, spinal cord injury; PCNL, 19 Vaidyanathan S, Johnson H, Singh G nephrostomy tract dilator. Urology 2001; percutaneous nephrolithotomy. et al. Atrophy of kidney following extra 58: 693–6
384 © 2005 BJU INTERNATIONAL Original Article MULTIMODAL MANAGEMENT OF UROLITHIASIS IN RENAL TRANSPLANTATION CHALLACOMBE et al.
Multimodal management of urolithiasis in renal transplantation
BEN CHALLACOMBE, PROKAR DASGUPTA, RICHARD TIPTAFT, JONATHAN GLASS, GEOFF KOFFMAN, DAVID GOLDSMITH and MOHAMMED S. KHAN Departments of Urology, Renal Medicine and Transplantation, Guy’s and St Thomas’ Hospitals, and GKT School of Medicine, London, UK Accepted for publication 8 March 2005
OBJECTIVE lithotripsy (ESWL), flexible ureteroscopy stent insertion before a second procedure and and in situ lithotripsy, percutaneous four required a nephrostomy tube to relieve To report the largest single series of renal nephrolithotomy (PCNL), open pyelolithotomy obstruction. Two patients had flexible transplant patients (adults and children) with and open cystolitholapaxy. ureteroscopy and stone extraction, three had urolithiasis, assess the risk factors associated a PCNL and one had open cystolithotomy. with urolithiasis in renal transplant recipients, PCNL failed in one patient who subsequently and report the outcome of the multimodal RESULTS had successful open pyelolithotomy. All management by endourological and open patients were rendered stone-free when procedures. Thirteen patients had renal calculi, seven had different treatments were combined. ureteric calculi and one had bladder calculi. The incidence of urolithiasis was 21/2085 CONCLUSIONS PATIENTS AND METHODS (1.01%) in the series. Urolithiasis was incidentally discovered on routine US in six The incidence of urolithiasis in renal The records of all patients undergoing renal patients, six presented with oliguria or anuria, transplant patients is low. There is a high transplantation between 1977 and 2003 were including one with acute renal failure, four incidence of metabolic causes and therefore reviewed. In all, 2085 patients had a renal with a painful graft, three with haematuria, renal transplant patients with urolithiasis transplant at our centre and 21 (17 adults and one with sepsis secondary to obstruction and should undergo comprehensive metabolic four children) developed urinary tract calculi. infection and in one, urolithiasis was found screening. Management of these patients Their mode of presentation, investigations, after failure to remove a stent. Ten patients requires a multidisciplinary approach by renal treatments, complications and outcomes (63%) had an identifiable metabolic cause for physicians, transplant surgeons and were recorded. Investigations included one urolithiasis, two by obstruction, two stent- urologists. or more of the following; ultrasonography related, one secondary to infection and in six (US), plain abdominal X-ray, intravenous no cause was identifiable. Thirteen required KEYWORDS urography, nephrostogram and computed more than one treatment method; 13 (69%) tomography. Management of these calculi were treated by ESWL, eight of whom required nephrolithiasis, renal transplantation, involved extracorporeal shock wave multiple sessions; eight required ureteric treatment, outcome
INTRODUCTION conceivable that increasing transplantation is made the emergency management of acute likely to have increased the number of renal obstruction easier. However, such facilities Since the first calculus in a renal transplant grafts placed with calculi already in situ; the and expertise are not widely available and [1] was described in 1975, urolithiasis has so-called ‘donor-gifted allograft lithiasis’ [4]. hence such patients are best managed in been recognized as a complication, although Several general and transplant-specific centres that are well equipped and have uncommon [2], of renal transplantation. conditions may predispose a patient to expertise to offer the appropriate treatment/ It is currently thought that urolithiasis developing urolithiasis, e.g. more intervention. We reviewed our renal complicates 0.4–1% [3] of all renal concentrated and alkaline urine [5]. Although transplant patients (adults and children) transplants. the presentation of urinary stones is often with urolithiasis, assessed the risk factors atypical and with no pain in most of these associated with the condition, and report the With advances in immunosuppression, donor patients, heightened awareness of this outcome of management by endourological card distribution and national transplant condition has enabled clinicians to diagnose and open procedures. programmes, including laparoscopic and transplant urolithiasis at an earlier stage. hand-assisted laparoscopic surgery, renal transplantation is becoming increasingly The steady development of minimally invasive PATIENTS AND METHODS common. The resulting improvement in graft methods has revolutionized the management and patient survival has led to frequent of urolithiasis in renal transplant patients. All cases of renal transplantation at our presentation of the less common and longer- Simultaneous progress in interventional institution from 1977 to 2003 were reviewed, term complications of transplantation. It is radiological techniques and expertise has comprising a series of 2085 consecutive renal
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transplants. All procedures were either FIG. 1. performed or assisted by a transplant X-ray showing a lower pole consultant using a standard technique. calculus and ureteric stent in a Information on the incidence and transplanted kidney. management of urolithiasis was accumulated by retrospective case-note analysis.
For the overwhelming majority of cases a Lich-Gregoir extravesical ureteroneocystostomy with an extravesical seromuscular tunnel was performed, using the upper transplant ureter. A 7 F, 16-cm JJ stent is routinely placed before completing the anastomosis, and removed after 6 weeks by flexible cystoscopy (Fig. 1). Although stenting is controversial and some centres use it selectively, in our unit it is used routinely. A recent meta-analysis [6] comparing stented to unstented extravesical ureteroneocystostomy showed that stented anastomoses have lower complication rates (3.2% vs 4.8% in case series analysis). Although stenting generally predisposes to urinary calculi, it reduces other cyclosporin and azathioprine. The remainder removal. Two patients required open complications and our stone incidence rate of have now been switched to a combination of procedures for stone clearance; an open ª1% is similar to that in other centres not mycophenalate mofetil, tacrolimus and pyelolithotomy for a large staghorn calculus routinely stenting. No patient in this series prednisolone. in the allograft after an unsuccessful PCNL, developed stent encrustation. and an open cystolithotomy for multiple large Patients presented with urolithiasis at a bladder calculi. After treatment all patients A Foley catheter drained the bladder for at mean (range) of 3.7 (0.17–18) years after were entered into a surveillance programme least 4 days. Immunosuppression included transplantation; eight presented within a year with regular US of their renal transplant. No prednisolone, azathioprine and cyclosporin of their transplant. Presentation was with grafts failed as a result of urolithiasis and at until 1999, when mycophenalate mofetil loin pain over the graft in four patients, present all patients are stone-free, although replaced the azathioprine. haematuria in three, oliguria or anuria in six, one is continuing to form regular stones but sepsis in one, acute renal failure detected by which are amenable to ESWL. One patient was Urolithiasis presenting with graft dysfunction, rising serum creatinine levels in one or on left with significant residual fragments after haematuria, unexplained fever, pain, or routine US in six. All but six of the patients ESWL, which subsequently passed anuria was investigated by immediate had a recognized predisposing condition spontaneously. ultrasonography (US) and early liaison with towards renal tract lithiasis. Most commonly the urological surgeon was implemented for this was recurrent confirmed UTI (six patients) cases of obstruction. although four had hyperparathyroidism and DISCUSSION four had uric acid calculi associated with hyperuricaemia. Other predisposing factors The incidence of urolithiasis in renal RESULTS included ileal conduit urinary diversion, transplants at our institution is ª1% Mitrofanoff diversion, and heavy stent (21/2085), with women outnumbering men, The mean (range) lead time to presentation encrustation at the time of removal (Table 2). which is similar to previously published series after transplantation was 3.6 (0.5–18) years. [7]. Predisposing risk factors for stone Twenty-one patients presented with renal Only two patients were able to spontaneously formation were present in most renal allograft urolithiasis (eight men and 13 pass their stones with no intervention; both allograft recipients. Some of these were women; mean age 41 years, range 15–64), calculi were in the upper pole and were 4 documented before transplantation, e.g. gout although there were six patients aged and 4.5 mm in diameter. Three required and ileal conduit formation, while others >60 years and five aged £18 years (Table 1). percutaneous nephrostomy drainage and were only discovered after biochemical There were 18 cadaveric and three live-donor subsequent ESWL. In all, 13 patients had investigation following calculus formation, kidney recipients in the series. The ESWL, with eight requiring multiple sessions e.g. hyperparathyroidism and recurrent UTIs. predisposing renal diseases included reflux to clear their stones. ESWL was delivered with Attempts have previously been made to nephropathy in six patients, hypertension in the patient prone, with the stones located identify the importance of risk factors in this four, glomerulonephritis in three and two had using US and X-ray on a Modulith (Storz, situation; Harper et al. [5] investigated risk adult polycystic kidney disease. Over half of Germany). Five patients needed a ureteric JJ factors for stone formation in five patients the patients (11) were treated with a triple stent, two a percutaneous nephrolithotomy and compared them to 41 transplant patients immunosuppressive regimen of prednisolone, (PCNL) and two flexible ureteroscopic stone with no stones. They reported that although
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TABLE 1 The demographics of patients with renal transplant urolithiasis
Age at Patient presentation Original kidney disease Donor, year Immunosuppression Treatment 1 37 Glomerulonephritis Cadaveric 1991 Cy,Az,Pr 1998 2 63 APKD Cadaveric 1988 Cy, Az, Pr 2000 3 38 Chronic pyelonephritis, reflux Cadaveric 1993 Cy, Az, Pr 1995 4 16 Bilateral VUR Live 1984 Cy, Pr 1989 5 45 Henoch Schonlein purpura Cadaveric 1991 Cy, Az, Pr 1997 6 28 Nephrotic syndrome Cadaveric 1990 Cy, Az, Pr 1993 7 43 Reflux nephropathy Cadaveric 1997 Cy, MMF 2000 8 64 Analgesic nephropathy Cadaveric 1977 Az, Pr 1995 9 30 Glomerulonephritis Cadaveric 1996 Cy, Az, Pr 1996 10 44 Hydronephrosis, hypertension Live 1990 Cy, Az, Pr 1990 11 63 APKD, hypertension Cadaveric 1994 Cy, Az, Pr 1994 12 61 NIDDM, hypertension Cadaveric 2000 MMF, Pr 2001 13 61 Genitourinary TB, adenocarcinoma Cadaveric 1990 Cy, Pr 2001 14 18 Reflux nephropathy Cadaveric 1999 MMF, Cy, Pr 1999 15 18 Reflux nephropathy Cadaveric 1999 Cy, Pr 1999 16 17 Reflux nephropathy/spina bifida Cadaveric 1998 Cy, Az, Pr 2000 17 15 Dysplastic R kidney, Hinman syndrome, neuropathic bladder Live 1999 Pr, Cy 2000 18 63 Single kidney, hypertension Cadaveric 2003 Tac, MMF, Pr 2003 19 48 Glomerulonephritis Cadaveric 2003 Tac, MMF 2003 20 52 Glomerulonephritis Cadaveric 2002 Tac, MMF, Pr 2003 21 39 Reflux nephropathy Cadaveric 2003 Tac, MMF, Pr 2004
Cy, cyclosporin; Az, azathioprine; Pr, prednisolone; N, Neoral; MMF. mycophenolate mofetil; Tac, tacrolimus; APKD, adult polycystic kidney disease; TB, tuberculosis; NIDDM, non-insulin dependent diabetes mellitus.
TABLE 2 The predisposing conditions, treatments and outcome of patients with renal transplant urolithiasis
Patient Predisposing conditions Treatment Outcome 1 None identified Passed stone Clear 2 Gout Nephrostomy, ESWL ¥ 1 Clear 3 Ileal conduit, spina bifida ESWL ¥ 2 Clear 4 Recurrent UTIs ESWL ¥ 1 Clear 5 Hyperparathyroidism PCNL + Open pyelolithotomy Clear 6 Hyperparathyroidism PCNL + stent, 3 ¥ ESWL Clear 7 Gout Stent + ESWL Clear 8 None identified Stent + ESWL Clear, recurrent ¥ 3 9 Stent encrustation at removal ESWL + spontaneous passage Clear 10 None identified Nephrostomy, ESWL ¥ 4 Clear 11 Gout ESWL ¥ 3 Clear 12 Nephrostomy in intensive unit Stent, ESWL ¥ 2 Fragments <2 mm 13 Hyperparathyroidism, gout, UTI FURS via cutaneous ureterostomy ¥ 3 Clear 14 Stent encrustation Stent + ESWL ¥ 6 Clear 15 Hyperparathyroidism, UTIs Stent + ESWL ¥ 4 Clear 16 Recurrent UTIs, Mitrofanoff Open cystolithotomy Clear 17 Recurrent UTIs, Stent + FURS Clear 18 None identified Nephrostomy + JJ stenting + ESWL Clear 19 Recurrent UTIs Passed stone Clear 20 None identified Nephrostomy + passed stone Clear 21 None identified PCNL Clear
FURS, flexible ureteroscopic removal of stone; Success was complete clearance (clear)/fragments <2 mm. Mean (range) stone size 8.1 (4–17) mm.
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patients with calculi in transplants passed reported as the primary procedure of choice ESWL. If this failed, flexible ureterorenoscopy significantly more concentrated and alkaline by some centres [14], we only used three and holmium laser fragmentation, although urine, there were other factors contributing to PCNLs in the present 21 patients, probably technically difficult in these kidneys, can be stone formation. This is reflected in the because most calculi were <1.5 cm in attempted. For larger stones, PCNL gives the present series, where seven different risk diameter and there is an on-site ESWL best chance of complete stone clearance. factors were identified (Table 2). machine. In general, for patients with obstructing calculi, we opted for swift CONFLICT OF INTEREST The question of whether grafts may have been resolution of the obstruction via nephrostomy transplanted with calculi already in situ has (in four patients) or insertion of a ureteric JJ None declared. been investigated by several centres. Donor- stent (in eight), followed by one or more graft lithiasis was described by Van-Gansbek sessions of ESWL. For unobstructive smaller REFERENCES et al. [8] in 1985 and has led to calls for stones of <1.5 cm, treatment with ESWL is preoperative screening for renal lithiasis in usually sufficient. This has led to successful 1 Rattiazzi LC, Simmons RL, Markland C, some transplant centres. Transplanted kidneys stone clearance in the 13 cases managed in Casali R, Kjellstrand CM, Najarian JS. with pre-existing stones possibly require this way. Fears that the position of the Calculi complicating renal transplantation conservative and expectant treatment to transplanted kidney would impair stone into ileal conduits. Urology 1975; 5: 29– preserve renal function, as stones are likely to clearance with ESWL do not appear to have 31 recur. In contrast, Lu et al. [9] reported that been a feature of the present series. There are 2 Mundy AR, Podesta ML, Bewick M, these patients can be successfully treated potential difficulties in locating transplant Rudge CJ, Ellis FG. The urological with percutaneous procedures soon after calculi because of the overlying bony pelvis complications of 1000 renal transplants. transplantation, and suggest that pre- [4], but most patients can be treated while Br J Urol 1981; 53: 397–402 transplant US should be implemented to prone. Flexible ureteroscopy was necessary in 3 Rhee BK, Bretan PN Jr, Stoller ML. reduce the risk of ‘donor-gifted calculi’. Most two patients after the failure of ESWL; this Urolithiasis in renal and combined centres would delay PCNL in the initial period method and disintegration of stones with pancreas/renal transplant recipients. after transplantation because of the higher electrohydraulic lithotripsy or holmium laser J Urol 1999; 161: 1458–62 levels of immunosuppression and potential is a challenging but effective means for 4 Bhadauria RP, Ahlawat R, Kumar RV, risks of sepsis and poor wound healing. treating stones in transplant kidneys. Access Srinadh ES, Banerjee GK, Bhandari Torrecilla et al. [10] suggested that the to these kidneys may be difficult because of M. Donor-gifted allograft lithiasis: detection of renal calculi in cadaveric renal their position in the pelvis and the location of extracorporeal shockwave lithotripsy with donors is not a reason to refuse the graft for the neo-ureteric orifice. This is usually over table module using the Lithostar further transplantation, as long appropriate achieved by introducing the ureteroscope Plus. Urol Int 1995; 55: 51–5 endourological expertise is available. Recently over a guidewire. Instruments with ‘active’ 5 Harper JM, Samuell CT, Hallson PC, the group from Michigan [11] reported the ex- secondary deflection are particularly useful in Wood SM, Mansell MA. Risk factors for vivo ureteroscopic clearance of renal calculi in reaching calculi in transplanted kidneys. The calculus formation in patients with renal 10 kidneys before transplantation, finding position of calculi within the renal collecting transplants. Br J Urol 1994; 74: 147–50 it to be a feasible means of rendering a system tends to vary considerably from day to 6 Mangus RS, Haag BW. Stented stone-bearing kidney stone-free without day because these kidneys are relatively versus nonstented extravesical compromising ureteric integrity or renal horizontal, making it difficult to compare ureteroneocystostomy in renal allograft function. clearance rates between the upper and lower transplantation: a metaanalysis. Am J poles. All patients presenting with obstructed Transplant 2004; 4: 1889–96 Treatment protocols for calculi in the kidneys clearly had calculi at the PUJ or within 7 Klingler HC, Kramer G, Lodde M, transplanted kidney should mimic those for the upper ureter. Marberger M. Urolithiasis in allograft single kidneys in general. Because of the kidneys. Urology 2002; 59: 344–8 superficial position of the transplanted In conclusion, despite significant 8 Van-Gansbeke D, Zalcman M, Matos C. kidney, nephrostomy drainage and improvements in immunosuppression, Lithiasic complications of renal subsequent PCNL is relatively straightforward, surgical advances and diagnostic imaging, the transplantation: the donor graft lithiasis. although we recommend that this be carried incidence of transplant urolithiasis is Urol Radiol 1985; 7: 157–60 out on larger calculi (>1.5 cm) in specialist essentially unchanged over the last 20 years 9 Lu HF, Shekarriz B, Stoller ML. Donor- centres with a large PCNL experience, because [15]. Transplant urolithiasis requires renal gifted allograft urolithiasis: early of the greater importance of the single kidney. physicians and urologists to maintain percutaneous management. Urology Percutaneous removal of calculi from vigilance and a high index of suspicion. We 2002; 59: 25–7 transplanted kidneys was first described in recommend that such patients be managed in 10 Torrecilla OC, Gonzalez-Satue C, Riera 1985 by Hulbert et al. [12], and is now often specialist centres that have all readily CL et al. Incidence and treatment of the treatment of choice when there is a available endourological methods. There urinary lithiasis in renal transplantation. significant stone burden. Encrusted stents should be access to an on-site lithotripsy Actas Urol Esp 2001; 25: 357–63 and obstructing clots can also be removed machine, flexible ureterorenoscopes with 11 Rashid MG, Konnak JW, Wolf JS Jr et al. with this technique [13], and it has the holmium laser, and urologists with significant Ex vivo ureteroscopic treatment of calculi advantage of potentially removing all stone experience of PCNL. Most patients with calculi in donor kidneys at renal transplantation. fragments at one procedure. Although of <1.5 cm can be rendered stone-free with J Urol 2004; 171: 58–60
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12 Hulbert JC, Reddy P, Young AT et al. The 14 Abbott KC, Schenkman N, Swanson SJ, Correspondence: Shamim Khan, Consultant percutaneous removal of calculi from Agodoa LY. Hospitalised nephrolithiasis Urologist & Transplant Surgeon, Department transplanted kidneys. J Urol 1985; 134: after renal transplantation in the United of Urology, Guy’s Hospital, London, SE1 9RT, 324–6 States. Am J Transplant 2003; 3: 465–70 UK. 13 Gedroyc WM, MacIver D, Joyce MR, 15 Streeter EH, Little DM, Cranston DW, e-mail: [email protected] Saxton HM. Percutaneous stone and Morris PJ. The urological complications stent removal from renal transplants. Clin of renal transplantation: a series of 1535 Abbreviations: US, ultrasonography; PCNL, Radiol 1989; 40: 174–7 patients. BJU Int 2002; 90: 627–34 percutaneous nephrolithotomy.
© 2005 BJU INTERNATIONAL 389 Original Article ASYMPTOMATIC BACTERIURIA IN MEN WITH ORTHOTOPIC ILEAL NEOBLADDERS ABDEL-LATIF et al.
The role of asymptomatic Asymptomatic bacteriuria in men with bacteriuria in patients with urinary diversion in general has been orthotopic ileal neobladders: possible reported as having a significant relationship to nocturnal enuresis role prognostically in several published studies. Authors from MOHAMED ABDEL-LATIF, AHMED MOSBAH, MAGDY S. EL BAHNASAWY, Mansoura, with considerable ESSAM ELSAWY and ATALLAH A. SHAABAN experience in the constructing the Urology & Nephrology Center, Mansoura University, Egypt Accepted for publication 10 March 2005 orthotopic ileal neobladder, have evaluated the incidence of OBJECTIVE to 42%, 28% and 27% at 1, 6, 12 and asymptomatic bacteriuria in such 18 months, respectively. There was a patients prospectively, and have To assess prospectively the incidence with significant correlation between the presence assessed its possible effect on time of asymptomatic bacteriuria in patients of bacteriuria and NE during the first neobladder function. with orthotopic ileal neobladders, and the 6 months, but it was not sustained after that. possible effect on neobladder function. The age of the patients was also related significantly to the incidence of NE; at PATIENTS AND METHODS 6 months, only one of 18 men aged £50 years had NE, while 19 of 29 aged >50 years had In all, 47 patients (mean age 52.7 years, SD 8.7, (P < 0.001). At 1 year all patients aged range 31–68) with uncomplicated orthotopic £50 years were nocturnally continent, while ileal neobladders were prospectively half of those aged >50 years had NE evaluated. With no antibiotic manipulation, (P = 0.001). consecutive urine cultures were assessed monthly. Continence was assessed by direct CONCLUSIONS information from the patients at each follow- up visit. Ileal neobladders are associated with a high incidence of asymptomatic bacteriuria during RESULTS the first year after surgery. There was spontaneous clearance of bacteriuria with Overall, 797 samples were cultured from the time, with no antimicrobial manipulation. 47 patients (mean 17.6, SD 7.1). There was a Soon after surgery there was a significant steady decrease in the incidence of positive association between bacteriuria and NE. The cultures, from 74.5%, to 35.6% and 6.7% at 1, effect of antimicrobials on patients with NE 6 and 18 months, respectively. While there should be evaluated. was persistently sterile urine in only eight patients (17%), 32 had occasional and seven KEYWORDS had persistent bacteriuria. Escherichia coli was the commonest organism (76.6%) neobladders, bacteriuria, nocturnal enuresis followed by Klebsiella pneumonia (15.7%); 54% of E. coli and 38% of K. pneumonia infections were sensitive to nitrofurantoin. INTRODUCTION Diurnal continence was achieved in 98% of the patients at 6 months after surgery. There The orthotopic ileal neobladder has been was a gradual decrease in the frequency of considered by many investigators as the nocturnal enuresis (NE) with time, from 87%, standard method of urinary diversion after
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radical cystectomy for bladder cancer [1–3]. 200 FIG. 1. Bacteriuria is frequent but asymptomatic in The relative frequency of different most patients with an orthotopic neobladder; 180 pathogens in patients with such neobladders have lower rates of positive 160 positive urinary cultures. urine cultures (3–34%) [4–6] than cutaneous reservoirs, which are almost always colonized 140 with bacteria [7]. The importance of such 120 bacteriuria remains controversial. The harmful 100 effects of bacteriuria on refluxing kidneys, confirmed experimentally in dogs, cannot be 80 directly related to humans [8]. One of the 60 main complications of the orthotopic ileal No. of positive cultures neobladder is nocturnal enuresis (NE). Large 40 series show that 15–40% of patients require 20 pads or other protection during sleep, compared with <10% during the daytime 0 [1–3,9]. Studies investigating the incidence of E. coli Klebsiella Pseudomonas P. mirabilis Others such bacteriuria with time and its impact on pneumonia aeruginosa nocturnal urinary control are sparse.
In the present study we evaluated the incidence of asymptomatic bacteriuria and thereafter. Inclusion criteria were normal Patients were followed up regularly every its change with time after surgery, and kidneys before surgery, no upper tract month after surgery (mean 17.6 months, SD determined the most common pathogenic obstruction afterward, and no stones, chronic 7.1, range 7–30) by a history, physical organisms. The possible relationship between retention, local recurrences or distant examination and urine culture. The such bacteriuria and NE was also assessed. metastases. All selected patients had a radiological evaluation consisted of renal and residual urine of <50 mL after voiding, pelvic ultrasonography monthly. CT and confirmed by catheter insertion after voiding a bone scan were used when clinically PATIENTS AND METHODS once, then verified by monthly pelvic indicated. Continence and a voiding diary ultrasonography. All patients had no history were assessed by direct information from the Of 173 patients with orthotopic neobladders of cardiac diseases, hypertension, diabetes patients at each follow-up visit. Patients were (147 men and 26 women) constructed mellitus or administration of systemic considered continent if they were completely between January 2002 and January 2004, 47 chemotherapy or radiation therapy, or other dry during the day and night, with no need for men were included in the present study (mean comorbidities that could affect the outcome. protection by pads or condom catheters. age 52.7 years, SD 8.7, range 31–68). Women were excluded as most of them had a large Clean-catch midstream urine samples The results were evaluated statistically with residual urine volume after voiding, that were obtained monthly for cultures and Fisher’s exact test, using two-tailed P values, predisposed to bacteriuria. All patients had antimicrobial susceptibility testing. The with P < 0.05 considered to indicate an orthotopic bladder substitution after well-mixed urine was sampled with a 1 mL significant differences. radical cystectomy for bladder cancer. The calibrated microbiological loop and plated neobladders were constructed using onto the surface of the following culture detubularized terminal ileal segments with media: cysteine lactose electrolyte-deficient, RESULTS fashioning of a W-shaped pouch. A 5-cm long blood agar, Schaedler anaerobic agar and intact ‘chimney’ was preserved for direct Sabouraud dextrose agar. Cultures were Overall, 797 samples were cultured from the uretero-intestinal anastomosis on one side, incubated (respectively for each type), 47 patients (mean 17.6, SD 7.1); there was while the other ureter was implanted using a aerobically at 35–37 ∞C for 18–24 h, significant bacterial growth in 239 cultures serous-lined extramural tunnel, as previously anaerobically in the Oxoid Anaerobic System, (29.6%). The incidence of positive cultures described [1,10]. Nerve-sparing cystectomy and in ambient air for 1–4 weeks for fungal during the first follow-up visit was 74.5%; was attempted only in a few patients (five) isolation. there was then a steady decline in the and was therefore unsuitable for statistical incidence of positive cultures to 35.6%, analysis. Our policy was to start broad- All isolated bacteria were identified by using 33% and 6.7% at 6, 12 and 18 months, spectrum parenteral antibiotics on the MicroScan WalkAway 40 (Dade Behring Inc., respectively. None of urine cultures were morning of the operation and continued USA) dried identification panels for Gram- positive at 24 months (22 patients). for 5 days afterward, then change to negative bacteria type 2 and antimicrobial an oral antimicrobial (trimethoprim- susceptibility tested using MIC determination Escherichia coli was the commonest sulphamethoxazole) as long as the urethral panels (Negative Urine MIC panel type 10) in organism, constituting 76.7% of positive catheter was indwelling (20 days) and for the same machine. A urine culture containing cultures, followed by Klebsiella pneumonia 2 weeks after its removal. None of the present >105 colony-forming units/mL was (15.7%) (Fig. 1). Proteus and Pseudomonas patients was treated with antimicrobial drugs considered as positive. infections were detected in 5.5% of positive
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TABLE 1 Pattern of asymptomatic bacteriuria TABLE 2 Antimicrobial susceptibility to cultured organisms among 47 patients with orthotopic ileal neobladders Susceptibility, % Drugs E. coli K. pneumonia P. aeruginosa Pattern of urine culture N (%) Nitrofurantoin 54 38 0 Persistently sterile 8 (17) Trimethoprim-sulphamethoxazole 8.3 0 0 Occasional bacteriuria: Ciprofloxacin 18.6 37.5 0 same organism 20 (43) Norfloxacin 25 35 0 different organisms 12 (26) Piperacillin-tazobactam 91.9 57.1 80 Persistent bacteriuria: Amoxicillin-calvulinic acid 57.3 42.9 – same organism 3 (6) Imipenem 100 100 100 different organisms 4 (9) Ceftazidime 50 Cefotaxime 41.4 28.6 10 Gentamycin 40 50 10 Amikacin 98 90 70 cultures. Thirty-two patients (68%) had occasional bacteriuria, 20 with the same organisms and 12 with different organisms. Eight patients (17%) had persistently sterile TABLE 3 Correlation between bacteriuria and NE urine cultures on all sampling occasions. Only seven patients (15%) had persistent Follow-up, Nocturnal continence, n (%) bacteriuria; three with the same organism and months Cultures continent enuresis total P four with different organisms (Table 1). 1 sterile 4 8 12 (25) bacteriuria 2 33 35 (75) 0.030 Table 2 shows the antimicrobial susceptibility 2 sterile 8 12 20 (43) for different organisms. The most effective bacteriuria 3 24 27 (57) 0.035 antimicrobial agents against E. coli were 3 sterile 12 9 21 (45) imipenem, amikacin and piperacillin- bacteriuria 6 20 26 (55) 0.033 tazobactam. The susceptibility of E. coli to the 4 sterile 17 6 23 (49) commonly used antimicrobial nitrofurantoin bacteriuria 5 19 24 (51) 0.001 was 54%. The most effective antimicrobial 5 sterile 20 8 28 (60) agents against K. pneumonia were imipenem bacteriuria 6 13 19 (40) 0.016 and amikacin; none of cultures with K. 6 sterile 21 8 29 (64) pneumonia were sensitive to trimethoprim- bacteriuria 5 11 16 (36) 0.016 sulphamethoxazole, while 38% were sensitive 12 sterile 18 6 24 (67) to nitrofurantoin. bacteriuria 8 4 12 (33) 0.7 18 sterile 20 8 28 (93) Daytime continence was assessed in all bacteriuria 2 – 2 (7) 1.00 patients at 1 month after surgery; 18 were 24 sterile 18 4 22 (100) totally continent, 15 were incontinent bacteriuria – – – requiring condom-catheter drainage and 14 had stress urinary incontinence. At 6 months after surgery diurnal continence was complete in 46 patients (98%). 12 months all patients aged £50 years were DISCUSSION nocturnally continent, while half of those For nocturnal continence, during the first aged >50 years had NE (P = 0.001). The clinical significance of bacteriuria in month 87% of patients were enuretic; there patients with an orthotopic ileal neobladder was a gradual decrease in the frequency of There was a significant correlation between is controversial. Advocates of using an enuretic patients with time, the frequency of the presence of positive cultures and antireflux system propose that the high NE being 42%, 28% and 27% at 6, 12 and nocturnal continence during the first incidence of bacteriuria may lead to renal 18 months, respectively (Table 3). Four of 22 6 months (Table 3, Fig. 2). During the first deterioration. However, the cited findings patients (18%) had NE 2 years after surgery; follow-up visit, 94% of patients with were generally based on occasional urine three of them had occasional enuresis and bacteriuria had NE, compared to 67% of those sampling, and studies meticulously one used a condom catheter. The age of the with sterile urine. After 6 months, 69% of investigating the rate of bacteriuria over time patients was significantly related to the patients with bacteriuria had NE compared to and its impact on reservoir function are incidence of NE; at 6 months only one of 18 28% of those with sterile urine. These lacking. By repeated monthly urine culture we men aged £50 years had NE, while 19 of 29 significant correlations were not sustained found substantial bacterial colonization of the aged >50 years had NE (P < 0.001). At thereafter. urinary tract. The high incidence of
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asymptomatic bacteriuria during the first year 100 FIG. 2. after surgery is in agreement with the results 90 Association between bacteriuria of Iwakiri et. al [6]. E. coli was the most 80 (red) and NE (green) during the common organism isolated in the present 70 2 years after surgery. The number cultures, which coincides with the results of 60 of patients assessed at 6, 12, 18 Keegan et al. [11], who found that the E. coli 50 and 24 months was 45, 36, 30 and strains isolated from the reservoirs were less 40 22, respectively. likely to carry determinants of virulence, e.g. P 30 and S fimbriae and toxins, compared to Patient percentage 20 community-acquired E. coli strains. 10 0 Repeated cultures showed not only a 2 4681012141618202224 spontaneous decrease in the incidence of Months after surgery bacteriuria, but also a spontaneous change in the organisms in 41% of patients with bacteriuria, with no antimicrobial manipulation. Reaching maturity both in the with most studies showing that patients rate restricted the indication of nerve-sparing urodynamic characteristics of the reservoir, reach the new baseline at 6–12 months after radical cystectomy to a highly selected group and the patients’ understanding of their new surgery [3]. Although daytime continence is of patients in this series. voiding pattern, might explain the steady generally satisfactory, NE remains a concern; decline in asymptomatic bacteriuria with it develops as a consequence of absent El-Bahnasawy et al. [22] reported that the time. sensation that permits excessive nocturnal incidence of bacteriuria was significantly urine volumes to overcome the impaired higher among enuretics, but they did not The reasons for the greater incidence of continence mechanisms of the urethra. assess the influence of treating such infection bacteriuria in ileal neobladders than in normal This situation is mainly caused by loss on the level of continence. Urodynamic bladders and in those after radical of the physiological storage reflexes after assessment of patients with asymptomatic prostatectomy remain a matter of cystoprostatectomy [16]. Jakobsen et al. [17] bacteriuria showed no correlation with any of controversy [6]. It has been hypothesized that reported a decrease of ª20% in the urethral the cystometric characteristics [23]. In the the intestine is incapable of inhibiting closure pressure during the deep stage of present study there was a significant bacterial proliferation, in contrast to rapid-eye movement sleep. The definition of correlation between bacteriuria and NE urothelium. Thus intestine that normally nocturnal continence used in the present during the first 6 months after surgery. The exists in symbiosis with bacteria, with no study was complete dryness with no pad use dramatic decline in bacteriuria, from 75% at 1 inflammatory reaction, may render the urine or other methods of protection. We month to 36% at 6 months, paralleling pouch less bacteriostatic, promoting bacterial recommend that all patients should use maturation, could explain the lack of a growth and may thereby serve as a source of regularly timed voiding soon after surgery. significant correlation of NE with bacteriuria infection [12]. In contrast, Mansson et al. [13] The present incidence of NE at 1 month after after 6 months. The decline in the number of showed that the chemical differences in surgery was 87% and decreased consistently patients from 47 to 22 over the 2-year study reservoir urine did not promote bacterial with time. Daytime continence was achieved period might also contribute to the lack of a growth compared with urine from an intact by 98% of patients at 6 months and remained significant correlation after 6 months. bladder. There was a spontaneously stable during the follow-up; these results However, these correlations could be decreasing incidence of bacteriuria with time. are similar to those published previously coincidental and not a cause-and-effect The mechanism of this acquired defence with [1–3]. relationship. time is unknown. Studies investigating host- response variables in patients with a The mean age of the present patients was The relationship between bacteriuria and neobladder and bacteriuria showed no 10 years less than that of a ‘standard’ cohort incontinence can be detected from the significant host reaction, indicating a ‘silent’ with a neobladder [2,3], possibly explaining reciprocal effect of bacterial flora and colonization rather than an active infection the rapid regaining of continence in these intestinal motility. It is well known that [14]. A high level of immunoglobulin in urine younger patients, who had early development decreased intestinal motility leads to bacterial from patients with intestine incorporated into of bladder cancer associated with overgrowth and subsequent bacterial the urinary tract was reported [6] but the schistosomiasis in Egypt [18]. The effect translocation. However, bacterial overgrowth significance of this finding remains obscure. of attempted nerve-sparing cystectomy either suppresses or exaggerates motility, Terai et al. [15] reported high levels of on continence is confirmed by many depending on the type of organism and/or its secretory IgA in the urine of intestinal investigators, as the preserved autonomic endotoxins [24]. Experimental data showed reservoirs, and concluded that long-term innervation probably contributes to pressure that applying enterotoxins of E. coli and some secretory IgA secretion in such reservoirs is an generation by the sphincter mechanism at other species leads to an exaggerated important host defence system. rest [19,20]. The incidence of local pelvic migrating motor complex and acceleration of recurrence after radical cystectomy and an spontaneous motility [24]. Not only this Urinary continence after orthotopic orthotopic Kock pouch was ª21% in a series effect, but these enterotoxins may lead to substitution appears to improve with time, of 353 men from our centre [21]. This high secretory fluid production. Both effects, if
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occurring within intestinal reservoirs, will serous-lined extramural ureteral 4; Chapt. 106. 8th edn. Philadelphia: WB result in NE. reimplantation: experience with 450 Saunders Co, 2002: 3745–88 patients. J Urol 2001; 165: 1427–32 13 Mansson W, Colleen S, Mardh PA. Urine Moreover, the associated inflammatory effect 2 Hautmann RE, de Petriconi R, Gottfried from continent caecal reservoir. Eur Urol of bacteria and/or its enterotoxins may HW, Kleinschmidt K, Mattes R, Paiss T. 1989; 16: 18–22 also induce contractile changes even after The ileal neobladder. complication and 14 Akerlund S, Campanello M, Kaijser B, the disappearance of the bacteria. This functional results in 363 patients after 11 Jonsson O. Bacteriuria in patients with a was documented by some, in that an years of followup. J Urol 1999; 161: 422– continent ileal reservoir for urinary inflammatory process involving the 8 diversion doesn’t regularly require intestinal wall, whether clinically as in Crohn’s 3 Studer UE, Zingg EJ. Ileal orthotopic antibiotic treatment. Br J Urol 1994; 74: disease and pouchitis of the ileal reservoir bladder substitution. What we have 177–81 after total colectomy, or experimentally, is learned from 12 years experience with 15 Terai A, Arai Y, Kawakita M, Okada Y, known to be associated with changes in 200 patients. Urol Clin North Am 1997; Yoshida O. Urinary immunoglobulins in contractile response of enteric smooth 24: 781–93 patients with continent urinary reservoirs muscles [25]. 4 Wood DP Jr, Bianco FJ Jr, Pontes JE, and ileal conduits. Int J Urol 1995; 2: 166– Heath MA, DaJusta D. Incidence and 71 Whether treating asymptomatic bacteriuria is significance of positive urine cultures in 16 Steers WD. Voiding dysfunction in the beneficial remains controversial. While some patients with an orthotopic neobladder. orthotopic neobladder. World J Urol 2000; authors found that prophylactic antibiotics J Urol 2003; 169: 2196–9 18: 330–7 did not seem to reduce the bacterial burden 5 Wullt B, Holst E, Steven K, Carstensen J 17 Jakobsen H, Steven K, Stigsby B, [5–11], some gastroenterologists have et al. Microbial flora in ileal and colonic Klarskov P, Hald T. Pathogenesis of reported that oral bacteriotherapy not only neobladders. Eur Urol 2004; 45: 233–9 nocturnal urinary incontinence after modified intestinal microflora but also 6 Iwakiri J, Freiha FS, Shortliffe LM. ileocaecal bladder replacement. Continues clinically improved intestinal motility in Prospective study of urinary tract measurement of urethral closure pressure irritable bowel syndrome [26]. infection and urinary antibodies during sleep. Br J Urol 1987; 59: 148– after radical prostatectomy and 52 Despite there being no data showing the cystoprostatectomy. Urol Clin North Am 18 Ghoneim MA. Bilharziasis of the benefit of prophylactic antibiotic therapy in 2002; 29: 251–8 genitourinary tract. Br J Urol 2002; 89 patients with a reconstructed lower urinary 7 Mansson W, Colleen S, Mardh PA. The (Suppl. 1): 22–30 tract, some authors advocate this regimen. microbial flora of the continent cecal 19 Turner WH, Danuser H, Moehrle K, Further studies are needed to elucidate the urinary reservoir, its stoma and the Studer UE. The effect of nerve sparing long-term effects of antimicrobial treatment peristomal skin. J Urol 1986; 135: cystectomy technique on postoperative on microbial ecology, and the clinical benefit 247–50 continence after orthotopic bladder of such treatment in patients with NE. Long- 8 Kristjansson A, Abol-Enein H, Alm P, substitution. J Urol 1997; 158: 2118– term studies on renal function in patients Mokhtar AA, Ghoneim MA, Mansson 22 with an orthotopic neobladder should also be W. Long-term renal morphology and 20 Stenzl A, Colleselli K, Poisel S et al. conducted to assess the possible effects of function following enterocystoplasty rational and technique of nerve sparing such asymptomatic bacteriuria in (refluxing or anti-reflux anastomosis): An radical cystectomy before an orthotopic uncomplicated cases. experimental study. Br J Urol 1996; 78: neobladder procedure in women. J Urol 840–6 1995; 154: 2044–9 In conclusion, ileal neobladders are associated 9 Steven K, Poulsen AL. The orthotopic 21 Shaaban AA, Mosbah A, El-Bahnasawy with a high incidence of asymptomatic Kock ileal neobladder. functional results, MS, Madbouly K, Ghoneim MA. The bacteriuria during the first year after surgery. urodynamic features, complication and urethral Kock pouch. Long-term There was spontaneous clearance of survival in 166 men. J Urol 2000; 164: functional and oncological results in men. bacteriuria with time, with no antimicrobial 288–95 BJU Int 2003; 92: 429–35 manipulation. Soon after surgery there was a 10 Hollowell CM, Christiano AP, Steinberg 22 El-Bahnasawy M, Osman Y, Shaaban significant association between bacteriuria GD. Technique of Hautmann ileal AA. The urodynamic features of and NE. The effect of antimicrobials in neobladder with chimney modification: orthotopic ileal reservoirs: a comparison patients with orthotopic bladder substitution interim results in 50 patients. J Urol 2000; between Hemi-Kock pouch and W and NE should be assessed further. 163: 47–50 neobladder. African J Urol 2001; 7: 66–73 11 Keegan SJ, Graham C, Neal DE et al. 23 El Bahnasawy MS, Osman Y, Gomha CONFLICT OF INTEREST Characterization of Escherichia coli MA, Shaaban AA, Ashamallah A, strains causing urinary tract infections in Ghoneim MA. Nocturnal enuresis in men None declared. patients with transposed intestinal with an orthotopic ileal reservoir: segments. J Urol 2003; 169: 2382–7 Urodynamic evaluation. J Urol 2000; 164: REFERENCES 12 McDougal WS. Use of intestinal segment 10–3 and urinary diversion. In Walsh PC, Retik 24 Reeves-Darby VG, Turner JA, Prasad R 1 Abol-Enein H, Ghoneim MA. Functional AB, Kavoussi LR, Vaughan ED Jr, Novick et al. Effect of cloned Salmonella results of orthotopic ileal neobladder with AC, Wein AJ eds, Campbell’s Urology. Vol. typhimurium enterotoxin on rabbit
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intestinal motility. FEMS Microbiol Lett 26 Bazzocchi G, Gionchetti P, Almerigi PF, Correspondence: Mohamed Abdel-Latif, 1995; 134: 239–44 Amadini C, Campieri M. Intestinal Urology & Nephrology Center, Mansoura, 25 Wells RW, Blennerhassett MG. microflora and oral bacteriotherapy in Egypt. Persistent and selective effects of irritable bowel syndrome. Dig Liver Dis e-mail: [email protected] inflammation on smooth muscle cell 2002 September; 34 (Suppl. 2): S48– contractility in rat colitis. Pflugers Arch 53 Abbreviations: NE, nocturnal enuresis. 2004; 448: 515–24
396 © 2005 BJU INTERNATIONAL Original Article VESICOSTOMY FOR THE HOSTILE BLADDER IN MYELODYSPLASIA MORRISROE et al.
Vesicostomy is a well-known Vesicostomy revisited: the best management of the neuropathic bladder in children, and authors treatment for the hostile bladder in from Sacramento describe their myelodysplastic children? experience with this in what they very appropriately name the SHELBY N. MORRISROE, R. COREY O’CONNOR, DANA K. NANIGIAN, “hostile bladder” of ERIC A. KURZROCK and ANTHONY R. STONE myelodysplastic children. Department of Urology, University of California Davis, Sacramento, California Accepted for publication 18 March 2005 Other papers in this section suggest that inguinal hernia in female OBJECTIVE patients required concomitant bladder infants should act as a cue to check augmentation. the sex chromosomes, evaluate To evaluate the effects of vesicostomy on the nocturnal enuresis in children at urinary tract of myelodysplastic children in CONCLUSIONS whom conservative bladder management 7.5 years old, and describe the with clean intermittent catheterization (CIC) Vesicostomy in myelodysplastic children is efficacy of tolterodine as a first- has failed to preserve upper and lower urinary effective in preventing and/or resolving the line treatment for non-neurogenic tract function. deleterious consequences of a ‘hostile’ bladder. The procedure is uncomplicated, well voiding dysfunction in children. PATIENTS AND METHODS tolerated, reversible and should be considered in managing children in whom conservative Sixteen children with myelodysplasia management by CIC has failed. underwent vesicostomy. Indications included worsening hydronephrosis, vesico-ureteric KEYWORDS reflux (VUR), recurrent urinary tract infections (UTIs), and increasing renal insufficiency vesicostomy, myelodysplasia, treatment despite CIC and/or difficulty with CIC. The outcome mean (range) age at vesicostomy was 36.5 (9–82) months and the follow-up 7.4 (2–16) years. INTRODUCTION
RESULTS The goals of urological care in children with myelodysplasia are to prevent urinary tract Hydronephrosis resolved or improved in 12 of deterioration and achieve continence at an 14 children, the incidence of UTI decreased to appropriate age. With >90% of these children one or fewer per year in 10, VUR resolved or having neurological involvement of the improved in nine, and renal function bladder [1,2] early detection and proactive improved or stabilized in six of seven patients. treatment can significantly decrease One patient initially presented with renal incapacitating bladder dysfunction and the insufficiency and subsequently required future need for surgical intervention [3–5]. dialysis despite vesicostomy. Complications The primary bladder management in spina occurred in three of 15 children, and included bifida is clean intermittent catheterization stomal stenosis and bladder calculi. The (CIC). The initiation and use of CIC has vesicostomy was closed in six patients after a been shown to decrease or eliminate mean of 4.4 (1.5–9) years. Four of these hydronephrosis and upper tract damage in
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>80% of patients with myelodysplasia [6]. fluoro-urodynamics were used to determine TABLE 1 Indications for vesicostomy, and McGuire et al. [7] reported that high detrusor vesico-urethral function and the degree, if complications afterward, in 15 patients storage or voiding pressures and low bladder any, of VUR. When required, vesicostomies compliance may put the upper tracts at risk in were occluded using a Foley catheter balloon Indication/complication N myelodysplastic children. Hence, the aim of to facilitate urodynamic studies. Urodynamics Worsening hydronephrosis 14 long-term bladder management in these were performed with an infusion rate of 8– Recurrent UTIs 14 patients is to maintain low storage pressures 20 mL/min. An improvement in the incidence VUR 11 and efficient bladder emptying. Older children of UTI was subjectively defined as a decrease Impaired renal function 7 refractory to this treatment may additionally from four or more to one or fewer per year. Non-compliance with CIC 3 require augmentation cystoplasty to protect Urethral false passage 1 the urinary tract. Younger patients in whom Complication conservative bladder management fails may Peristomal dermatitis 4 undergo vesicostomy to maintain low- RESULTS Stomal stenosis 1 pressure drainage. It is often temporary Bladder calculi 1 and reversed later in life, when the child Ten girls and six boys (mean age at can be managed with anticholinergics and vesicostomy 36.5 months, range 9–82) were CIC with or without bladder augmentation. identified. The operative time was <1 h for We retrospectively reviewed a cohort of each case; the mean (range) follow-up was patients with spina bifida who had a 7.4 (2–16) years. Vesicostomy provided overall The incidence of complications was low and vesicostomy after failed conservative resolution, improvement or stabilization of included peristomal dermatitis, bladder calculi management. the preoperative indications in 14 of 15 and stomal stenosis, easily managed with patients. One patient with recurrent UTIs and dilatation (Table 1). Bladder prolapse did not hydronephrosis died from unrelated causes occur in any patient. No child developed 2 years after a successful vesicostomy. upper tract calculi. PATIENTS AND METHODS Although the patient’s indications for vesicostomy resolved, he was excluded Six patients had the vesicostomy closed The institutional review board approved this from the analysis of outcome because of at a mean (range) of 4.4 (1.5–9) years retrospective study. A review of 380 patients the limited follow-up. after diversion. Concomitant procedures with myelodysplasia seen from 1988 to at the time of closure included ureteric 2002 identified 16 children (10 girls and six Of the 14 patients with hydronephrosis, eight reimplantation in two patients for continued boys) treated with vesicostomy. Indications achieved complete resolution, four improved high-grade reflux, augmentation cystoplasty included worsening hydronephrosis, recurrent and two stabilized. Ten of 14 patients with in four for small bladder capacity and UTI, VUR, impaired renal function, recurrent UTIs improved after vesicostomy cystolitholapaxy in one. Two children who did noncompliance with CIC, and urethral false to one or fewer UTI per year. Four patients not require augmentation were found to have passage (Table 1). Impaired renal function was are currently maintained on suppressive a bladder capacity of >300 mL and normal defined as a serum creatinine level of antibiotics for recurrent infections. Of the compliance during urodynamic studies. With >125 mmol/L or unilateral renal function of 11 patients with VUR, five resolved after a mean of 9.5 years after vesicostomy closure <35% on a nuclear scan. All patients had vesicostomy while four had a significant no patient has had recurrent VUR, worsening more than one indication for vesicostomy. improvement. Two of the four patients with hydronephrosis or frequent UTIs. The procedure was carried out according to minimal residual VUR are maintained on the Blocksom technique, which emphasizes suppressive antibiotics. Despite resolution To date, nine patients have not had the creating the vesicostomy from the bladder of upper tract dilation, high-grade reflux vesicostomy closed; the mean time since dome to minimize the risk of prolapse [8]. continued in two patients, necessitating placing the vesicostomy was 7.2 (2–16) years. Conservative bladder management with CIC, ureteric reimplantation at the time of Four patients did not have the social support anticholinergics and prophylactic antibiotics vesicostomy reversal. necessary for adequate bladder management. had failed in all patients. Prophylactic Three patients have been lost to follow-up antibiotics were given to all patients with Six of the seven patients with impaired renal and two are due to have the vesicostomy VUR and/or recurrent UTI. After vesicostomy, function before surgery had improved or closed. antibiotics were discontinued when imaging stabilized serum creatinine levels after studies showed resolution of VUR, and in vesicostomy. One patient with long-standing patients with recurrent UTI after an infection- hydronephrosis and renal insufficiency DISCUSSION free period of ≥6 months. progressed to end-stage renal failure after vesicostomy. Early proactive treatment of the The upper tracts were followed with periodic high-pressure bladder with CIC and renal ultrasonography and serum creatinine Of the four patients with an indication for anticholinergics significantly decreases the measurements. Renal nuclear scans were vesicostomy being either noncompliance incidence of poor bladder compliance, upper obtained in children with high-grade VUR, or difficulty with CIC, one has had the tract deterioration and the subsequent need evidence of renal scarring or renal size vesicostomy closed and learned self- for surgery [3–5]. In the subset of patients discrepancy on ultrasonography. Yearly catheterization. with myelomeningocele refractory to medical
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management, surgery may be the only option eight patients (44%) formed upper or lower Campbell’s Urology, Vol. 3 Chapter 65, 8th to prevent continued renal deterioration. urinary tract calculi and two (11%) reported edn. Philadelphia: WB Saunders Co, 1998: Since its introduction in children by Duckett recurrent pyelonephritis. In the present study, 2019–53 [9] and Michie et al. [10] vesicostomy has been one child had a bladder stone while no 2 Smith ED. Urinary prognosis in spina shown to reverse upper tract dilatation patients developed upper tract calculi or bifida. J Urol 1972; 108: 815–7 associated with neurogenic bladder recurrent pyelonephritis. It is possible that the 3 Kaefer M, Pabby A, Barbey M, Bauer dysfunction [11–16]. Mandell et al. [15] used prophylactic use of antibiotics in selected SB. Improved bladder function after vesicostomy in 10 infants with neurogenic patients in the present cohort may have prophylactic treatment of the high risk bladder dysfunction, with resulting diminished the incidence of infection and neurogenic bladder in newborns with improvements of the upper urinary tract in all stone formation. myelomeningocele. J Urol 1999; 162: patients; however, the median follow-up was 1068 short, at only 24 months. Bruce et al. [16] Four patients had concomitant procedures at 4 Tarcan T, Bauer S, Olmedo E, Khoshbin reported on vesicostomy in 24 children with the time of vesicostomy closure. One patient S, Kelly M, Darbey M. Long-term follow- hostile bladders. After a follow-up of with a diminished bladder capacity had up of newborns with myelodysplasia and <2 years, the results were successful in 23 bladder augmentation. Augmentation normal urodynamic findings: Is follow-up patients, while only one went on to require cystoplasty and bilateral ureteric necessary. J Urol 2001; 165: 564 supravesical diversion. reimplantation was used in two children with 5 Edelstein RA, Bauer SB, Kelly MD et al. small-capacity bladders and persistent VUR. The long-term urological response of In the present series, the long-term results in One boy with a bladder calculus had neonates with myelodysplasia treated 15 high-risk children with spina bifida show cystolitholapaxy and augmentation at the proactively with intermittent that vesicostomy is effective. There was an time of closure. There were no complications catheterization and anticholinergic improvement in the upper urinary tract in 13 from any additional procedure. No patients therapy. J Urol 1995; 154: 1500–4 patients, and the complications after had recurrent VUR, hydronephrosis or UTIs 6 Tanaka H, Kakizaki H, Kobayashi S, vesicostomy were minor, with four of 15 after vesicostomy closure. Shibata T, Ameda K, Koyanagi T. patients developing peristomal dermatitis, The relevance of urethral resistance in each easily and successfully managed with Nine patients, with a mean duration of children with myelodysplasia: its topical therapy. One boy formed bladder >7 years since placing the vesicostomy, have impact on the upper urinary tract calculi and had litholapaxy at the time the not had it closed. Complications in this group deterioration an the outcome of vesicostomy was taken down and the bladder were minimal and included peristomal conservative management. J Urol 1999; augmented. Also, one patient developed mild dermatitis in three and stomal stenosis in one. 161: 929–32 stomal stenosis that was treated with The reasons for prolonged vesicostomy are 7 McGuire EJ, Woodside JR, Borden intermittent dilatation. With a mean follow- varied; most include lack of social support to TA, Weiss RM. Prognostic value of up of >7 years, no patient had a stomal allow for adequate bladder management after urodynamic testing in myelomeningocele prolapse. The present complication rate is reversal. patients. J Urol 1981; 126: 205–9 similar or better than in other published 8 Blocksom BH Jr. Bladder pouch for studies. With a mean follow-up of 22 months, In conclusion, the long-term outcomes of tubeless cystostomy. J Urol 1957; 78: Bruce and Gonzalez [16] reported a 17% vesicostomy in myelodysplastic patients are 398–401 complication rate, mainly consisting of stomal effective in reversing the deleterious 9 Duckett JW Jr. Cutaneous vesicostomy stenosis. The authors did not comment on consequences of a hostile bladder when in childhood: The Blocksom technique. peristomal skin excoriation. Noe et al. [11] conservative treatments fail. Vesicostomy Urol Clin North Am 1974; 1: 485–95 reported complications in 15 of 35 (43%) obviates the need for more invasive 10 Michie AJ, Borns P, Ames MD. patients after a Blocksom vesicostomy, procedures and effectively postpones Improvement following tubeless including recurrent UTI in six and significant definitive therapy in patients who are suprapubic cystostomy of bladder prolapse in two. In addition, although not yet suitable for lower urinary tract myelomeningocele patients with not considered a complication by the authors, reconstruction. The procedure is hydronephrosis and recurrent acute nearly a third of patients were treated for uncomplicated, well tolerated, easily pyelonephritis. J Pediat Surg 1966; 1: peristomal reactions and dermatitis. reversible and should be strongly considered 347–52 in myelodysplastic patients in whom 11 Noe NH, Jerkins GR. Cutaneous To date, only one other study has examined conservative therapy fails. vesicostomy experience in infants and the long-term outcomes of vesicostomy in children. J Urol 1985; 134: 301–3 patients with myelomeningocele; Hutcheson CONFLICT OF INTEREST 12 Cohen JS, Harback LB, Kaplan GW. et al. [17] published the 13-year results of 18 Cutaneous vesicostomy for temporary patients treated with vesicostomy at a mean None declared. urinary diversion in infants with of 2.6 years old. Similar to the present neurogenic bladder dysfunction. J Urol findings, indications for vesicostomy were REFERENCES 1978; 119: 120–1 corrected or improved in 89% of patients. 13 Sonda LP, Solomon MH. Twenty-year Complications included stomal stenosis, 1 Bauer SB. Neurogenic dysfunction of the outcome of cutaneous vesicostomy. J Urol temporary ureteric obstruction and lower urinary tract in children. In Walsh 1980; 124: 326–8 peristomal skin excoriation. Furthermore, PC, Retik AB, Vaughan ED, Wein AJ eds, 14 Allen TD. Vesicostomy for the temporary
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diversion of the urine in small children. 17 Hutcheson JC, Cooper CS, Canning University of California Davis, 4860 Y Street, J Urol 1980; 123: 929–31 DA, Zderic SA, Snyder HM III The Suite 3600, Sacramento, California, 95817, 15 Mandell J, Bauer SB, Colodny AH, Retik use of vesicostomy as permanent USA. AB. Cutaneous vesicostomy in infancy. urinary diversion in the child with e-mail: [email protected] J Urol 1981; 126: 92–3 myelomeningocele. J Urol 2001; 166: 16 Bruce RR, Gonzales ET. Cutaneous 2351–3 Abbreviations: CIC, clean intermittent vesicostomy: a useful form of temporary catheterization. diversion in children. J Urol 1980; 123: Correspondence: Anthony R. Stone, Vice- 927–8 Chair and Professor, Department of Urology,
400 © 2005 BJU INTERNATIONAL Original Article ANDROGEN INSENSITIVITY SYNDROME AND INGUINAL HERNIA IN FEMALE INFANTS DEEB and HUGHES
Inguinal hernia in female infants: a cue to check the sex chromosomes?
ASMA DEEB and IEUAN A. HUGHES University Department of Paediatrics, Cambridge University, Cambridge, UK Accepted for publication 30 March 2005
OBJECTIVES history of CAIS, were recorded. A CONCLUSION questionnaire detailing different indications To review the clinical presentation of for considering CAIS in female infants with a Most clinicians agreed that CAIS should be complete androgen insensitivity syndrome hernia was distributed to members of the considered in all female infants with inguinal (CAIS) and assess the current practice of British Association of Paediatric Surgeons and hernia, as this is the commonest mode of considering the diagnosis of CAIS in female the British Society for Paediatric presentation in childhood. Macroscopic infants presenting with inguinal hernia. Endocrinology and Diabetes. inspection of the internal genital structures coupled, perhaps, with gonadal biopsy is PATIENTS AND METHODS RESULTS recommended. Fluorescence in situ hybridization offers a rapid and reliable AIS arises from target tissue resistance to the More than half of patients with CAIS method to check the sex chromosomes. actions of androgens due to molecular presented with inguinal hernia, of which half Liaison between the paediatric surgeon and abnormalities in the androgen receptor. were bilateral and a third contained gonads. endocrinologist is essential in management of Patients with CAIS are born with normal Completed questionnaires were returned by infants with CAIS. external female genitalia, and although 87 surgeons and 64 endocrinologists, and inguinal hernias are uncommon in female most of the surgeons and endocrinologists KEYWORDS infants, they are a well-known presentation of would consider CAIS in all female infants CAIS. Such patients were identified from the with a hernia. Bilateral hernias, hernias inguinal hernia, androgen insensitivity Cambridge Intersex Database and details of containing gonads and a family history of syndrome, female presentation, presence and laterality of CAIS would prompt clinicians to consider the inguinal hernia and contents, and family diagnosis.
INTRODUCTION encoding for these proteins have been primary amenorrhoea. However, early reported in males with cryptorchidism but diagnosis is important for genetic counselling Androgen insensitivity syndrome (AIS) is one with preserved testicular function [6]. By and a choice in the timing of gonadectomy. cause of XY sex reversal; it arises from target contrast, the second phase of inguinoscrotal The present study was designed to review the tissue resistance to the actions of androgens descent is androgen-dependent and the site type of clinical presentation of many patients and occurs in 1 : 20 000–64 000 male births of the gonads in CAIS exemplifies the role of with CAIS, and to obtain information from [1]. A spectrum of mutations in the X-linked the androgen receptor in this process [7,8]. endocrinologists and surgeons about whether androgen receptor gene give rise to varying The presentation of gonads in the hernial sacs the diagnosis of CAIS should be considered in degrees of androgen insensitivity; the most of a female infant should prompt a suspicion a female infant with inguinal hernia. complete form (complete AIS, CAIS) manifests of a CAIS diagnosis by inspection of the as infants born with normal female external gonadal morphology. The diagnosis may be genitalia. The diagnosis might be suspected in made retrospectively in an older child who PATIENTS AND METHODS infancy if there are inguinal hernial swellings previously had an inguinal hernia repair in from testicular descent. The incidence of infancy and whose younger sibling has now Cases of CAIS recorded on the Cambridge inguinal hernia in children is 1–4%, with presented with CAIS. This case scenario was Intersex Database were analysed for details of estimates of a male to female preponderance observed in five families recorded on the the type of presentation, presence and of 10 : 1 [2,3]. Testicular descent is generally Cambridge Intersex Database. It was laterality of inguinal hernia and contents, and subdivided into two phases [4]. The initial suggested that female infants presenting family history of CAIS. A questionnaire transabdominal migration, which takes place with inguinal hernia should be karyotyped [9], detailing a series of investigation options for before birth, is independent of androgens; but this was seldom considered in a recent female infants presenting with inguinal gubernaculum development is a critical survey of surgical practice [10]. hernia (Table 1) was designed and distributed component of this phase and is regulated by to paediatric surgeons and endocrinologists; insulin-like 3, produced by Leydig cells, and its The diagnosis of CAIS classically occurs in these were identified through the registries of receptor, GREAT/LGR8 [5]. Mutations in genes adolescence because of investigation for the British Association of Paediatric Surgeons
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and the British Society for Paediatric TABLE 1 Response to the questionnaire Endocrinology and Diabetes.
Response, n CAIS should be considered in: options Surgeons (87) Endocrinologists (64) RESULTS 1 All female infants presenting with an inguinal hernia 54 52 Analysis of the Cambridge Intersex Database 2 Only in female infants with bilateral inguinal hernias 5 identified 120 cases of CAIS (Fig. 1). The 3 Only for inguinal hernias containing gonads 6 4 median (range) age at presentation was 4 In female infants with a family history of inguinal 00 11 (0.4–64) years; 57% presented with hernias (female sibling/cousin) inguinal hernia, half had bilateral hernias, and 5 In infants with a family history of CAIS 6 equal proportions were right or left-sided. (female sibling/cousin) Gonads were palpable in the hernial sacs in a 2 and 5 4 8 third of cases. There was a family history of 3 and 5 6 CAIS in 85% of cases. In 3% of cases the Other options chosen by surgeons: diagnosis was established antenatally because Inspection of gonads and internal genitalia 4 of the need to perform a karyotype for CAIS diagnosis not worth considering as association with 2 unrelated reasons. hernia presentation is low
Completed questionnaires were returned by 87 of 102 surgeons approached (85%) and by 64 of 89 (72%) endocrinologists, from 28 reported in other comparable series of FIG. 1. The mode of clinical presentation of CAIS. IH, endocrine centres throughout the UK. Most of patients [13,14]. In a prospective study of 32 inguinal hernia, FH, positive family history of CAIS; the surgeons (62%) and endocrinologists girls admitted for hernia repair, all had a 46XX PA, primary amenorrhoea; AD, antenatal diagnosis. (80%) would consider the diagnosis of CAIS in karyotype [15]. Percentages of total number in each category are any female infant presenting with inguinal shown on the bars. hernia. Bilateral hernias were considered an In the present study, most surgeons reported indication to consider the diagnosis of CAIS that they consider CAIS in all girls presenting 80 by nine surgeons and eight endocrinologists; with inguinal hernia. This view was 70 12 surgeons and four endocrinologists chose strengthened if the hernia was bilateral, 60
the ‘palpable gonads’ option, and 16 surgeons contained gonads or there was a family tients
a 50 and eight endocrinologists were encouraged history of CAIS. The Cambridge Intersex 40 to consider the diagnosis in the presence Database contained an equal incidence of 30
of a family history of CAIS. No surgeon or unilateral and bilateral hernias and only a mber of p u 20 endocrinologist chose the option of a family third of CAIS patients had hernias containing N history of inguinal hernia in a sibling or a gonads. There was also a positive family 10 cousin (Table 1). history in this group of patients, which would 0 certainly influence the decision to investigate. IH FH PA AD Two surgeons were opposed to considering However, several instances were recorded CAIS in girls presenting with inguinal hernia where an older relative had presented with because of the low incidence of the inguinal hernia and the diagnosis not made considered in female infants presenting with association with inguinal hernia, and four until this was established in the index case. inguinal hernia. surgeons commented that inspecting the Examining the contents of the hernial sac gonads and the internal genitalia was a very might not readily distinguish a testis from an The approach will depend on available useful guide to further management. ovary in infancy and biopsy has been facilities and expertise. In some centres, recommended before hernia repair proceeds obtaining a preliminary karyotype result by [16]. fluorescence in situ hybridisation is possible DISCUSSION within 24 h of sample collection, thus Burge et al. [10] surveyed 32 surgeons in minimizing parental anxiety whilst awaiting a The possibility that female infants presenting the UK and Ireland to determine if they full karyotype result. An experienced with inguinal hernia might have CAIS has excluded CAIS in girls with inguinal hernia. ultrasonographer can provide precise details been the subject of several studies. Of 17 In contrast to the present study, 41% on the location and morphological nature of prepubertal girls admitted for inguinal did not investigate for CAIS because of inguinal masses in infants. Inspection of the herniotomy, two had an XY karyotype [11]. a low incidence of an association with gonads at surgery should determine their The inguinal masses were biopsied and this inguinal hernia. Nevertheless, the authors nature. The Fallopian tube and ovary are confirmed the presence of testicular tissue. believed that this practice should change found in 15–20% of sliding hernias in girls In a larger series of 124 infants and children and there appears to be a consensus from [13]. This might be sufficient to definitively with inguinal hernias, three were found to the present study that a diagnosis of exclude the presence of a testis but many have CAIS [12]. A similar incidence was CAIS and related conditions should be surgeons will biopsy the gonad and perhaps
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explore the contralateral side. It is essential Androgen receptor defects: historical, diagnostic procedures and management that gonads should not be removed until full clinical, and molecular perspectives. in the UK. Arch Dis Child 1997; 77: 305–9 discussion has taken place with the family Endocr Rev 1995; 16: 271–321 10 Burge DM, Sugarman IS. Exclusion of and appropriate investigations to establish a 2 Maisonet L. Inguinal hernia. Pediatr Rev androgen insensitivity syndrome in girls diagnosis have been completed. 2003; 24: 34–5 with inguinal hernias: current surgical 3 Kristiansen CT Snyder WH Jr. Inguinal practice. Pediatr Surg Int 2002; 18: 701–3 An inguinal hernia is the commonest hernia in female infants and children. 11 Pergament E, Heimler A, Shah P. presentation of CAIS in childhood and there is West J Surg Obstet Gynecol 1956; 64: Testicular feminisation and inguinal now a firm opinion, amongst paediatric 481–4 hernia. Lancet 1973; 2: 740–1 surgeons and endocrinologists, that the 4 Hutson JM Beasley SW. Descent of 12 Gans SL, Rubin CL. Apparent female diagnosis of CAIS and other causes of the Testis. London: Edward Arnold 1992: infants with hernias and testes. Am J Dis complete XY sex reversal should be considered 1–187 Child 1962; 104: 82–6 in all female infants with inguinal swellings. 5 Adham IM Agoulnik AI. Insulin-like 3 13 Goldstein IR, Potts WJ. Inguinal hernia Accordingly, investigating such infants to signalling in testicular descent. Int J in female infants and children. Ann Surg exclude CAIS is probably justifiable, although Androl 2004; 27: 257–65 1958; 148: 819–22 the approach chosen should be decided by the 6 Ferlin A Simonato M Bartolini L et al. 14 Jagiello G, Atwell JD. Prevalence of clinician, based on individual circumstances The INSL3-LGR8/GREAT ligand-receptor testicular feminization. Lancet 1962; 1: and available expertise. pair in human cryptorchidism. J Clin 329 Endocrinol Metab 2003; 88: 4273–9 15 German J, Simpson JL, Morillo-Cucci G, ACKNOWLEDGEMENTS 7 Barthold JS, Kumasi-Rivers K, Passarge E, De Mayo AP. Testicular Upadhyay J, Shekarriz B, Imperato- feminisation and inguinal hernia. Lancet The participation of members of the British Mcginley J. Testicular position in the 1973, 891 Association of Paediatric Surgeons and the androgen insensitivity syndrome: 16 Carmichael DH, Vorse HB. Female British Society of Paediatric Endocrinology implications for the role of androgens inguinal hernias and testicular and Diabetes is gratefully acknowledged. in testicular descent. J Urol 2000; 164: feminization. South Med J 1981; 74: 497–501 772–3 CONFLICT OF INTEREST 8 Lim HN, Hughes IA, Hawkins JR. Clinical and molecular evidence for the Correspondence: Asma Deeb, University None declared. role of androgens and WT1 in testis Department of Paediatrics, Addenbrooke’s descent. Mol Cell Endocrinol 2001; 185: Hospital, Cambridge, CB2 2QQ, UK. REFERENCES 43–50 e-mail: [email protected] 9 Viner RM, Teoh Y, Williams DM, 1 Quigley CA, De Bellis A, Marschke. KB Patterson MN, Hughes IA. Androgen Abbreviations: (C)AIS, (complete) androgen el-Awady MK Wilson EM French FS. insensitivity syndrome: a survey of insensitivity syndrome.
© 2005 BJU INTERNATIONAL 403 Original Article NOCTURNAL ENURESIS IN CHILDREN BUTLER et al.
Nocturnal enuresis at 7.5 years old: prevalence and analysis of clinical signs
RICHARD J. BUTLER, JEAN GOLDING*, KATE NORTHSTONE* and THE ALSPAC STUDY TEAM* Clinical Psychology, Child & Adolescent Mental Health Services, East Leeds Primary Care Trust, Leeds, and *Unit of Paediatric and Perinatal Epidemiology, Institute of Child Health, University of Bristol, Bristol, UK Accepted for publication 18 February 2005
OBJECTIVE problems, and signs related to the wetting CONCLUSION behaviour; 8269 (73.5%) questionnaires were To determine the prevalence of nocturnal returned and 8151 contained information on At 7.5 years old the incidence of bedwetting is enuresis (NE) in a large cohort of children at the frequency of bedwetting. high, but only 2.6% of this large population- 7.5 years old, and to examine the frequency of based sample wet at a frequency meeting variables such as gender, severity, associated RESULTS the definition of NE. Although a small elimination problems, and clinical signs within percentage of children had both daytime the identified group. In all, 1260 children (15.5%) at 7.5 years wet wetting and bedwetting, the evidence the bed, but most wet once or less a week, and suggests that these are discrete problems. SUBJECTS AND METHODS only 215 (2.6%) met the Diagnostic and Amongst children with NE, indicators of Statistical Manual of Mental Disorders (fourth bladder overactivity were present, supporting Of an original cohort of 13 971 infants alive at edition) criteria of NE (wetting at least twice a the view of heterogeneity and the importance 12 months, 11 251 who were still active in the week). A higher prevalence was reported in of individual assessment in deciding on Avon Longitudinal Study of Parents and boys than girls and 266 children (3.3%) had appropriate treatment. Children (ALSPAC) survey, were followed at both daytime wetting and bedwetting, with 91 months. The mother or main carer was 189 (2.3%) having both daytime soiling and given a questionnaire which asked, amongst bedwetting. Daytime urgency increased with KEYWORDS other items, about the presence and severity of bedwetting and occurred in 28.9% frequency of bedwetting, other elimination of children with NE. nocturnal enuresis, prevalence, children
INTRODUCTION age seems apposite when taking a cross- Several factors influence the variation in sectional survey of prevalence; Table 1 prevalence; there are different gender profiles Nocturnal enuresis (NE), according to the outlines recent studies of prevalence at [4], with significant differences between boys Diagnostic and Statistical Manual of Mental 7 years of age [4–18]. and girls at 7 years old [7], but many studies Disorders, fourth edition (DSM IV) [1], is only present an overall prevalence rate. There defined as an involuntary voiding of urine There is variation in prevalence, ranging at is also variability about what severity level during sleep, with a severity of ‘at least twice 7 years from 5% of boys and 0.5% of girls in constitutes NE, ranging from ‘more than one a week’, in children aged >5 years in the Hong Kong [13] to 16.2% of boys and 18.7% wet/week’ to ‘more than one wet/6 months’. absence of congenital or acquired defects of of girls in the Sudan [6]. Yeung et al. [19] Some studies offer more than one criterion the CNS. It has been suggested that parental re-evaluated their prevalence rates in Hong [4,8] but only very rarely is the severity of ‘≥2 concern and child distress should also play a Kong with a sample of 16 512 children aged wets/week’, identified as the definition of NE part in determining the clinical significance 5–19 years, using the same criteria (frequency [1] used in epidemiological studies. Children of the problem [2]. The DSM IV definition of wetting was defined as ‘at least once every manifestly vary in wetting frequency; only demands greater severity of bedwetting than 3 months’) as in their previous survey, and ª15% of bedwetting children wet every night earlier DSM classifications (III; III-R) where reported an increased rate of 16.2% (20.5% [20], although most wet more than once a frequency of wetting was defined as ‘at least boys, 11% girls). Although they gave no values week [4]. once a month’ for children aged >6 years. for 7-year-olds, prevalence rates in Hong Kong are now considered similar to those in Detailed analysis of types of enuresis is rarely Although epidemiological surveys have been Western countries, and Yeung et al. [19] considered in epidemiological surveys. undertaken in various parts of the world, suggested that the previous low prevalence However, in a Swedish survey [8], NE was comparisons are problematic because of rate was a result of ‘parental indifference to found in 7% of girls (of whom 3% were inconsistent methods [3]. Given that many the problem’. However, generally, bedwetting monosymptomatic) and in 12% of boys (of treatment interventions for NE become appears to be more prevalent in Eastern and whom 7% were monosymptomatic), whereas seriously considered at 7 years old, with Far Eastern countries than in European Chiozza et al. [15] found that, in Italy, NE implications for service development, this countries [4–18]. that was non-monosymptomatic was more
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TABLE 1 The prevalence of NE at 7 years old
Reference Country Definition of NE Sample Prevalence (%) [4] Holland >1/month 2600 (total sample) 15.3 (boys); 7.1 (girls) >2/months 156 (7 years) 12.5 (boys); 5.9 (girls) [5] New Zealand No definition 1107* 10.3 [6] Sudan
common than monosymptomatic NE. The going to sleep and large wet patches Of the original cohort, 11 251 (80%) remained categorization between NE that is might indicate a lack of vasopressin release active in the study at 91 months old. When monosymptomatic or not has recently [25,27]. the child reached this age, all mothers or main emerged as important, based on the absence carers were sent a questionnaire and invited or presence of bladder dysfunction [21,22]. The aim of the present study was to determine to complete several items, amongst which Monosymptomatic enuresis refers to children the prevalence of NE in a large cohort of were questions about the child’s night-time who report no bladder or voiding problems children at 7.5 years old, and to examine the wetting, daytime wetting and soiling. The associated with their wetting, whereas frequency of variables such as gender, carer was asked to indicate how often the non-monosymptomatic enuresis refers severity, associated elimination problems and child: (i) soiled his/her pants during the day; to bedwetting associated with bladder clinical signs within the identified group. (ii) soiled his/her pants at night; (iii) wet his/ overactivity and voiding problems. This herself during the day; (iv) wet the bed at classification is important in considering night. The following options were given: (a) the most appropriate treatment, and forms SUBJECTS AND METHODS never; (b) occasional accidents – less than a fundamental tenet of the ‘three-systems’ once a week; (c) about once a week; (d) 2–5 model advanced by Butler and Holland [22], The Avon Longitudinal Study of Parents and times a week; (e) nearly every day; (f) more which proposes that NE arises from: (i) Children (ALSPAC) [28] is an ongoing than once a day. The mothers were further bladder overactivity and/or (ii) a lack of population-based study investigating a wide asked to identify whether their child: (i) woke nocturnal arginine vasopressin release, range of environmental and other influences soon after wetting; (ii) seemed to wet soon leading to polyuria; and (iii) an inability on the health and development of children. after going to sleep; (iii) seemed upset when to wake from sleep to bladder sensations. Pregnant women resident in the former Avon the bed was wet, with the frequency options Although using different terminology, Neveus Health Authority in South-west England, of (a) never; (b) sometimes; (c) often; or (d) [23] also proposed that three causative having an estimated date of delivery between always. factors underpin NE. 1 April 1991 and 31 December 1992, were invited to take part, resulting in a cohort of The representative nature of the ALSPAC It was suggested that each system can be 14 541 pregnancies, of which 13 971 children sample has been investigated by comparison identified through the presence of clinical were alive at 12 months old. The primary with the 1991 National Census data of signs [22]. Bladder overactivity can be source of data collection was by self- mothers with infants aged <1 year who were identified by frequent daytime voiding (>7 completed questionnaires administered resident in the county of Avon. The ALSPAC voids/day); a sense of urgency; low or variable during pregnancy (8, 18 and 32 weeks sample had a slightly greater proportion of functional bladder capacity; small voided of gestation) and at various ages of mothers who were married or cohabiting, volumes; variability in the size of the wet the child. More detailed information who were owner-occupiers and who had a car patch; and waking during or immediately on the ALSPAC study is available at in the household. The study had a smaller after wetting [24–26]. Wetting soon after http://www.alspac.bris.ac.uk. proportion of ethnic minority mothers. Ethical
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approval for the study was obtained from the TABLE 2 Severity of bedwetting related to gender, daytime wetting, soiling and arousability to void ALSPAC Ethics Committee and the Local Ethics Committees of United Bristol and Bedwetting severity North Bristol Trusts (formerly Southmead and 1 (multiple) 2 (frequent) 3 (infrequent) 4 (never) Total Frenchay Health Care Trusts). Bedwetting, n (%) RESULTS Boy 13 (0.3) 137 (3.3) 694 (16.6) 3341 (79.8) 4185 Girl 6 (0.2) 59 (1.5) 351 (8.9) 3544 (89.5) 3960 In all, 8269 questionnaires were returned at Total 19 (0.2) 196 (2.4) 1045 (12.8) 6885 (84.5) 8145 91 months (response rate 73.5%), of which Daytime wetting, n (%) 8151 responded to the question on the Multiple (>1/day) 4 (21.1) 5 (2.6) 0 2 (0) 11 frequency of bedwetting. Of those Frequent (≥2/week) 3 (15.8) 11 (5.7) 23 (2.2) 31 (0.4) 68 responding, there was a shortfall in the more Infrequent (£1/week) 5 (26.3) 36 (18.4) 179 (17.2) 325 (4.7) 545 socially disadvantaged groups (maternal No daytime wetting 7 (36.8) 144 (73.5) 839 (80.6) 6522 (94.8) 7512 education level; housing tenure; maternal Total 19 196 1041 6880 8136 social class and maternal age: chi-square Soiling, n (%) P < 0.001) than in those not responding. Multiple (>1/day) However, there were no significant Day 1 (5.3) 2 (1) 2 (0.2) 2 (0) 7 differences evident in these factors and the Night 1 (5.3) 2 (1) 0 0 3 bedwetting variables (multiple wetting; NE; Frequent (≥2/week) infrequent bedwetting; no bedwetting). Day 1 (5.3) 9 (4.6) 13 (1.3) 36 (0.5) 59 Despite the sample attrition, there appeared Night 0 0 2 (0.2) 7 (0.1) 9 to be no relation between socio-economic Infrequent (£1/week) status and bedwetting, and so the sample Day 6 (31.6) 19 (9.7) 136 (13.1) 326 (4.8) 487 estimates are considered as representative of Night 2 (10.6) 6 (3.1) 27 (2.6) 19 (0.3) 54 the general population. No soiling Day 11 (57.9) 165 (84.6) 891 (85.5) 6521 (94.7) 7588 At 7.5 years old, 1260 children (15.5%) wet Night 16 (84.2) 185 (95.9) 1012 (97.2) 6855 (99.6) 8068 the bed, most of whom (978; 12%) wet ‘less Total than once a week’ and 67 (0.8%) wet ‘once Day 19 195 1042 6885 8141 a week’, thus 1045 (82.9%) of bedwetting Night 19 193 1041 6881 8134 Arousability to void, n (%) children wet ‘at most once a week’. The Never wakes 11 (73.3) 103 (53.6) 586 (56.9) 5433 (79.7) 6133 remaining 215 children (2.6%) wet at a Wakes once/night 0 57 (29.7) 384 (37.3) 1190 (17.5) 1631 frequency meeting the DSM IV definition Wakes twice/night 2 (13.3) 16 (8.3) 33 (3.2) 54 (0.8) 105 of NE (‘at least twice a week’); 112 (1.4%) Wakes ≥3 times/night 1 (6.7) 6 (3.1) 2 (0.2) 12 (0.2) 21 wet 2–5 times a week, 84 (1.0%) nearly Don’t know 1 (6.7) 10 (5.2) 25 (2.4) 127 (1.9) 163 every night, and 19 (0.2%) ‘more than once Total 15 192 1030 6816 8053 a night’.
Table 2 shows a higher rate of bedwetting in boys (20.2%) than in girls (10.5%), and when frequency of bedwetting ‘at least twice/week’ mostly ‘infrequent’ (no more than once a Nearly 80% of non-bed wetting children did is considered, the relative difference between week) but 79 (0.9%) had ‘severe’ daytime not wake to void (Table 2). Just over 40% of boys and girls is even greater, at 150 boys wetting. Only 266 (3.3%) children had both ‘frequent’ and ‘infrequent’ bedwetting (3.6%) vs 65 girls (1.6%). daytime wetting and bedwetting, of whom children woke to void during the night, some only a very few (0.2%) had both ‘frequent/ more than once. During the day, 60 children For further analysis, bedwetting was multiple’ bedwetting and ‘frequent/multiple’ (10.6%) at 7 years of age still required a categorized according to clinical usefulness as daytime wetting. reminder to toilet (Table 3) and children with follows: (i) multiple bedwetting (at least once NE were far more likely to need a reminder a night); (ii) frequent bedwetting (in line with Daytime soiling was reported in 553 children than children who were dry at night the definition of NE; at least twice a week); (iii) (6.8%), mostly ‘infrequent’ (no more than (P < 0.001). infrequent bedwetting (no more than once a once a week), with 66 (0.8%) having severe week); (iv) not bedwetting (never wet the bed) daytime soiling. Only 189 children (2.3%) had The need to hurry to the toilet to pass urine in both daytime soiling and bedwetting, while the day (urgency) increased with the severity As shown in Table 2, 990 children (12.1%) had 364 (4.5%) of the children had daytime soiling of bedwetting (Table 3; P < 0.001); 28.9% of isolated bedwetting (bedwetting with no and no bedwetting (Table 2). Night-time children with NE showed urgency. In terms of daytime wetting), whilst 358 (4.4%) had soiling was rare; only 66 children (0.8%) had daytime urinary frequency, children with no isolated daytime wetting. There was some night-time soiling, and this was mostly NE very rarely voided as often as 10 times/day daytime wetting in 624 children (7.7%), ‘infrequent’ (no more than once a week). (Table 3), whereas the proportion of children
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TABLE 3 Severity of bedwetting related to the frequency the child voids during the day without a reminder, daytime urgency and daytime voiding frequency
Bedwetting severity 1 (multiple) 2 (frequent) 3 (infrequent) 4 (never) Total Daytime voids without a reminder, n (%)* Never goes without a reminder 1 (5.3) 16 (8.2) 76 (7.3) 767 (11.2) 860 Sometimes goes without a reminder 7 (36.8) 32 (16.4) 62 (6.0) 232 (3.4) 333 Often goes without a reminder 5 (26.3) 49 (25.1) 275 (26.4) 842 (12.3) 1171 Always goes without a reminder 6 (31.6) 98 (50.3) 629 (60.4) 5007 (73.1) 5740 Total 19 195 1042 6848 8104 Daytime urgency, n (%)† Dash to toilet 10 (55.6) 56 (28.9) 177 (17.1) 474 (6.9) 717 Can hold for <5 min 2 (11.1) 65 (33.5) 309 (29.8) 1407 (20.6) 1783 Can hold for >5 min 6 (33.3) 73 (37.7) 550.(53.1) 4954 (72.5) 5583 Total 18 194 1036 6835 8083 Daytime frequency, n (%)‡ Voids <5/day 2 (11.1) 48 (24.6) 306 (29.7) 2716 (39.9) 3072 Voids 5–9/day 10 (55.6) 101 (51.8) 488 (47.4) 2641 (38.8) 3240 Voids ≥10/day 3 (16.7) 11 (5.6) 23 (2.2) 72 (1.1) 109 Don’t know 3 (16.7) 35 (17.9) 213 (20.7) 1378 (20.2) 1629 Total 18 195 1030 6807 8050
Chi-square tests (value, degrees of freedom, two-sided asymptotic significance): *Pearson (332.260, 9, <0.001); likelihood ratio (251.664, 9, <0.001); linear-by- linear association (24.892, 1, <0.001); †Pearson (367.817, 6, <0.001); likelihood ratio (301.447, 6, <0.001; linear-by-linear association (344.504, 1, <0.001); ‡Pearson (130.224. 9, <0.001); likelihood ratio (99.149, 9, <0.001); linear-by-linear association (1.333, 1, 0.248).
DISCUSSION TABLE 4 Severity of bedwetting related to waking after wetting and wetting soon after sleep Epidemiological surveys of NE have been Bedwetting severity undertaken in various parts of the world. 1 (multiple) 2 (frequent) 3 (infrequent) Total Many of these have adopted a cross-sectional Wakes after wetting, n (%)* methodology and use varying definitions of Never 14 (82.4) 100 (52.1) 164 (16.4) 278 what constitutes NE, and for any given age, Sometimes 2 (11.8) 51 (26.6) 250 (24.9) 303 they typically include <1000 individuals. The Often 0 19 (9.9) 98 (9.8) 117 present study, part of a longitudinal survey of Always 1 (5.9) 22 (11.5) 491 (49.0) 514 all children born over a 21-month period in Total 17 192 1003 1212 the County of Avon, UK, in 1991–92, selecting Wets soon after sleep, n (%) 7.5 years as a clinically appropriate age, Never 4 (26.7) 73 (42.2) 766 (85.6) 843 provided >8000 responses. This is the largest Sometimes 5 (33.3) 84 (48.6) 116 (13.0) 205 epidemiological sample of bedwetting Often 2 (13.3) 15 (8.7) 6 (0.7) 23 reported since the national cohort of 1958. Always 4 (26.7) 1 (0.6) 7 (0.8) 12 Total 15 173 895 1083 Three studies have reported prevalence rates based on two criteria for NE, with predictably Chi-square tests (value, degrees of freedom, two-sided asymptotic significance): *Pearson (178.135, 6, disparate results. Verhulst et al. [4] compared <0.001); likelihood ratio (173.148, 6, <0.001); linear-by-linear association (150.539, 1, <0.001). the (WHO International Classification of Diseases) ICD-10 definition of bed wetting ‘at least once a month’ [29] with wetting ‘more than twice a month’; Hellstrom et al. [8] with >10 voids/day increased with wetting or ‘always’ after wetting (Table 4; P < 0.001). examined rates at ‘more than once in severity (P < 0.001). Rates for children wetting ‘soon after sleep’ 3 months’ and ‘more than once a week’; are shown in Table 4. Of children with NE, whilst Chiozza et al. [15] compared DSM III Children with multiple night-time wetting 57.9% ‘sometimes’, ‘often’ or ‘always’ wet (wetting ‘at least once a month’) with DSM IV rarely woke after wetting, but 21.4% of soon after sleep, unlike children with (wetting ‘at least twice a week’). The present children with NE and 58.8% of children with infrequent bedwetting, who tended not to study examined the prevalence in relation to infrequent bedwetting tended to wake ‘often’ wet soon after sleep. three clinically appropriate divisions: multiple
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wetting (‘more than once a night’); NE defined frequent category of bedwetting was ‘less theoretically and empirically [22,27] that this in terms of DSM IV criteria (wetting ‘at least than once a week’ [15]. categorization enhances clinical effectiveness twice a week’); and infrequent bedwetting (‘at by identifying appropriate treatments. Butler most once a week’). Nearly twice as many boys as girls were and Holland [22] highlighted various clinical bedwetting at 7 years of age, the same ratio signs to assist identification. Signs of bladder In the Avon study, at 7 years old the as Verhulst et al. [4] reported in Holland. overactivity include daytime urgency, prevalence of bedwetting (at any frequency) For NE, the rate of 3.6% of boys and 1.6% frequency and waking during or immediately was 15.5%. Whilst caution is required in of girls is almost identical to the Italian after wetting [24–27]. The current comparison with other surveys, because of epidemiological work, where 3.0% of epidemiological survey suggests urgency is different methods, this rate is in accord with boys and 1.5% of girls were found to be rare in children not wetting the bed, yet other European countries. Verhulst et al. [4] bedwetting ‘at least twice a week’ [15]. occurs in 28.9% of those with NE. This is found a prevalence rate of 15.3% for boys in entirely in accord with Watanabe et al. [10], Holland; Devlin [9] reported 13–17% in the Most bedwetting children had no daytime who found bladder overactivity in 28% of Republic of Ireland, and Serel et al. [14] found wetting or soiling, and might be regarded as Japanese bedwetting children, and Kosar et al. a prevalence of 15.1% in Turkey. However, having isolated bedwetting. Similarly, a large [31] in 38% of Turkish children. Daytime such rates are noticeably higher than those percentage of children with daytime wetting toileting frequency (≥10 voids/day) was rare reported in northern Europe, with Jarvelin showed no NE (isolated daytime wetting), in non-bedwetting children, in line with et al. [7] reporting a prevalence of 6.4% in suggesting the presence of discrete problems Swedish studies which suggest children who Finland, and Hellstrom et al. [8] reporting a with differing causes. A few children (3.3%) are dry tend to void 2–8 times/day, with no prevalence of 11.9% for boys and 7.7% for had both daytime wetting and bedwetting, differences between boys and girls [8,32]. girls in Sweden. a rate in accord with the Australian Frequency was increased with severity of epidemiological survey where, in a sample of bedwetting in the present study, although as The prevalence of NE (using the DSM IV children aged 5–12 years, 4% had both the upper limit a criterion was set at >10 definition) in the Avon study was much daytime wetting and bedwetting [12]. Most voids/day, there were few children with such a lower, the rate in this survey being 2.6%, children with daytime soiling showed no degree of frequency overall. Waking after corresponding in general with Chiozza et al. bedwetting, suggesting that, as with daytime wetting was reported in many children with [15], who found wetting ‘twice a week’ in 3% wetting, the two problems have different NE, particularly in those with infrequent of boys and 1.5% of girls. Although causes. The few children (2.3%) with both bedwetting, where 49% always woke after bedwetting is reported to have a fairly high daytime soiling and bedwetting suggests a wetting, suggesting that these children have a prevalence rate, the proportion of children significant clinical challenge. Night-time high degree of bladder overactivity. The matching DSM IV criteria is substantially soiling was rare (0.8%), and shows that presence of the three signs of bladder smaller. In Europe, 2–3% of children at 7 years although bowel control at night might be overactivity endorses the notion of old might be expected to be bedwetting expected to be achieved at 36 months by heterogeneity amongst bedwetting children at a severity to be defined as NE. However, virtually all children [30], a small but clinically and highlights the importance of identifying severity is not the sole determining factor significant group lack nocturnal bowel control children with non-monosymptomatic in a clinical context; both DSM IV [1] at 7 years. enuresis. The observed rates of the three signs and Butler [2] advocate the presence of of bladder overactivity are not equally spread accompanying distress, concern and potential Nearly 80% of children who never wet the bed through the population of children with NE, psychological impact as important in also never wake to void, suggesting that they emphasizing the importance of individual determining both definition and clinical have low nocturnal urine production and assessment and intervention in clinical appropriateness. adequate functional bladder capacity [22]. practice. That ª20% who do wake to void (nocturia) Only a minority of children wet every night or suggests that their arousability to full bladder Wetting soon after sleep has been identified nearly every night; including those who wet signals enables them to remain dry at night. as a sign of low vasopressin release [24]. It is, ‘more than once a night’, only 1.2% of the Of the frequent and infrequent bedwetting in practice, often difficult to determine the total population (8.2% of the bedwetting children, 40% also wake at least once a night point at which a child wets at night, unless population) wet every night. This is many to void, suggesting that they have either there is a parental check a few hours after the fewer than in the USA, where 15% of children severe NE (wet at night despite also waking to child goes to sleep or if the wetting happens are reported to wet every night [20], or in void), or have inconsistent arousability (able just before waking in the morning. Malaysia, where 20% of the enuretic to wake to void on some nights and not on Nevertheless, respondents to the present population wet every night [18]. Most others). survey were able to judge the degree to which children (12.8% of the total population; their child wet soon after wetting. By its 82.9% of those who wet the bed) wet The heterogeneity of NE is now well accepted, nature, multiple wetting would be associated infrequently (‘no more than once a week’). with current thinking distinguishing children with wetting soon after sleep. As many This compares with Bower et al. [12] in an with monosymptomatic NE (lack of daytime children with NE wet soon after sleep, it Australian survey of children aged 5–12 years, signs of bladder overactivity) from children suggests that a high proportion have low who found 13.8% of the total population wet with non-monosymptomatic NE (bedwetting vasopressin release, as suggested by infrequently (‘no more than once in 2 weeks’), with associated daytime signs of bladder Norgaard et al. [33] and Rittig et al. [34]. and an Italian survey that found the most overactivity). It has been argued both This contrasts with children with infrequent
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wetting, most of whom did not wet soon after 5 Fergusson DM, Horwood LJ, Shannon Kong schoolchildren: a critical reappraisal sleep. FT. Factors related to the age of from a large epidemiological study. BJU attainment of nocturnal bladder control: Int 2001; 87 (Suppl. 1): 52 ACKNOWLEDGEMENTS an 8-year longitudinal study. Pediatrics 20 Foxman B, Valdez RB, Brook RH. 1986; 78: 884–90 Childhood enuresis: prevalence, perceived We are extremely grateful to all the mothers 6 Rahim SI, Cederblad M. Epidemiology of impact, and prescribed treatments. and other carers who have taken part in this nocturnal enuresis in a part of Khartoum, Pediatrics 1986; 77: 482–7 study for several years and continue to do so, Sudan. I. The extensive study. Acta 21 van Gool JD, Nieuwenhuis E, ten and to the midwives for their cooperation and Paediatr Scand 1986; 75: 1017–20 Doeschate IO, Messer TP, de Jong TP. help in recruiting the mothers during 7 Jarvelin MR, Vikevainen-Tervonen L, Subtypes in monosymptomatic nocturnal pregnancy. The whole ALSPAC study team Moilanen I, Huttunen NP. Enuresis in enuresis. II. Scand J Urol Nephrol Suppl comprising of interviewers, computer seven-year-old children. Acta Paediatr 1999; 202: 8–11 technicians, clerical workers, research Scand 1988; 77: 148–53 22 Butler RJ, Holland P. The three systems: scientists, volunteers, and managers, continue 8 Hellstrom AL, Hanson E, Hansson S, a conceptual way of understanding to make the study possible. The ALSPAC study Hjalmas K, Jodal U. Micturition habits nocturnal enuresis. Scan J Urol Nephrol could not have been undertaken without the and incontinence in 7-year-old Swedish 2000; 34: 270–7 financial support of the Wellcome Trust, the school entrants. Eur J Paediatrics 1990; 23 Neveus T. Oxybutynin, desmopressin and Medical Research Council, National Institutes 149: 434–7 enuresis. J Urol 2001; 166: 2459–62 of Health, and various UK Government 9 Devlin JB. Prevalence and risk factors for 24 Lettgen B. Differential diagnoses for Departments and Charitable Trusts. The childhood nocturnal enuresis. Ir Med J nocturnal enuresis. Scand J Urol Nephrol ALSPAC study is part of the WHO initiated 1991; 84: 118–20 Suppl 1997; 183: 47–9 European Longitudinal Study of Pregnancy 10 Watanabe H, Kawauchi A, Kiramori T, 25 Norgaard JP, Rittig S, Djurhuus JC. and Childhood. We are also grateful to: the Azuma Y. Treatment system for nocturnal Nocturnal enuresis: an approach to Enuresis Information and Resource Centre enuresis according to an original treatment based on pathogenesis. in Bristol, East Leeds Primary Care Trust, classification system. Eur Urol 1994; 25: J Paediatr 1989; 114: 705–10 Leeds Mental Health Trust Library, and Sarah 43–50 26 Yeung CK, Chiu HN, Sit FK. Bladder Gasson Psychological Assistant, for their 11 Kalo BB, Bella H. Enuresis: prevalence dysfunction in children with refractory support and assistance during the course and associated factors among primary monosymptomatic primary nocturnal of this study. school children in Saudi Arabia. Acta enuresis. J Urol 1999; 162: 1049–55 Paediatr 1996; 85: 1217–22 27 Butler RJ, Robinson JC, Holland P, 12 Bower WF, Moore KH, Shepherd RB, Doherty-Williams D. Investigating the CONFLICT OF INTEREST Adams RD. The epidemiology of three systems approach to complex childhood enuresis in Australia. Br J Urol childhood nocturnal enuresis: medical None declared. 1996; 78: 602–6 treatment interventions. Scand J Urol 13 Yeung CK. Nocturnal enuresis in Hong Nephrol 2004; 38: 117–21 Kong: different Chinese phenotypes. 28 Golding J, Pembrey M, Jones R et al. REFERENCES Scand J Urol Nephrol Suppl 1997; 183: ALSPAC – the Avon Longitudinal Study 17–22 of Parents and Children. I. Study 1 American Psychiatric Association. 14 Serel TA, Akhan G, Koyuncouglu HR methodology. Paediatr Perinat Epidemiol Diagnostic and Statistical Manual of et al. Epidemiology of enuresis in Turkish 2001; 15: 74–87 Mental Disorders; DSM IV, 4th edn. children. Scand J Urol Nephrol 1997; 31: 29 World Health Organisation. The ICD-10 Washington DC: American Psychiatry 537–9 Classification of Mental and Behavioural Press, 1995 15 Chiozza ML, Bernardinelli L, Caione Disorders: Diagnostic Criteria for 2 Butler RJ. Nocturnal Enuresis: The Child’s P et al. An Italian epidemiological Research. Geneva: WHO, 1993 Experience. Oxford: Butterworth multicentre study of nocturnal enuresis. 30 Stein Z, Susser M. Social factors in the Heinemann, 1994 Br J Urol 1998; 81 (Suppl. 3): 86–9 development of sphincter control. Dev 3 Krantz I, Jylkas E, Ahlberg BM, Wedel 16 Lee SD, Sohn DW, Lee JZ, Park NC, Med Child Neurol 1967; 9: 692–706 H. On the epidemiology of nocturnal Chung MK. An epidemiological study of 31 Kosar A, Arikan N, Dincel C. enuresis: a critical review of methods enuresis in Korean children. BJU Int 2000; Effectiveness of oxybutynin hydrochloride used in descriptive epidemiological 85: 869–73 in the treatment of enuresis nocturna – studies on nocturnal enuresis. Scand J 17 Chang P, Chen WJ, Tsai WY, Chiu YN. a clinical and urodynamic study. Scand J Urol Nephrol Suppl 1994; 163: 75–82 An epidemiological study of nocturnal Urol Nephrol 1999; 33: 115–8 4 Verhulst FC, van der Lee JH, Akkerhuis enuresis in Taiwanese children. BJU Int 32 Mattsson SH. Voiding frequency, GW, Sanders-Woudstra JA, Timmer FC, 2001; 87: 678–81 volumes and intervals in healthy school Donkhorst ID. The prevalence of 18 Kanaheswari Y. Epidemiology of children. Scand J Urol Nephrol 1994; 28: nocturnal enuresis: do DSM III criteria childhood nocturnal enuresis in Malaysia. 1–11 need to be changed? A brief research J Paediatr Child Health 2003; 39: 118–23 33 Norgaard JP, Pedersen EB, Djurhuus JC. report. J Child Psychol Psychiatry 1985; 19 Yeung CK, To LK, Sit FK, Sihoe JD, Chan Diurnal anti-diuretic hormone levels in 26: 989–93 S. Primary nocturnal enuresis in Hong enuretics. J Urol 1985; 134: 1029–31
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34 Rittig S, Knudsen UB, Norgaard JP, Correspondence: Dr Richard J. Butler, Abbreviations: DSM, Diagnostic and Pedersen EB, Djurhuus JC. Abnormal Department of Clinical Psychology, Unit 2, Statistical Manual of Mental Disorders; diurnal rhythm of plasma vasopressin and Gateway, Whackhouse Lane, Yeadon, Leeds ALSPAC, The Avon Longitudinal Study of urinary output in patients with enuresis. LS19 7XY, UK. Parents and Children; NE, nocturnal enuresis. Am J Physiol, 1989; 256: F664–71 e-mail: [email protected]
410 © 2005 BJU INTERNATIONAL Original Article TOLTERODINE FOR NON-NEUROGENIC VOIDING DYSFUNCTION IN CHILDREN AYAN et al.
Efficacy of tolterodine as a first-line treatment for non-neurogenic voiding dysfunction in children
SEMIH AYAN, KEMAL KAYA, KAHRAMAN TOPSAKAL, HAKAN KILICARSLAN, GOKHAN GOKCE and YENER GULTEKIN Department of Urology, Medical Faculty, Cumhuriyet University, Sivas, Turkey Accepted for publication 2 February 2005
OBJECTIVE with specific emphasis on the voiding pattern. 13.8 (2.79) and 14.5 (2.44) before and Anticholinergic treatment with tolterodine 6.43 (3.79) and 7.50 (3.34) after treatment. To assess the effect of antimuscarinic (1 mg twice daily) was started in all patients; treatment with tolterodine combined with they were also informed about conservative CONCLUSION behavioural modification as a first-line management, including timed voiding, double treatment, before invasive investigation, in voiding and relaxation of the pelvic floor Tolterodine combined with behavioural children with non-neurogenic voiding during voiding. At the start and after modification for dysfunctional voiding in dysfunction but no obvious anatomical or 3 months, the dysfunctional voiding symptom children with no neurological or anatomical neurogenic cause. score (DVSS) was completed twice by all abnormality can be recommended as a first- patients. line treatment before invasive evaluation. PATIENTS AND METHODS Additionally, the DVSS appears to provide RESULTS accurate and objective data for monitoring The study comprised 44 children presenting the effect of treatment in such children. with voiding dysfunction (30 girls and 14 For all patients the mean (SD) DVSS was boys, mean age 7 years, range 5–14); all 14.0 (2.67) and 6.68 (3.67) before and after KEYWORDS had a noninvasive evaluation consisting of treatment, respectively; the difference was a history, urine analysis, renal and bladder statistically significant (P < 0.001). The mean voiding dysfunction, tolterodine, ultrasonography and physical examination, scores for girls and boys, respectively, were dysfunctional voiding symptom score
INTRODUCTION the value of urodynamics and radiological or PATIENTS AND METHODS cystoscopic evaluation [13–16]. The results of Dysfunctional voiding is one of the many recent studies support the view that the Voiding dysfunction was defined as commonest clinical entities in paediatric routine use of urodynamics, radiological incontinence, frequency, urgency or urology, with ª40% of such patients evaluation and cystoscopy do not change obstructive symptoms with or with no presenting to paediatric urologists [1,2]. therapy or influence final outcome in most recurrent afebrile UTI, with no obvious Symptoms include daytime and night-time children with voiding dysfunction, and these anatomical or neurogenic cause. The study wetness, urgency, frequency or infrequency, methods may not be necessary, provided that included 44 children presenting with these constipation or fecal incontinence. UTI a thorough history is taken and the child features (30 girls and 14 boys, mean age is very common in these patients [3–5]. examined physically [15,16]. The lack of a 7 years, (range 5–14). All patients had a Anticholinergic medication and strict universally accepted objective means for noninvasive evaluation consisting of a behavioural modification are the cornerstones detecting and monitoring the effect of history, urine analysis, renal and bladder of treating functional voiding disorders and therapy is another negative factor that ultrasonography and a physical examination, incontinence in children [1,6]. As a widely hampering the reporting of standardized with specific emphasis on voiding pattern. used agent for treating incontinence and outcomes for voiding dysfunction studies in Exclusion criteria were detection of an overactive bladder in adults, tolterodine is children. abnormality with renal ultrasonography, a effective and safe, with reportedly fewer large post-void residual urine volume, a adverse effects than oxybutynin in children in The aim of the present study was to assess the history of febrile UTI, a history of failed recent studies [7–11]. effect of antimuscarinic treatment with previous therapy, and a positive neurological tolterodine combined with behavioural examination, including back lesions and There is no consensus on the diagnostic modification as a first-line treatment before an abnormal voiding pattern. Informed features or detection and monitoring of invasive investigation in children with no consent was obtained from the parents. dysfunctional voiding. A history, physical obvious anatomical or neurogenic cause. To Anticholinergic treatment with tolterodine examination, voiding diaries and quantitatively standardize dysfunctional (1 mg twice daily) was started in all patients uroflowmetry curves, with detection of voiding symptoms in children, the [17] and maintained for 3 months. Patients postvoid residual urine, are methods for dysfunctional voiding symptom score (DVSS) were also informed about conservative diagnosis [12]. There is no agreement about was used [12]. management, including timed voiding, double
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voiding, and relaxation of the pelvic floor in children. Although behavioural TABLE 1 The presenting symptoms and during voiding. Patients with dysfunctional modification is the most important, associated complaints in 44 children bowel elimination (15, eight girls and seven pharmacological and biofeedback methods boys) were treated with a high-fibre diet and have also been used [14,18–20]. Children Symptoms N laxatives if necessary. At the start and after with voiding dysfunction often undergo Diurnal enuresis 29 3 months, the DVSS (Appendix) was radiological, urodynamic or even cystoscopic Frequency/urgency 17 completed twice by all patients. Parents were evaluation to identify an anatomical or Constipation and/or encopresis 16 asked to record the side-effects during drug neurogenic cause [15]. However, recently Nocturnal enuresis 14 treatment. The paired t-test was used to the role of these methods in evaluating, History of afebrile UTI 10 compare the means, with P < 0.05 considered managing and in the outcome has been Giggle incontinence 1 to indicate statistical significance. intensively criticised [12–16]. Although video- urodynamics have increasingly gained favour for evaluating dysfunctional voiding, and RESULTS non-neurogenic voiding dysfunction has also been classified according to urodynamic bladder contractions, pelvic floor overactivity A summary of the presenting symptoms and findings, its role in management and final and poorly learned voiding are the main associated complaints is shown in Table 1. outcome compared with the cost- preceding factors. Among the drugs used Compliance, including the use of medication effectiveness has been debated [4,15,21]. for treating the hyperactive bladder, as scheduled and adhering to behavioural Soygür et al. [16] did not recommend video- antimuscarinic agents are still regarded as modification, was good for all patients. For all urodynamics in children with non-neurogenic first-line therapy. To date there are few patients, the mean (SD) DVSS was 14.0 (2.67) voiding dysfunction, as it does not generally reports on the use of tolterodine in children. and 6.68 (3.67) before and after treatment, change the management of these children. Goessl et al. [11] published the first study of respectively; the difference was statistically They concluded that a detailed voiding history tolterodine in children with detrusor hyper- significant (P < 0.001). The respective mean and physical examination is sufficient for a reflexia, and reported that the drug improved (SD, range) DVSS of girls and boys before correct diagnosis. the compliance of the bladder in these treatment was 13.8 (2.79, 8–20) and 14.5 children. Munding et al. [7] reported that (2.44, 3–20), and after treatment was Parekh et al. [15] retrospectively evaluated the tolterodine may be beneficial for reducing 6.43 (3.79) and 7.50 (3.34). The mean scores records of 1153 children with dysfunctional wetting episodes in children with voiding for a subgroup of DVSS questions (numbers 1, voiding disorder and concluded that the dysfunction, with no severe adverse effects. 2, 6 and 7) related to detrusor hyperactivity incidence of upper tract changes and positive Hjalmas [8] published pharmacokinetic data were also significantly different before and anatomical findings in these children was too and reported that the overactive bladder in after treatment, at 7.63 (1.97) and 2.59 (1.04) low to justify routine radiological evaluation children may be a potential future indication (P < 0.001). and cystoscopy. They used video-urodynamics for tolterodine. Raes et al. [10] evaluated in only 40 of the patients who remained the efficacy and tolerability of tolterodine No patient discontinued therapy because of refractory to standard treatment for voiding in unselected children with detrusor side-effects of tolterodine; 14 (31%) reported dysfunction, and in those with positive hyperactivity, and concluded that tolterodine dry mouth and two (4%) reported headache radiological or cystoscopic findings. They is well tolerated in children and offers an after the first few days of treatment, but the concluded that, in these patients, a effective treatment which is better than effects were not severe. All but four patients urodynamic study may possibly have affected unselective antimuscarinic drugs for adverse (three girls and one boy) improved with treatment, e.g. changing the dose of effects. tolterodine treatment; three of these had the anticholinergics or considering the addition highest DVSS (20, and two of 17) before of a second-line agent, but it was unlikely that We used the DVSS to evaluate the effect of treatment. All four had a urodynamic study urodynamics would have affected the tolterodine for dysfunctional voiding in the and voiding cysto-urethrography (VCUG). An ultimate outcome. The coexistence of voiding present children; the DVSS includes 10 a-blocking agent was initiated in one girl dysfunction with VUR is well known, with a quantitative and qualitative urological because she had a ‘spinning-top’ deformity reported incidence of up to 50% by some variables assessed by age-appropriate detected on VCUG and detrusor-sphincter groups [22–25]. However, in the study by questions for children, and has been used as dyssynergia on urodynamics. Detrusor Parekh et al. [15], again the incidence of high- an objective instrument to grade voiding instability was detected in two girls and one grade VUR in the patients with voiding dysfunction in children [12]. In that study, boy on urodynamics, and grade 1 unilateral dysfunction presenting with afebrile UTI was there was a significant difference in the reflux with VCUG in one girl. They remain negligible (0.4%), which differs from the rate scores of 104 patients referred for under medical treatment and behavioural in previous studies. The incidence of other dysfunctional voiding and 54 age-matched modification. positive anatomical findings, in the form of controls with a normal voiding history. trabeculations, a dilated posterior urethra, Subsequently the score was reported to etc., was also very low in their series, reliably quantify the improvement in voiding DISCUSSION at ª10%. symptoms in 48 of 104 patients who had behavioural modification and completed a There is no universally accepted approach for Although the precise pathophysiology of mailed questionnaire [26]. They also reported evaluating and treating voiding dysfunction dysfunctional voiding is unclear, uninhibited the beneficial use of the DVSS in predicting
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resolution of VUR in children with voiding complex of dysfunctional voiding, urinary 17 Hjalmas K, Hellström AL, Mogren dysfunction [27]. In the present study, tract infection and vesicoureteral reflux. K et al. Safety, efficacy and although the mean score of the girls after International Reflux Study in Children. pharmacokinetics of tolterodine in treatment was slightly higher, the scores J Urol 1992; 148: 1609–703 pediatric patients with overactive bladder. recorded were generally consistent with the 6 Schulman SL, Quinn CK, Plachter N Invited lecture of 2nd Congress of the ICSS, optimum thresholds determined (6.03 for et al. Comprehensive management of Denver: August, 1999 boys and 9.02 for girls) in the original voiding dysfunction. Pediatrics 1999; 18 Koff SA, Wagner TT, Jayanthi VR. study [12]. 103: E31 The relationship among dysfunctional 7 Munding M, Wessells H, Thornberry B, elimination syndromes, primary The limitation of the present study is that Riden D. Use of tolterodine in children vesicoureteral reflux and urinary tract there was no comparative group treated by with dysfunctional voiding: an initial infections in children. J Urol 1998; 160: only behavioural modification. The response report. J Urol 2001; 165: 926–8 1019–22 to the drug might not be as good for those 8 Hjalmas K, Hellstrom AL, Mogren K, 19 Wiener JS, Scales MT, Hampton J, King with initially higher scores, possibly because Lackgren G, Stenberg A. The overactive LR, Surwit R, Edwards CL. Long-term the natural history of the disorder is that a bladder in children: a potential future efficacy of simple behavioral therapy for proportion of the children will improve indication for tolterodine. BJU Int 2001; daytime wetting in children. J Urol 2000; spontaneously with no therapy, or the 87: 569–74 164: 786–90 improvement obtained with the combination 9 Nijman RJ. Role of antimuscarinics in the 20 Snodgrass W. The impact of treated of tolterodine and behavioural modification in treatment of nonneurogenic daytime dysfunctional voiding on the nonsurgical all patients was mainly a result of behavioural urinary incontinence in children. Urology management of vesicoureteral reflux. modification. 2004; 63: 45–50 J Urol 1998; 160: 1823–5 10 Raes A, Hoebeke P, Segaert I, Van 21 Ewalt DH, Bauer SB. Pediatric In conclusion, we recommend the use of Laecke E, Dehoorne J, Vande Walle J. neurourology. Urol Clin North Am 1996; tolterodine combined with behavioural Retrospective analysis of efficacy and 23: 501–9 modification as a first-line treatment for tolerability of tolterodine in children with 22 Lyon RP, Tanagho EA. Distal urethral dysfunctional voiding in children with no overactive bladder. Eur Urol 2004; 45: stenosis in little girls. J Urol 1965; 93: neurological or anatomical abnormality, 240–4 379–82 before invasive evaluation; tolterodine is well 11 Goessl C, Sauter T, Michael T, Berge 23 Kendall AR, Karafin L. Urinary tract tolerated in children. The DVSS appears to B, Staehler M, Miller K. Efficacy and infection in children. fact and fantasy. provide accurate and objective data in tolerability of tolterodine in children with J Urol 1972; 107: 1068–72 monitoring the effect of treatment in children detrusor hyperreflexia. Urology 2000; 55: 24 Immergut M, Culp D, Flocks RH. The with voiding dysfunction. 414–8 urethral caliber in normal female children. 12 Farhat W, Bagli DJ, Capolicchio G et al. J Urol 1967; 97: 693–5 The dysfunctional voiding scoring system. 25 Tanagho EA, Mccurry E. Pressure and CONFLICT OF INTEREST quantitative standardization of flow rate as related to lumen caliber and dysfunctional voiding symptoms in entrance configuration. J Urol 1971; 105: None declared. children. J Urol 2000; 164: 1011–5 583–5 13 Glazier DB, Murphy DP, Fleisher MH, 26 Farhat W, McLorie GA, O’Reilly S, REFERENCES Cummings KB, Barone JG. Evaluation Khoury A, Bagli DJ. Reliability of of the utility of video-urodynamics in the pediatric dysfunctional voiding 1 Rushton HG. Wetting and functional children with urinary tract infection and symptom score in monitoring response disorders. Urol Clin North Am 1995; 22: voiding dysfunction. Br J Urol 1997; 80: to behavioral modification. Can J Urol 75–93 806–8 2001; 8: 1401–5 2 Snodrass W. Relationship of voiding 14 Hoebeke P, Van Laecke E, Van Camp 27 Upadhyay J, Bolduc S, Bagli DJ, dysfunction to urinary tract infection and C, Raes A, Van De Walle J. One McLorie GA, Khoury AE, Farhat W. vesicoureteral reflux in children. Urology thousand video-urodynamic studies in Use of the dysfunctional voiding 1991; 38: 341–4 children with non-neurogenic bladder symptom score to predict resolution 3 Norgaard JP, van Gool JD, Hjalmas K sphincter dysfunction. BJU Int 2001; 87: of vesicoureteral reflux in children with et al. Standardization and definition in 575–80 voiding dysfunction. J Urol 2003; 169: lower tract dysfunction in children. 15 Parekh DJ, Pope JC, Adams MC, Brock 1842–6 International Children’s Continence JW 3rd. The use of radiography, Society. Br J Urol 1998; 81 (Suppl 3): urodynamic studies and cystoscopy in the Correspondence: Semih Ayan, Department of 1–16 evaluation of voiding dysfunction. J Urol Urology, Medical Faculty, Cumhuriyet 4 van Gool JD, Vijverberg MA, deJong TP. 2001; 165: 215–8 University, Sivas, Turkey. Functional daytime incontinence: clinical 16 Soygur T, Arikan N, Tokatli Z, Karaboga e-mail: [email protected] and urodynamic assessment. Scand J Urol R. The role of video-urodynamic studies Nephrol Suppl 1992; 141: 58–69 in managing non-neurogenic voiding Abbreviations: DVSS, dysfunctional voiding 5 van Gool JD, Hjalmas K, Tamminen- dysfunction in children. BJU Int 2004; 93: symptom score; VCUG, voiding cysto- Mobius T et al. Historical clues to the 841–3 urethrography.
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Patient Name: Hospital Number: Reason for Referral: Date:
Almost Less than About half Almost every Over the last month never half the time the time time Not available 1. I have had wet clothes or wet underwear during the day. 0 1 2 3 NA 2. When I wet myself, my underwear is soaked. 0 1 2 3 NA 3. I miss having a bowel movement every day. 0 1 2 3 NA 4. I have to push for my bowel movements to come out. 0 1 2 3 NA 5. I only go to the bathroom one or two times each day. 0 1 2 3 NA 6. I can hold onto my pee by crossing my legs, squatting or doing the “pee dance”. 0 1 2 3 NA 7. When I have to pee, I cannot wait. 0 1 2 3 NA 8. I have to push to pee. 0 1 2 3 NA 9. When I pee it hurts. 0 1 2 3 NA 10. Parents to answer. Has your child experienced something stressful like the 01 2 3 NA example below? TOTAL NO (0) YES (3)
414 © 2005 BJU INTERNATIONAL Investigative Urology
EDITORS Helmut Klocker Jack Schalken Bill Watson ASSOCIATE EDITORS Georg Bartsch David Neal
EDITORIAL BOARD Karl-Eric Andersson Kazem Azadzoi Olivier Cussenot Christopher Foster Robert Getzenberg Martin Gleave Hans Lilja Marston Linehan Norman Maitland Bruce Malkowicz Joel Nelson John Stein Ulf-Håkan Stenman Christian Stief George N. Thalmann Dan Theodorescu Tapio Visakorpi
BJUINTERNATIONAL EDITOR-IN-CHIEF JOHN M. FITZPATRICK Original Article INHIBITION OF BLADDER CARCINOMA CELL INVASION BY PP2 CHIANG et al.
The src-family kinase inhibitor PP2 suppresses the in vitro invasive phenotype of bladder carcinoma cells via modulation of Akt
GEORGE J. CHIANG*, BRIAN R. BILLMEYER*, DAVID CANES*, JOHN STOFFEL*, ALIREZA MOINZADEH*, CHRISTINA A. AUSTIN†, MONIKA KOSAKOWSKI†, KIMBERLY M. RIEGER-CHRIST*†, JOHN A. LIBERTINO* and IAN C. SUMMERHAYES*† *Department of Urology, Lahey Clinic Medical Center, and †Cell and Molecular Biology Laboratory, R.E. Wise MD Research and Education Institute, Burlington MA, USA G.J.C, and B.R.B. were equal contributors to this work Accepted for publication 9 March 2005
OBJECTIVE with an assessment of the activation status of inactivation of Akt in all cells and a mitogen-activated protein kinase and Akt concomitant reduction in in vitro invasive To evaluate PP2 as a modulator of the signalling pathways. Altered invasive capacity capacity. cadherin/catenin complex in late-stage linked to these variables was determined in bladder carcinoma cells, and to assess its standard in vitro invasion assays. CONCLUSIONS potential invasion-suppressor activity in this model. These results show that PP2 inhibits bladder RESULTS carcinoma cell growth and can modulate plakoglobin expression in a subset of cell lines. MATERIALS AND METHODS PP2 elicited concentration-dependent growth In addition, PP2 can suppress the in vitro inhibition in all bladder cell lines within the invasive capacity of bladder carcinoma cells A panel of five human bladder carcinoma panel, with growth suppression recorded at by modulating the activation status of Akt. cells, characterizing late-stage disease, was 10–35 mmol/L PP2. Distinct morphological used to determine the concentration for 50% changes were recorded in cell lines exposed to KEYWORDS inhibition of PP2 in cell-proliferation assays. PP2, accompanied by up-regulation of Modulation of cadherin/catenin expression by plakoglobin expression in a subset of lines. bladder, carcinoma, PP2, invasion, Akt PP2 was determined in Western blot analysis, Exposure of cells to PP2 resulted in signalling
INTRODUCTION To adopt a targeted therapeutic approach to directly involved in invasion [14,15], where invasive bladder cancer it is necessary to loss of E-cadherin in bladder cancer Identifying the molecular events underlying understand the events that underlie this progression has been recorded as a frequent bladder tumorigenesis defines different very complex process. The frequency of p53 event in late-stage disease and is indicative of pathways to bladder cancer, facilitating the mutations in bladder tumours is higher in poor survival [16]. Restoration of E-cadherin design of targeted therapeutics [1] to high-grade and high-stage tumours than in expression to carcinoma cells has been shown complement established therapies. Recent low-grade lesions [6,7]. Along with loss of to suppress invasion, both in in vitro and in examples of such investigational therapeutic expression of the retinoblastoma gene vivo models. In bladder cancer, novel strategies used in bladder cancer trials include product in late-stage bladder disease [8,9], expression of N-cadherin has also been farnesyl transferase inhibitors designed to alterations associated with these two loci are identified in tumour progression [17] linked to inhibit cell signalling in ras-transformed cells indicative of a poor outcome in patients with an invasion-promotion role in carcinoma cells and the use of growth factor inhibitors, bladder cancer [10–12]. Alternative molecular [18]. In addition, loss or altered expression of targeted at the tyrosine kinase family of changes implicated in the prognosis in different catenin members in bladder tumours membrane receptors [2]. Presently, grade and bladder cancer include FGFR-3, c-myc, H-ras, has been linked to poor prognosis [19,20]. stage best define the risk of progression in c-erbB-1 and c-erbB-2 (for review see [13]), Within this adhesion complex there are bladder cancer, where the 5-year survival where changes associated with each loci may several different players, altered in bladder rate after surgery for muscle infiltrative define a subpopulation of bladder tumours tumorigenesis, with potential roles in disease (T2–T4), remains poor, as low as with different clinical behaviours. However, invasion. 10% for stage T4 disease [3–5]. Novel there is little direct evidence that changes agents with invasive-suppressor activity associated with these gene loci are primarily To target the modulation of the cadherin would be desirable additions to the current involved in the acquisition of the invasive complex, with the goal of suppressing options for chemotherapeutic agents in phenotype in bladder tumours. In contrast, invasion, it is important to know the bladder cancer. the cadherin family of adhesion molecules is mechanism of inactivation, or activation, of
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different components throughout tumour bromophenol blue) and sheared through a serum. After incubation, cells were washed progression. For instance, loss of expression 26 G needle. Lysates were then assayed for and maintained in standard medium with of the invasive-suppressor gene E-cadherin in protein concentration using the BSA method serum. At 48 h after transfection, cells were bladder cancer is reportedly regulated by (Pierce, Rockford, IL). After determining the split into puromycin-containing medium methylation events associated with the protein content, b-mercaptoethanol (1%) (2 mg/mL) to select for successfully promoter region of the gene [21,22]. Loss or was added to each sample. Samples were transfected colonies. Individual colonies reduced expression of plakoglobin in late- boiled for 5 min and protein was loaded in selected in puromycin were ring-cloned stage bladder cancer occurs, at least partly, as each lane of a 7.5% or 12.5% polyacrylamide 2 weeks later. a result of acetylation events [23,24]. Hence, gel. Proteins were transferred overnight onto demethylating and/or histone deacetylase nitrocellulose. Membranes were blocked in The following antibodies were used: N- inhibitors, are suitable agents for testing the 10% milk in Tris buffered saline with 0.05% cadherin clone 13A9 (1 : 200; kindly provided potential to restore cadherin function. Tween (TBST) and placed on primary antibody by Dr M Wheelock, University of Nebraska, Another class of agents representing src overnight at 4 ∞C. After incubating with the Omaha, NE); a-catenin (1 : 200), b-catenin, kinase-family inhibitors have been shown to primary antibody, blots were washed in TBST g-catenin and p120 (Transduction modulate cadherin/catenin expression and three times for 15 min each, and secondary Laboratories, Lexington KY); mitogen- have antimetastatic activity in vivo [25,26]. To antibody linked to horseradish peroxidase was activated protein kinase (MAPK), date these have been tested in models where incubated with the blots for 1 h at room phosphorylated MAPK, Akt and elevated levels of src activity accompany temperature. Blots were then washed as phosphorylated Akt (Cell Signalling progression [27,28], an event that does not described above and developed with an ECL Technology, Beverly, MA); E-cadherin (1 : 500, occur in urothelial neoplastic progression kit (Amersham, Arlington Heights, IL). Zymed, San Francisco, CA), PTEN (Chemicon [29]. In the present study we investigated the Int., Temecula, CA), b-actin (Sigma). All potential invasive-suppressor activity of the For immunoprecipitation and Src kinase assay, antibodies were used at 1 : 1000 dilution src family kinase inhibitor PP2 within a panel subconfluent dishes of cell lines were lysed in unless otherwise indicated. All biochemical of bladder cell lines, evaluating the expression PBS-TDS buffer (PBS pH 7.4, 1% Triton X-100, inhibitors (PD98059, 40 mmol/L, LY294002, status of different cadherin complex 0.5% sodium deoxycholate, 2 mmol/L phenyl- 20 mmol/L, PP2 15 mmol/L, Akt inhibitor; components and changes in signalling events methylsulphonyl fluoride, 100 units 1 L-6-hydroxymethyl-chiro-inositol triggered by exposure to PP2. aprotinin). Lysis was carried out on ice for 2-(R)-2–0-methyl-3–0-octadecylcarbonate 20 min followed by clarification in a 20 mmol/L) were purchased from Calbiochem MATERIALS AND METHODS microfuge at 4 ∞C. Supernatants were (San Diego, CA). removed and a 10-mL aliquot taken for The human bladder carcinoma cell lines J82, protein estimation using the BSA protein Cells used in growth factor assays were T24, UM-UC-3, EJ, KK47 and HU456 were assay system. For immunoprecipitation, the maintained until subconfluent and then maintained in Dulbecco’s Modified Eagle’s protein concentration was standardized washed with PBS, followed by an overnight Medium (DMEM) supplemented with 7.5% between samples, using 400 mg protein for incubation in serum-free DMEM. Assays fetal bovine serum and penicillin/ each preparation. Lysates were incubated designed to assess the signalling pathways streptomycin. overnight at 4 ∞C with Mab327 (Oncogene activated by the action of growth factors Science, Manhasset, NY), followed by adding (epidermal growth factor, EGF, Sigma; A stock solution of PP2 (3.3 mmol/L; Sigma, protein A-Sepharose beads and a further heregulin-b, EGF domain, US Biological, St. Louis, MO), dissolved in dimethyl 90 min incubation. Immune complexes were Swampscott MA; human basic fibroblast sulphoxide (DMSO), was aliquoted and stored washed three times in PBS-TDS and three growth factor (bFGF), Peprotech, Rock Hill NJ; at -20 ∞C. The effect of PP2 or DMSO on the times in 0.1% PBS. Immunocomplexes were human insulin, Lilly, Indianapolis, IN) involved growth and viability of bladder carcinoma incubated with [32P]-ATP in kinase buffer exposure of cells to growth factor (20 ng/mL) cells was determined by cell counting using a (50 mmol/L 4-(2-hydroxyethyl)-1-piperazine- for 1 h in the continued absence of serum. haemocytometer. Cells were seeded at a ethanesulphonic acid, pH 7.4, 5 mmol/L Cells were then lysed and analysed by Western 5 density of 5 ¥ 10 cells per 60 mm dish in MnCl2, 5 mmol/L MgCl2) for 20 min at room blot. The same protocol was followed for DMEM supplemented with 7.5% serum, and temperature. The antibody bead complex was invasion assays where the presence of the allowed to attach overnight. After 24 h the washed three times in PBS and run in 12.5% growth factor was maintained throughout medium was replaced daily with fresh polyacrylamide gels. Gels were dried and the course of the assay. medium containing the appropriate exposed to X-ray film. concentration of PP2 or DMSO. Cells were In vitro invasion was assayed using modified counted at various intervals after the start of For the transfection assay, J82 cells were Boyden chambers consisting of Transwell treatment. At each time point cell viability plated at 3 ¥ 105 cells per 60 mm dish 24 h (Corning Costar Corp., Cambridge, MA) was assessed by trypan blue exclusion. All before lipofection. Either the puromycin gene membrane filter inserts in 24-well tissue experiments were performed in triplicate. alone or the wild-type PTEN gene (generous culture plates. For invasion assays the upper gift from Dr KM Yamada, Bethesda, MD) surfaces of the membranes were coated with For Western blot analysis, subconfluent dishes plus the puromycin-resistance gene were Matrigel (Collaborative Biomedical Products, of cells were washed in PBS followed by lysis mixed with lipofectin reagent (Gibco BRL, Bedford, MA) and placed into 24-well tissue in hot sample buffer (2 ¥ ESB-0.08 mol/L Tris, Gaithersburg, MD, USA) and incubated with culture plates containing 600 mL of NIH/3T3 pH 6.8; 0.07 mol/L SDS, 10% glycerol, 0.001% cells at 37 ∞C overnight in the absence of conditioned media (experimental) or serum-
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free DMEM (control); 1 ¥ 105 cells were added FIG. 1. 100 A to each Transwell chamber and allowed 90 Effect of PP2 on a panel of bladder to invade toward the underside of the cell lines in vitro (UMUC, green 80 membrane for 8 h (J82), 16 h (UM-UC-3) or dotted line; J82, red closed 24 h (T24, EJ, KK47) at 37 ∞C. Cells that passed 70 squares; T24, green closed circles; through the membrane were fixed in 60 EJ, red dashed line; KK47, light methanol, stained with crystal violet and 50 green open circles): A, cells were counted under light microscopy. In additional treated with PP2 at 5, 10, 20, 50,
% Control 40 assays, cells were pre-incubated for 1 h 100 mmol/L, control cells received 30 (PD98059, 40 mmol/L; SB203580, 20 mmol/L; DMSO; B, cells were exposed to LY294002, 20 mmol/L; PP2, 15 mmol/L, Akt 20 PP2 at 15 mmol/L for 3 days. Cells inhibitor, 20 mmol/L) before adding to the 10 were harvested at different times, Matrigel-coated wells and maintained over 0 counted using a haemocytometer and assessed for trypan blue the course of the assay in the presence of 1 10 100 inhibitor. All assays were performed in Log[dose mmol/L] exclusion. Cell numbers were triplicate and repeated three times. recorded as percentage control, 80 B the latter represented by DMSO exposed cells. Immunocytochemical staining was performed 70 on an automated immunocytochemical processor (Ventana ES, Medical Systems, 60 Tucson, AZ). Plakoglobin and acetylated 50 histone 4 antibody were used at dilutions of 40 1 : 500 and 1 : 50, respectively. Cells were plated at subconfluent levels on sterile glass % Control 30 slides and allowed to attach and spread over a 20 24-h period. PP2 or DMSO vehicle was added 10 to the medium and cells maintained for a further 18 h. Cells were fixed in 3.7% formalin 0 for 15 min, washed in three changes of PBS 24 h 48 h 72 h and permeabilized in 0.5% Triton X-100 in PBS for 5 min.
RESULTS the five cell lines showed a significant cadherin complex components within the reduction in plakoglobin expression. Each of same experiment (data not shown). Figure 1A shows that PP2 elicited dose- the cell lines is derived from a late-stage Immunocytochemical staining of dependent growth inhibition in all the bladder tumour and harbour molecular changes morphologically responsive cell lines revealed carcinoma cell lines in the study panel. The indicative of invasive bladder cancer [30]. Cell increased membrane-associated plakoglobin concentration required to inhibit growth by morphological changes associated with after exposure to PP2 (Fig. 3).
50% (IC50) was 10–35 mmol/L of PP2. Trypan exposure to PP2 were recorded in several blue exclusion, assayed on floating cells and bladder carcinoma cell lines, consistent with ALTERED IN VITRO INVASIVE POTENTIAL IN those remaining attached to dishes, revealed the observations by Nam et al. [25] in colon THE PRESENCE OF PP2 >99% loss of viability in the former, with only carcinoma cells, where alterations were 60% of attached cells retaining the ability to accompanied by up-regulation of different The effect of exposure to PP2 on the invasive exclude the dye. Cell viability from these elements of the cadherin/catenin complex. potential of N-cadherin expressing bladder experiments was further confirmed in colony- Figure 2 is a representative blot showing a carcinoma cell lines was analysed using forming assays (data not shown). Figure 1B concentration-dependent increase in standard in vitro Matrigel invasion assays. As shows the time-dependent growth inhibition plakoglobin expression in bladder cell lines J82 and UM-UC-3 were highly invasive in this of bladder carcinoma cells after continuous after a 48-h exposure to PP2. In cell lines assay, the effect of exposure to PP2 was exposure to one concentration of PP2 expressing low levels of plakoglobin, assayed over 8 and 16 h, respectively. The representing the IC50. Half the cells were killed increased expression of this catenin member, same invasion assay involving T24, EJ and by 48 h in cell lines exposed to PP2, causing a in response to PP2 exposure, was recorded in KK47 were performed over 24-h. Figure 4 progressive decline in cell number sustained cell lines EJ, UM-UC-3 and T24, but not J82. shows decreased invasion associated with all during the experimental period. Bladder cell line KK47 constitutively expresses bladder carcinoma cell lines exposed to PP2. high levels of plakoglobin comparable to that MODULATION OF CADHERIN/CATENIN recorded in E-cadherin-expressing bladder MECHANISM OF ACTION OF PP2 INHIBITION EXPRESSION carcinoma cells (HU456). Re-probing blots OF INVASION with antibodies to E-cadherin, N-cadherin, All bladder carcinoma cell lines within the a-, b- and p120 catenins revealed no As PP2 is a src-family kinase inhibitor we panel lack E-cadherin expression and four of discernible change in expression of these initially assayed pp60src kinase activity in the
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FIG. 2. Levels of plakoglobin expression detected Fig. 3. Immunocytochemical staining for plakoglobin in bladder carcinoma cell line T24 treated with DMSO in Western blot analysis on total cell lysates of (A) and PP2 (B) for 18 h. Note the morphological change in the PP2-treated cells, characterized by a transition bladder carcinoma cells exposed to escalating from a fusiform shape (A) to a flattened epithelial shape (B), accompanied by accumulation of plakoglobin at concentrations of PP2. HU456 control represents the intercellular membrane (compare A and B). plakoglobin levels in E-cadherin expressing bladder carcinoma cells. Lanes were equalised for protein AB concentration within each experiment represented within one panel.
PP2
FIG. 4. In vitro invasion assay involving five bladder carcinoma cell lines conducted in the presence of DMSO (control, green) or PP2 (15 mmol/L, red). There was a significant reduction in invasive potential in all cell lines in the presence of PP2.
120 panel of bladder cell lines exposed to PP2. In 100 contrast to many carcinoma cell lines derived 80 from different organs, the endogenous level of src kinase activity is low in bladder cell lines 60
derived from late-stage tumours [29]. After % Control 40 exposure to PP2 no discernible change in pp60src activity was detected (data not 20 shown). To identify alternative signalling 0 proteins altered by the action of PP2, possibly T24 KK47 EJ UM-UC-3 J82 linked to the invasive phenotype, we Cell line investigated the activation status of MAP (Erk1 and Erk2) and Akt proteins, both of which have been implicated in many cellular pathways linked to tumorigenesis and FIG. 5. Western blot analysis of paired total cell lysates from the bladder carcinoma cell panel from cells invasion. Figure 5 is a Western blot, exposed for 18 h to DMSO (control) or PP2 (15 mmol/L). Blots were probed using antibodies to the MAPK, showing no change in the expression or phosphorylated MAPK, Akt and phosphorylated Akt. Each protein-standardized lysate was from the same phosphorylation status of MAPKs in bladder experiment and analysed in the same electrophoretic run. There was no change in the phosphorylation status cells exposed to PP2. In contrast, the same cell of MAPK within each treated and untreated pair, but significant dephosphorylation of Akt in the same lysate lines showed a reduction in phosphorylated from PP2-treated cells. Akt in the presence of PP2, indicative of deactivation of this signalling molecule. As these two different signalling proteins were analysed on the same cell lysates in the same electrophoretic run, it is likely that inactivation of Akt is a targeted PP2 event.
MODULATION OF AKT ACTIVITY AND EFFECT ON INVASION
To further establish a role for Akt in in vitro bladder cell invasion we used different experimental approaches to modulate the Akt activation status in selected bladder carcinoma cell lines. The J82 bladder
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FIG. 6. Western blot analyses showing: A, no PTEN FIG. 7. In vitro invasion assay using J82 puromycin-resistant control transfectants and J82 PTEN protein in the J82 bladder cell line (Puro2 and 4) with transfectants. There was a >50% reduction in invasive capacity after restoring PTEN expression in these cells. restoration of PTEN expression in J82 transfectants (WT6 and WT24). B, the activation status of Akt in 80 the same J82 Puro and PTEN-WT transfectants. Note 70 reduced phosphorylated Akt after restoring PTEN expression. 60
50 2 PTEN 40
Cells/mm 30
ACTIN 20 10 Akt 0 J82/PURO-2 J82/PURO-4 J82/PTEN J82/PTEN WT-6 WT-24 pAkt
Puro2 J82 Puro4 J82 WT6 J82 WT24 J82 FIG. 8. Western blot analysis showing the baseline activation status of Akt within an extended bladder carcinoma cell panel. Note that many late-stage bladder cell lines (e.g. UM-UC-3, T24, J82) show constitutively activated Akt.
carcinoma cell line showed activated Akt and is highly invasive in in vitro invasion assays. Akt activation in this cell line probably resulted from the loss of PTEN expression by gene deletion [31]. Restoring PTEN expression in the J82 cell line (Fig. 6A) significantly different signalling pathways showed FIG. 9. In vitro invasion assay showing enhanced reduced the phosphorylation status of Akt in significant inhibition of invasion associated invasion of EJ cells in the presence of EGF (20 ng/ transfected cells (Fig. 6B) and their invasive with all inhibitors, with PP2 reducing invasion mL). The same assay in the presence of EGF and potential in in vitro invasion assays (Fig. 7). close to baseline levels (Fig. 9). MAPK inhibitor (MEK–PD98059), src family kinase inhibitor (PP2), PI3 kinase inhibitor (LY294002) and In reciprocal experiments we sought to DISCUSSION Akt inhibitor showed a lower invasive capacity of EJ activate Akt in bladder carcinoma cells to cells in all experimental arms. Note that PP2 reduced assess the effects on invasive potential. The src family kinase inhibitor PP2 can act to the invasive capacity to near baseline levels. Figure 8 shows the baseline activation status inhibit in vitro cell invasion in a panel of of Akt within the panel of bladder carcinoma bladder carcinoma cell lines representative of 140 cells, where phosphorylated Akt was assayed late-stage tumours. In addition, PP2 caused 120 100 after maintaining cells in serum-free medium concentration-dependent cell death in all 2 for 24 h. Within this cell panel constitutive bladder cell lines and up-regulation of 80 levels of phosphorylated Akt closely plakoglobin in a subset of lines. Suppression 60 correlated with invasive potential, where EJ of the invasive phenotype by PP2 was cells/mm 40 and KK47 had the lowest level of activated mediated through the Akt signalling pathway, 20 Akt and were the least invasive. In initial where inactivation of Akt resulted in a 0 experiments we determined the effect of EGF, reduction in in vitro invasive capacity in EGF control PI3+EGF bFGF, heregulin and insulin on the activation bladder carcinoma cells. PP2+EGFMEK+EGF AKT+EGF status of MAPK and Akt. Adding EGF to serum-starved EJ cells activated both the MAP Different src family members are over- and Akt signalling pathways, and resulted in expressed and/or highly activated in several cancers is under investigation and remains a the most significant increase in in vitro human cancers, including colon, ovary, lung, promising strategy for targeted therapeutics. invasion potential amongst the growth oesophagus, skin and gastric carcinomas In bladder cancer, no increased src family factors tested. Repeating this experiment in [27,28]. In such cases the possibility of using tyrosine kinase activity has been recorded as the presence of biochemical inhibitors of tyrosine kinase inhibitors in treating these associated with neoplastic progression [29],
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but src activity has been reported to modulate bladder carcinoma cell lines in the present bladder carcinoma cell lines by modulating cadherin/catenin expression and function, study showed a reduction in phosphorylated the activation status of Akt. In contrast to contributing to the metastatic phenotype Akt after exposure to PP2, and a concomitant alternative carcinoma models there is no in alternative models [32]. The bladder cell reduction in invasive potential in in vitro compelling evidence that this event is carcinoma panel used in the present study is assays. Further confirmation of a role for Akt mediated through the src signalling pathway representative of late-stage disease, where in bladder cell invasion was shown by in the bladder model. However, consistent loss of E-cadherin, accompanied by down- inactivation of Akt after restoring PTEN with published reports [25], PP2 exposure can regulation of plakoglobin expression, was expression in bladder cells lacking the gene. act to modulate expression of the cadherin shown by all but the KK47 cell line. E-cadherin Restoring PTEN expression in J82 cells complex proteins. In the bladder model, PP2 and plakoglobin have invasion [14,15] or resulted in inactivation of Akt and reduced exposure resulted in up-regulation of tumour-suppressor activity [33,34], invasive potential of PTEN-transfected cells plakoglobin in a subset of bladder carcinoma respectively, and are characteristically silenced compared to puromycin control transfectants. cell lines with accumulation of this catenin in bladder cancer progression. These silenced Interestingly, in a previous study we identified family member at cell-cell borders. adhesion components represent attractive PTEN alterations within this bladder cell panel, Plakoglobin has been reported to have a targets for reactivation in a targeted revealing loss of the PTEN gene in two bladder tumour-suppressor function in some cancer therapeutic approach to bladder cancer. No cell lines and point-mutation events models [33,34], and one recent report of the restoration of E-cadherin expression was associated with an additional four cell lines action of PP2 in vivo showed restoration of detected in bladder carcinoma cells after [31]. Although we did not show the functional the cadherin/catenin adhesion system and a exposure to PP2, but up-regulation of significance of these different PTEN point reduction in in vivo metastases in a colon plakoglobin was recorded in a subset of the cell mutations, notably all bladder carcinoma cell cancer model [25]. The results in the present panel. There was no modulation of alternative lines reported as harbouring point mutational study suggest that PP2, and other members of catenin molecules after exposure to PP2. changes had an activated Akt status. this class of molecule, may have potential as invasion- suppressor agents in bladder cancer. The src family of tyrosine kinases represent To further show the involvement of Akt non-receptor protein kinases that are central activation in bladder cell invasion we in cell growth and differentiation. Indeed, src identified the EJ cell line as having a low ACKNOWLEDGEMENTS tyrosine kinases are becoming recognized as baseline level of activated Akt, a low in vitro pivotal agents in diverse cell signalling invasive potential and Akt activation in This work was supported by NIH 1DK59400 pathways [26–28]. In contrast to previous response to the action of different growth and a generous gift from the Lublin family. studies in alternative carcinoma models, there factors. Exposure of the EJ cell line to EGF was no discernible change in the pp60c–src resulted in marked activation of Akt and a kinase activity in the presence of PP2 in the significant increase in invasive capacity. CONFLICT OF INTEREST present study. This may reflect the sensitivity However, EGF also activated MAPK in EJ cells, of the assay, as the baseline level of src kinase hence, we used biochemical inhibitors to None declared. Source of funding: NIH, Lublin activity is low; or that kinase-mediated separate the effects of the MAP and Akt Foundation. changes in protein phosphorylation occurred signalling pathways. Not surprisingly, via a different member(s) of the src family; or different inhibitors of the PI3/Akt signalling that alternative cellular kinases were affected pathway reduced the invasive potential of EJ REFERENCES by the action of PP2. Although PP2 is reported in the presence of EGF, but the results were to inhibit src family kinase activity at similar with the MAPK inhibitor. In a previous 1 Nam N-H, Parang K. Current targets for nanomolar concentrations in in vitro kinase study we showed that novel expression of N- anticancer drug discovery. Current Drug assays, micromolar concentrations are cadherin in bladder carcinoma cells elicits the Targets 2003; 4: 159–79 necessary to invoke the same inhibition in invasive phenotype, with activation of Akt. In 2 Sternberg CN, Vgelzang NJ. intact cells, probably because of the this model the MAPK inhibitor did not Gemcitabine, paclitaxel, pemetrexed and permeability of the compound. At higher suppress the invasive phenotype. 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422 © 2005 BJU INTERNATIONAL Original Article EFFECTS OF SILDENAFIL ON SUPEROXIDE AND gp47 PHOX IN CORPUS CAVERNOSUM CELLS KOUPPARIS et al.
Sildenafil inhibits the formation of superoxide and the expression of gp47phox NAD[P]H oxidase induced by the thromboxane A2 mimetic, U46619, in corpus cavernosal smooth muscle cells
ANTHONY J. KOUPPARIS, JAMIE Y. JEREMY, SAIMA MUZAFFAR, RAJ PERSAD and NILIMA SHUKLA Urology and Bristol Heart Institute, Bristol Royal Infirmary, Bristol, UK Accepted for publication 24 March 2005
OBJECTIVE assessed using Western blot analysis. The CONCLUSIONS role of NAD[P]H oxidase and cGMP was To assess the effect of sildenafil on superoxide further studied by using specific inhibitors Sildenafil is a potent inhibitor of superoxide formation and p47phox (the active subunit of of each. formation in CVSMCs. This effect is mediated NADPH oxidase) expression in cultured corpus through the inhibition of PDE-5 which in turn cavernosal smooth muscle cells (CVSMCs). augments the inhibitory action of the NO- RESULTS cGMP axis on NAD[P]H oxidase expression and activity. This mechanism constitutes a MATERIALS AND METHODS Superoxide formation was significantly new pharmacological action of sildenafil, greater in cells incubated with U46619 after 1 consolidates the potential role of superoxide
CVSMCs derived from rabbit penis were and 16 h incubation than in controls, an in ED, and indicates that thromboxane A2 may incubated with U46619 (thromboxane A2 effect blocked by NADP(H) oxidase inhibitors. be an important mediator of intrapenile analogue) with or without sildenafil These effects of U46619 were inhibited by oxidative stress. for 1 or 16 h at 37∞C. Superoxide sildenafil (1 and 10 nmol/L), which in turn dismutase-inhibitable superoxide were negated by the guanylyl cyclase KEYWORDS formation was assessed using the inhibitor, ODQ; 10 nmol/L sildenafil reduction of ferricytochrome c measured inhibited p47phox expression induced by erectile dysfunction, oxidative stress, phox spectrophotometrically, and gp47 U46619. sildenafil, thromboxane A2
INTRODUCTION reactive nitrogen species [7]. As a result, that augments the action of NO by preventing the bioavailability of NO is decreased, the hydrolysis of cGMP [17,18]. In the context Penile erection is initiated by relaxation of the thereby impairing NO-dependent smooth of the above, it was shown that NO is also a corpus cavernosum, which is mediated by an muscle relaxation and therefore the potent inhibitor of NAD[P]H oxidase - increase in nitric oxide (NO) formation normal erectile response. There is increasing expression [10], which in turn reduces O2· released by both nonadrenergic, evidence that the excess production of formation in vascular smooth muscle cells - noncholinergic nerve fibres [1] and the O2· is caused by the over-expression of (SMCs) from other vascular tissue, an effect intracavernosal endothelium [2]. NO relaxes endogenous vascular NAD[P]H oxidase and mediated by cGMP [10]. It follows therefore cavernosal smooth muscle by activating that the up-regulation of this enzyme may that sildenafil (by enhancing cGMP levels) guanylyl cyclase that generates cGMP [2,3]. In play a role in promoting ED [5–8]. NAD[P]H may also inhibit the activity and expression of - turn, cGMP activates protein kinase G, which oxidase is rapidly up-regulated by cytokines NAD[P]H oxidase. By doing so, reduced O2· suppresses calcium mobilization, resulting in [9,10] and vasoconstrictors, including formation would augment NO bioavailability an erectile response [2,3]. Therefore, any thromboxane A2 [11]. In turn, thromboxane thereby improving the erectile response in process that reduces NO formation impairs A2 is a potent constrictor of the human patients with ED. normal erectile function. corpus cavernosum [12] and penile arteries [13], and as such is implicated in the causes To test these hypotheses, the effect of the - Major risk factors for vasculogenic erectile of ED [14–16]. It is also possible that the thromboxane A2 analogue, U44619, on O2· phox dysfunction (ED) are diabetes mellitus, pathogenic effect of thromboxane A2 in ED formation and the expression of gp47 (an smoking and dyslipidaemia [4]. In turn, involves an up-regulation of NAD[P]H oxidase active component of NAD[P]H oxidase [19]) these risk factors are associated with an expression. was assessed in isolated cavernosal cells - increase in superoxide (O2· ) formation in derived from the rabbit corpus cavernosum. - the vasculature [5,6]. O2· reacts with NO Sildenafil, now routine for treating ED, is a The effects of sildenafil on these systems were to form peroxynitrite (ONOO-) and other type-5 phosphodiesterase (PDE-5) inhibitor then studied both acutely (1 h) and for longer
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(16 h). The roles of NAD[P]H oxidase and FIG. 1. Effect of the thromboxane A2 mimetic, U46619 (10 nmol/L), on superoxide formation by rabbit cGMP were further studied by using specific CVSMCs over 1 (green bars) and 16 h (red bars) of incubation, and the effect of the NAD[P]H oxidase inhibitors of each. inhibitors, 10 mmol/L apocynin and 10 mmol/L DPI. Each point is the mean (SEM) from six animals. #P < 0.05, significantly greater than control; *P < 0.01 significantly less than U46619 alone.
12 #
MATERIALS AND METHODS 10 se a 8 All animals used were given humane care in # compliance with the rules and regulations of e rele * d 6 * Bristol University and the UK Home Office. * 4 * New Zealand White rabbits were killed with a peroxi mol/mg protein/h u S lethal overdose of barbiturates and the m 2 penises rapidly excised. The corpus cavernosum was dissected from the 0 surrounding the tunica albuginea. Cavernosal Control U46619 Apocynin DPI tissues were placed in Dulbecco’s Minimum Drugs Essential Medium (DMEM) with 10% fetal calf serum (FCS; both GibcoBRL, Paisley, Scotland) and cut into 2 mm2 pieces. Cavernosal vascular SMCs (CVSMCs) were prepared using using BCA-protein assay kit (Pierce, Rockford, 4% w/v SDS; 10% v/v glycerol; 4% v/v 2- previously described methods [10]. CVSMCs Illinois, USA). The results were expressed as mercaptoethanol; 2 mg/mL bromophenol - were maintained in DMEM (containing 10% mmol of O2· /mg protein per hour. blue). Samples of equal protein (100 mg) were FCS, 100 units/mL penicillin and 100 g/mL loaded onto 12% Tris-glycine SDS gels and - streptomycin) at 37 ∞C in a 95% air-5% CO2 To determine whether the source of O2· separated by electrophoresis. After transfer to incubator. For experimentation, subconfluent was NAD[P]H oxidase, cells were incubated nitrocellulose, the blots were primed with cultures of CVSMCs were growth-arrested by with the NAD[P]H oxidase inhibitors MoAb 48 (2.5 mg/mL final concentration), washing in sterile PBS (GibcoBRL) and diphenyleneiodonium chloride (DPI) and then incubated with goat antimouse antibody - incubating in quiescing medium (serum-free apocynin when measuring O2· using conjugated to horseradish peroxidase DMEM supplemented with 0.5% lactalbumin ferricytochrome c reduction, as described (1 : 2000 dilution) and developed by hydrolysate, 100 units/mL penicillin and above. Furthermore, to determine the role enhanced chemiluminescence (Amersham 100 mg/mL streptomycin) for 72 h [10–12]. of cGMP in mediating effects, cells were International). Rainbow markers (14–220 kDa; The following experiments were then carried also incubated over 16 h with the Amersham) were used for molecular weight out. soluble guanylyl cyclase inhibitor, 1H- determination. [1,2,4]oxadiazolo[3,4]quinoxalin-1-one (ODQ) To assess the effect of U46619 with or with no [10]. Data are expressed as the mean (SEM) with the - sildenafil on O2· formation, CVSMCs were number of rabbits used. Student’s unpaired t- incubated with the thromboxane A2 analogue, To assess the effects on NAD[P]H oxidase test or a one-way factorial ANOVA was used to U46619 for 1 or 16 h at 37 ∞C in a 95% air-5% protein, the effect of U46619 and sildenafil on determine difference among treatments, with phox CO2 incubator. Cells were then equilibrated in the expression of gp47 (an active catalytic P < 0.05 considered to indicate statistical DMEM with no phenol red for 10 min at 37 ∞C subunit of NAD[P]H oxidase [19]), in both the significance. Multiple group comparisons in a 95% air-5% CO2 incubator (Heraeus, Hera membranes and cytosol of CVSMCs was were made using one-way ANOVA. Cell, Kandro Laboratory Products, Germany); investigated using Western analysis. After 20 mmol/L horseradish cytochrome c (Sigma 16 h of incubation with U46619 (± sildenafil), Chemical Co., Poole, UK) with or without as described above, CVSMCs were rinsed in RESULTS 500 U/mL copper-zinc superoxide dismutase PBS and lysed with ice-cold hypotonic buffer
(SOD; Sigma) was added and incubated at (20 mmol/L HEPES, pH 7.5, 10 mmol/L The thromboxane A2 analogue U46619 was a
37 ∞C in a 95% air-5% CO2 incubator for 1 h. potassium acetate, 1.5 mmol/L magnesium potent stimulator of superoxide formation by The reaction medium was removed and acetate). Cells were incubated for 15 min on CVSMCs incubated for both 1 and 16 h reduction of cytochrome c determined at ice, removed and homogenized using a glass (Fig. 1). This effect was negated by the 550 nm in an Anthos Lucy 1 spectrometer homogenizer. Intact cells and nuclei were presence of the NADPH oxidase inhibitors, (Laboratory-tech International, Ringmer, East sedimented by centrifugation at 3000 g apocynin and DPI (Fig. 1). Over a 1-h - Sussex, UK) and converted to mmol O2· , using for 5 min at 4 ∞C [19]. Supernatants were incubation and after a 16-h incubation with -1 -1 a DE550nm of 21.1 mmol .cm as the removed and centrifuged at 20 000 g for 2 h U46619 and sildenafil, superoxide release by extinction coefficient. The reduction of at 4 ∞C, the resultant supernatant being the CVSMCs was inhibited by sildenafil in a dose- cytochrome c that was inhibitable with SOD cytoplasmic fraction and the pellet the dependant manner (Fig. 2a,b). The inhibitory - reflected actual O2· release [9–11]. CVSMCs membrane-enriched fraction. Cytoplasmic effect of sildenafil on superoxide formation by were rinsed in PBS, lysed with 0.1% v/v Triton- and membrane fractions were boiled in a 1 : 1 CVSMCs after a 16-h incubation was reversed X100 and total protein content measured ratio with Tris (50 mmol/L; pH 6.8 containing by ODQ (Fig. 3). Sildenafil (10 nmol/L) reduced
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FIG. 2. a It has long been established that The effect of sildenafil on thromboxane A2 is a potent constrictor of 7 # superoxide formation elicited both cavernosal and pudendal arterial smooth by incubation with 10 nmol/L 6 muscle [12,13], and as such its over- U46619 by cultured rabbit 5 production has been implicated in the CVSMCs over a 1-h (a) and 16-h causes of ED [14–16]. Although thromboxane
mol/mg protein/h 4 * (b) incubation. Data are the mean m A2 is formed by all vascular tissues, the
(SEM) from six animals. #P < 0.01, se, 3 pathological effect of thromboxane A2 is a * significantly greater than 2 thought to be negated by the concomitant U46619-treated than untreated e rele formation of prostacyclin (PGI ), which has d 2 controls; *P < 0.01, significantly 1 potent diametrically opposite properties to
less than U46619-treated cells. peroxi thromboxane A2 [14], which include the
u 0 S inhibition of NADPH oxidase expression [11]. b However, in disease states associated with ED, including diabetes mellitus and smoking, PGI2 12 # is diminished and thromboxane A2 increased [14]. Thromboxane A is also released by 10 2 activated/adherent platelets that are hyper- 8 * reactive in such disease states [5]. It was mol/mg protein/h m 6 suggested that as NO is a potent inhibitor of
se, *
a platelet adhesion, then reduced NO would 4 * * augment transient platelet adhesion and e rele
d 2 therefore enhance local release of thromboxane A [5]. Thus, it is proposed that 0 2 peroxi Control U46619 1 10 100 1000 u thromboxane A2 may be an important S Sildenafil, nmol/L pathogen in ED through different pathways, i.e. (i) direct vasoconstriction and (ii) increased NAD[P]H oxidase activity and expression, resulting in prolonged augmentation of O ·- FIG. 3. The effect of the guanylyl cyclase inhibitor, ODQ (1 mmol/L) on the sildenafil-mediated inhibition of 2 generation and negation of NO bioavailability. superoxide release from by rabbit CVSMCs after 16 h of incubation with U46619 (10 nmol/L). Each point is the mean (SEM) from six animals. *P < 0.01, significantly less than U46619 alone; $P < 0.01, significantly greater Second, the present study shows that than controls; #P < 0.01, significantly greater than sildenafil alone. sildenafil, via its effect on PDE-5 and - elevation of cGMP, potently inhibits O2· formation by CVSMCs in response to U46619, 12 $ both acutely and in the longer term. Sildenafil 10 also blocked the expression of U46619- 8 phox # stimulated gp47 protein expression over
mol/mg protein/h #
m 6 the longer term (16 h). These effects were
se, * blocked by ODQ, showing that the inhibitory a 4 * effects of sildenafil on NAD[P]H oxidase
e rele 2 expression and activity are mediated by d 0 guanylyl cyclase. This is expected, as sildenafil Control U44619 10 100 10 + 100 + peroxi is PDE-5 inhibitor, the enzyme which u
S ODQ ODQ hydrolyses cGMP to inactive GMP [3]. In a Sildenafil, nm previous study we showed that U46619 also up-regulated gp91phox and promoted an - increase in O2· formation by pulmonary phox - the expression of p47 induced by a 16-h The inhibition of U46619-mediated O2· arteries [11]. The 50% inhibitory dose (IC50) of - phox incubation with U46619 in both the formation by apocynin and DPI shows that sildenafil on O2· formation and gp47 membrane and cytosol of CVSMCs (Fig. 4). this effect is mediated by NAD[P]H oxidase. expression after 16 h incubation in the Furthermore, U46619 up-regulated the present study was 1–10 nmol/L. As sildenafil phox expression of gp47 protein over the longer inhibits PDE-5 activity at an IC50 of 3.5 nmol/ DISCUSSION incubation (16 h). As NAD[P]H oxidase L [20,21], these data indicate that the effects - - phox generates O2· , which reacts with NO to form of sildenafil on O2· formation and gp47 The present study shows that U46619 is a reactive nitrogen species [7], these data expression are indeed mediated by the - potent stimulator of O2· formation in corpus indicate that thromboxane A2 may promote inhibition of PDE-5. Therefore, the inhibition cavernosal smooth muscle cells, both acutely ED by negating the bioavailability of NO, both of NADPH oxidase and the concomitant - (over 1 h) and after a longer (16 h) exposure. acutely and in the longer term. reduction in O2· formation by sildenafil
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- PHOX would enhance NO formation, as O2· negates FIG. 4. Effect of 10 nmol/L sildenafil on the expression of p47 by cultured rabbit CVSMCs incubated with NO through a reaction that forms ONOO-. This 10 nmol/L U46619 for 16 h and assessed by Western blot analysis. p47PHOXprotein was not detectable in ‘antioxidative’ effect of sildenafil may untreated cells. A is the cytosolic p47PHOX control, B the cytosolic p47PHOX + sildenafil, C the membrane p47PHOX constitute an additional mechanism to that of control, and D the membrane p47PHOX + sildenafil. Data are the mean (SEM) from six animals. #P < 0.01, augmentation of NO-mediated relaxation of significantly less than controls. A representative blot is shown beneath the densitometric data. VSMCs, that would explain the therapeutic effect of the drug (Fig. 5). 2 1.8 These findings may be of therapeutic 1.6 relevance, as the concentrations at which 1.4 sildenafil elicits this indirect inhibitory effect 1.2 - on O2· formation in the present study are well 1 within the concentrations required to #
ensities (pixels) 0.8 d promote erection [1,2,20,21]. The inhibitory 0.6 - effect of sildenafil on O · formation in the Blot 2 0.4 present study was also apparent within 1 h, 0.2 again at therapeutic plasma concentrations. # 0 In turn, sildenafil is recommended to be taken ABCD only 1 h before any sexual activity [17,18,22]. - As sildenafil elicits an inhibition of O2· formation within 1 h it is not unreasonable to suggest that this ‘antioxidative’ effect may augment the therapeutic action of the drug. Additionally, novel PDE inhibitors have been FIG. 5. The proposed mechanism underlying the antioxidant effect of sildenafil and its effect on erectile - developed that act over a longer term, in that function. Risk factors for ED promote the endogenous expression of NADPH oxidase, which generates O2· in the patient can take the oral tablet in the penile tissue, the increased formation of which negates the pro-erectile activity of NO through direct morning and the effects of the drug persist chemical reactions to form pro-inflammatory species such as peroxynitrite (ONOO-). As sildenafil inhibits all day, provided that the appropriate PDE-5, the hydrolysis of cGMP is blocked. Increased cGMP promotes erection by augmenting smooth muscle psychogenic inputs (i.e. sexual arousal) are cell relaxation, despite reduced NO formation. However, as the NO-cGMP axis also inhibits NADPH oxidase also present [17]. Thus, the longer-term expression/activity, it follows that augmentation of cGMP levels would also promote the inhibition of this - enzyme. Reduced O ·- would further augment NO bioavailability, which would feed back into the loop to effects of sildenafil on the inhibition of O2· 2 formation, by suppressing NAD[P]H oxidase enhance the inhibition of NADPH oxidase expression and activity. expression, may also be an important attribute of the drug. NANC / endothelium In conclusion, thromboxane A increases the 2 - activity and expression of NAD[P]H oxidase Risk factors ONOO - - and the formation of O2· by CVSMCs. As O2· negates NO availability, reduced NO is NO associated with ED and increased + thromboxane A2 with risk factors for ED, so - that thromboxane A2 may be important in the O2· causes of ED through promoting intrapenile oxidative stress. Second, sildenafil has a NAD[P]H oxidase Guanylate cyclase potent inhibitory effect on the formation of - O2· through a reduction of both NAD[P]H oxidase activity and expression. These effects - are mediated through the inhibition of PDE-5 activity and therefore an augmentation of + Protein cGMP formation. The resultant decrease in Cyclic GTP - kinase G endogenous O2· would in turn increase the GMP bioavailability of intrapenile NO. Apart from augmenting CSM relaxation, enhanced NO + Sildenafil availability would further inhibit NAD[P]H oxidase activity and expression. This would Relaxation of create a ‘self-augmenting’ therapeutic loop VSMCs Inactive that would not only augment erection acutely Type V GMP but may have longer-term beneficial effects PDE in improving erectile function, particularly in
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those patients where increased tissue surgery. Curr Vasc Pharmacol 2004; 2: 16 Bornman MS, Franz RC, Jacobs DJ, Du
NAD[P]H oxidase expression is a causal factor. 229–36 Plessis DJ. Thromboxane B2 production Further studies are required to explore this 8 Koupparis A, Jeremy JY, Persad R, during erection. Andrologia 1986; 18: novel therapeutic pathway of PDE inhibition, Angelini GD, Shukla N. Smoking and 220–3 which in turn may lead to improved drug erectile dysfunction: the role of NADPH 17 Rosen RC, Kostis JB. Overview of design and efficacy. oxidase. BJU Int 2004; 94: 257–8 phosphodiesterase 5 inhibition in erectile 9 Muzaffar S, Jeremy JY, Angelini GD, dysfunction. Am J Cardiol 2003; 92: 9M– Stuart-Smith K, Shukla N. The role of 18M CONFLICT OF INTEREST the endothelium and nitric oxide 18 Langtry H, Markham A. Sildenafil. a synthases in modulating superoxide review on its use in erectile dysfunction. None declared. Source of funding: Shackman formation induced by endotoxin and Drugs 1999; 57: 967–89 Trust. cytokines in porcine pulmonary arteries. 19 Li JM, Mullen AM, Yun S et al. Essential Thorax 2003; 58: 598–604 role of the NADPH oxidase subunit p47 10 Muzaffar S, Shukla N, Angelini (phox) in endothelial cell superoxide REFERENCES GD, Jeremy JY. Nitroaspirins and production in response to phorbol ester morpholinosydnonimine, but not aspirin, and tumor necrosis factor-alpha. Circ Res 1 Cashen DE, McIntyre DE, Martin WJ. inhibit the formation of superoxide and 2002; 90: 143–50 Effects of sildenafil on erectile activity in the expression of gp91phox induced by 20 Boolell M, Allen MJ, Ballard SA et al. mice lacking neuronal or endothelial nitric endotoxin and cytokines in pig pulmonary Sildenafil. an orally active type 5 cyclic oxide synthase. Br J Pharmacol 2002; artery vascular smooth muscle cells and GMP-specific phosphodiesterase inhibitor 136: 693–700 endothelial cells. Circulation 2004; 110: for the treatment of penile erectile 2 Gonzalez-Cadavid NF, Ignarro LJ, Rajfer 1140–7 dysfunction. Int J Impot Res 1996; 8: 47– J. Nitric oxide and the cyclic GMP system 11 Muzaffar S, Shukla N, Lobo C, Angelini 52 in the penis. Mol Urol 1999; 3: 51–9 GD, Jeremy JY. Iloprost inhibits NADPH 21 Ballard SA, Gingell CJ, Tang K, Turner 3 Jeremy JY, Ballard S, Naylor A, Miller oxidase expression and superoxide release LA, Price ME, Naylor AM. Effects of MAW, Angelini GD. Effects of sildenafil, in porcine pulmonary arteries and cells sildenafil on the relaxation of human
a type-5 cGMP phosphodiesterase stimulated with thromboxane A2, corpus cavernosum tissue in vitro and on
inhibitor, and papaverine on cyclic GMP isoprostane F2a and cytokines. Br J the activities of cyclic nucleotide and cyclic AMP levels in the rabbit corpus Pharmacol 2004; 141: 488–96 phosphodiesterase isozymes. J Urol 1998; cavernosum in vitro. Br J Urol 1997; 79: 12 Hedlund H, Andersson KE, Fovaeus M, 159: 2164–71 958–63 Holmquist F, Uski T. Characterisation of 22 Goldstein I, Lue TF, Padma-Nathan H, 4 Sullivan ME, Thompson CS, Dashwood contraction mediating prostanoid Rosen RC, Steers WD, Wicker PA. Oral MR, Khan M, Jeremy JY, Morgan RJ. receptors in human penile erectile tissues. sildenafil in the treatment of erectile Nitric oxide and erection: is erectile J Urol 1989; 141: 182–6 dysfunction. NEJM 1998; 338: 1397–404 dysfunction another manifestation of 13 Coleman R. Methods in prostaglandin vascular disease? Cardiovasc Res 1999; receptor classification. In Slater T, ed. Correspondence: Anthony J. Koupparis, 43: 580–94 Prostaglandins and Related Substances: a Department of Urology, Bristol Royal 5 Jeremy JY, Angelini GD, Khan M et al. Practical Approach. Oxford: IRL Press, Infirmary, Bristol, UK. Platelets, oxidant stress and erectile 1987: 267–303 e-mail: [email protected] dysfunction: an hypothesis. Cardiovasc 14 Jeremy JY, Mikhailidis DP. Prostanoids Res 2000; 46: 50–4 and impotence. aetiological and Abbreviations: NO, nitric oxide; (C)VSMC, 6 Jones RWA, Rees RW, Minhas S, Ralph therapeutic implications. Br J Sex Med (cavernosal) vascular smooth muscle cell; ED, D, Persad RA, Jeremy JY. Oxygen free 1989; 16: 411–5 erectile dysfunction; PDE-5, type-5 radicals and the penis. Expert Opin 15 Lin JS, Lui SM, Chen CM, Chang WC. phosphodiesterase; DMEM, Dulbecco’s Pharmacother 2002; 3: 889–97 The change of urinary 11-dehydro- Minimum Essential Medium; FCS, fetal calf 7 Jeremy JY, Shukla. N, Muzaffar S, thromboxane B2 and 2,3-dinor-6-keto- serum; SOD, superoxide dismutase; DPI, Angelini GD. Reactive oxygen species, prostaglandin F1 alpha in arteriogenic diphenyleneiodonium chloride; ODQ, 1H- vascular disease and cardiovascular impotence. J Urol 1992; 148: 311–3 [1,2,4]oxadiazolo[3,4]quinoxalin-1-one.
© 2005 BJU INTERNATIONAL 427 Original Article RYANODINE RECEPTORS IN DETRUSOR INSTABILITY JIANG et al.
Loss of ryanodine receptor calcium-release channel expression associated with overactive urinary bladder smooth muscle contractions in a detrusor instability model
HAI-HONG JIANG, BO SONG, GEN-SHENG LU, QIAN-JUN WEN and XI-YU JIN Urology Center, Southwest Hospital, Third Military Medical University, Chongqing, China Accepted for publication 18 February 2005
OBJECTIVE RESULTS CONCLUSION
To investigate the changes in spontaneous In DI bladder muscle, spontaneous contractile These results provide the first characterization bladder smooth muscle contractions that activity persisted in the presence of blockers of a loss of regulation of spontaneous occur during detrusor instability (DI), and to for known neurotransmitter receptors in the contractile activity by RyRs in DI muscle test the possibility that altered function or bladder wall. The RyR blocker ryanodine associated with a significant decrease in RyR expression of ryanodine receptors (RyRs) significantly increased the spontaneous expression. RyRs in normal detrusor muscle could account for the increased bladder contractile frequency in normal bladder strips, act as negative-feedback regulators of contractions. but failed to affect spontaneous contractions spontaneous contractile activity, presumably in DI muscle. Caffeine inhibited spontaneous by releasing Ca2+ that activates Ca2+- MATERIALS AND METHODS contractile activity in both the DI and normal dependent K+ channels to decrease strips. After administering the L-type Ca2+ contractility. This mechanism might be After 8 weeks of partial bladder outlet channel antagonist nimodipine, the myogenic weakened in DI muscle, resulting in obstruction, DI was confirmed in female contractile activity was abolished in normal spontaneous contractile overactivity. experimental rats by filling cystometry. strips; in contrast, in DI strips, the amplitude Muscle strips were dissected from freshly of contractions was reduced but the KEYWORDS isolated bladders, and isometric tension frequency of contractions was unchanged. recorded in strips from DI and normal Western blot analysis showed that RyR detrusor instability, ryanodine receptor, bladders. The contractions were recorded expression was lower in DI muscle than in spontaneous contraction, sarcoplasmic during electrical stimulation or exposure to normal bladder muscle. reticulum various agents. Western blot analysis was used to determine RyR expression in DI and normal bladder muscle.
INTRODUCTION Ryanodine receptors (RyRs) in the the Third Military Medical University. sarcoplasmic reticulum (SR) are important Rats were anaesthetized with sodium Some studies and reviews have described a modulators of excitation-contraction pentobarbital (40 mg/kg). The lower abdomen myogenic basis for the increased excitability coupling in bladder myocytes [10,11]; Ca2+ was shaved and scrubbed using povidone- and contractile activity of bladder smooth release from RyRs might be triggered by Ca2+ iodine, and a vertical midline incision made. muscle that is associated with detrusor influx via voltage-dependent Ca2+ channels The urethra was exposed and a 3 F plastic instability (DI) in both animal models and (Ca2+-induced Ca2+ release [10,12]); Ca2+ catheter inserted into the bladder. Care was humans [1]. One of the most common causes release from RyRs in the form of Ca2+ taken to identify the ureters and bladder base, 2+ + of DI is BOO [2]. Spontaneous contractions activates Ca -activated K channels (KCa, and a 4/0 silk suture was passed around the
occur in strips of detrusor dissected from including BKCa) [13]. The characteristics of proximal urethra and tied over the catheter. animals or humans in vitro [3], and these spontaneous contraction of urinary bladder All BOO was induced by one investigator (J.H.). contractions are increased in detrusor strips smooth muscle appear to depend on these All rats were given three intraperitoneal with DI resulting from BOO [4,5]. The interactions [14,15]. In the present study, we injections of gentamicin within 48 h after spontaneous contractions are distinct from focused on the role of RyRs in normal and DI surgery. contractions mediated by motor nerves bladder muscle. because they are insensitive to nerve blockers, After 8 weeks of partial BOO, filling but they are sensitive to some ion-channel MATERIALS AND METHODS cystometry was used to determine bladder antagonists [6,7]. Furthermore, spontaneous instability in obstructed and control rats. The action potentials appear to initiate excitation- The studies used female Wistar rats aged 3–5 rats, anaesthetized as above, were placed contraction coupling in bladder muscle [8,9]. months from the Laboratory Animal Center of supine and the abdominal wall cleaned.
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Through the same incision, the urinary physiological saline with periodic changes of and stored at -80 ∞C until required [16]. All bladder was exposed and gently freed from bathing fluid. Steady-going spontaneous procedures were conducted at 4 ∞C. adhering tissues, emptied and then rhythmic contractions were generally cannulated, via an incision at the dome, with observed after 60–90 min of equilibration, SDS-PAGE was used with 5% (w/v) separating a plastic cannula (0.6 mm internal diameter), and were maintained for the remainder of the and 3% (w/v) stacking gels cast in a minigel which was purse-string sutured with silk experiment. After 90 min of equilibration, system. Rat detrusor muscle microsomes thread. The free tip of the bladder cannula 60 mmol/L KCl was added to the bathing (50 mg, total protein determined by a was connected to a pressure transducer medium to elicit a regular contractile modification of the Lowry method) were (Nidoc970 urodynamic testing machine, response. Only strips showing reproducible denatured for 5 min at 95 ∞C in loading buffer Chengdu, China) and to a peristaltic pump for contractile responses to 2–3 applications (0.1 mol/L Tris/HCl, pH 6.8, containing 2% w/v continuous infusion of warm furacillin of 60 mmol/L KCl were studied. To minimize SDS, 2% v/v 2-mercaptoethanol, 10% v/v solution (37 ∞C) into the urinary bladder at the possible effect of the activity of nerves glycerol and 50 mg/mL bromophenol blue). 10 mL/h. During infusion, intravesical in the detrusor strips, all experiments included Electrophoresis was performed at a constant pressure and voided urine volume were a cocktail that contained tetrodotoxin (a current (20 mA per gel) and gels either stained recorded continuously using a computer blocker of neuronal Na+ channels) and with Coomassie Brilliant Blue R250 or interface; DI was confirmed when antagonists for neurotransmitter receptors electrophoretically transferred on to spontaneous contractions appeared in known to be present in the bladder [14]. Immobilon-P (polyvinylidene difluoride) records of intravesical pressure, and when the The cocktail was prepared in physiological membrane (Millipore, USA) at 15 ∞C for 1 h amplitude of at least one contraction was saline, and contained (in mmol/L): 1 atropine at 28 v, then for 18 h at 400 mA. After
>15 cmH2O. Once DI was confirmed, the (muscarinic antagonist), 1 phentolamine blocking for 3 h with 4% w/v non-fat dried cannula was exteriorised through a (a-adrenergic antagonist), 1 propranolol milk proteins in PBS, the blot was incubated subcutaneous tunnel in the retro-scapular (b-adrenergic antagonist), 1 a,b-methylene overnight at 4 ∞C with RyR antibody (Santa area, where it was connected with a plastic ATP (purinergic depletor), and 1 tetrodotoxin Cruz Biochemicals, CA, USA). The immunoblot adapter to avoid the risk of removal by the rat. (Heibei Aquaculture Institute, Heibei, China). was developed with peroxidase-coupled The bladder was removed for muscle strip To verify the effectiveness of the antagonists secondary antibody (Beijing Zhongshan study within a week. on neurally mediated contractions, the strips Biotechnology Co., Beijing, China) and
were subjected to electrical stimulation to 3,3¢-diaminobenzidine/H2O2. The rats were killed by an overdose of sodium trigger nerve activity in the presence and pentobarbital, followed by exsanguination. absence of the cocktail. Strips were stimulated Data are presented as the mean (SEM) and the The urinary bladder was removed and rinsed in a modified organ chamber equipped with a number of preparations. In the smooth in ice-cold physiological saline, which was stimulating electrode for 2 s, using a 0.3-ms muscle physiology experiments, the agents made daily and contained (in mmol/L) pulse of 20 mA at 20 Hz (produced by State were applied for 15 min, with the last 5 min
119 NaCl, 4.7 KCl, 24 NaHCO3, 1.2 KH2PO4, Key Laboratory of Trauma, Burns and taken as the analysis period. Control data
2.5 CaCl2, 1.2 MgSO4, 0.023 EDTA and Combined Injury, Chongqing, China). The were obtained in the 5 min before applying 11 glucose, and was aerated with 95% contractions evoked by three successive the treatment agents. Differences were
O2-5% CO2 to obtain pH 7.4. Each bladder stimulations were averaged for each strip, assessed by t-test or one-way ANOVA, where muscle strip (0.8 ¥ 6 mm) was peeled away before and after exposure to the cocktail. appropriate, and the null hypothesis rejected from the mucosa and lamina propria with Ryanodine was prepared in dimethyl for P < 0.05. microscissors under a surgical microscope sulphoxide, caffeine in distilled water and (Shanghai Medical Instruments Co., Shanghai, nimodipine in ethanol (all from Sigma, China). The lamina propria was separated and as stock solutions in small aliquots RESULTS in the remaining bladder, labelled and at -20 ∞C). transferred into liquid nitrogen for storage To standardize the initial recording conditions, until subsequent assay. Physiological studies Crude SR microsomes were obtained from detrusor strips were stretched to a resting on muscle strips were initiated within 1 h of rat detrusor muscle in DI and normal load of 2 mN in length increments of 2–3 mm harvesting. preparations by differential centrifugation, after loading strips while slack for 20-min and stored at -80 ∞C. Partly thawed tissues incubation. Spontaneous contractions Miniature aluminium clips were placed at were homogenized in 10 volumes of appeared steadily ª60 min after stretch. The each end of the muscle strip to allow the strip homogenisation buffer (10 mmol/L Hepes, strips were then exposed to physiological to be mounted in a tissue bath. Individual pH 7.2, containing 0.25 mol/L sucrose, saline containing tetrodotoxin and a cocktail strips were placed in water-jacketed tissue 0.5 mmol/L EDTA, 1 mmol/L dithiothreitol, of blockers for transmitter receptors known to baths (2 mL) maintained at 37 ∞C. One end of 0.2 mmol/L PMSF, 1 mmol/L benzamidine, be expressed in bladder wall. In the presence the strip was attached to a stationary metal 10 mmol/L leupeptin, 1 mmol/L pepstatin A of the cocktail, spontaneous contractions hook and the other connected with a silk and 100 nmol/L aprotinin). Homogenates persisted in DI strips (Fig. 1); the mean suture to a force-displacement transducer were centrifuged (25 min at 4000 g) and spontaneous contraction frequency (Beijing Space Medico-engineering Institute; the supernatants re-centrifuged for a decreased while the mean amplitude Beijing; China) to measure isometric further 60 min at 100 000 g. Microsomal increased (Table 1). This persistence of contractility. Urinary bladder strips were pellets were re-suspended in four volumes of contractile activity in the presence of equilibrated at a resting load of 2 mN in homogenisation buffer, then rapidly frozen neurotransmitter antagonists suggests that
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FIG. 1. Contractions before and after the administration of the neurotransmitter antagonist cocktail FIG. 2. The contraction by electrical stimulation containing atropine, phentolamine, propranolol, a,b-methylene ATP and tetrodotoxin; spontaneous (0.3-ms pulse of 20 mA at 20 Hz for 2 s) was contractions were maintained, showing continuous records of contractile activity from a DI muscle strip; abolished in the presence of the antagonist cocktail. contractions from DI strips have a myogenic basis. Three traces show the change in stimulus-evoked contraction in a DI strip, in the absence of cocktail (no cocktail), and after 15 min in the presence of cocktail (cocktail), and after 15-min of washout (washout cocktail). S, start; E, end of stimulation. The cocktail blockers inhibit neurally-mediated contractions and responses to stimulation reappear when the cocktail is washed out.
Frequency, TABLE 1 Treatment contractions/min Amplitude, mN The response of frequency No cocktail 3.8 (1.8) 2.05 (1.01) and amplitude, as the mean Cocktail 2.9 (0.6) 3.79 (1.08)* (SEM), to the cocktail, Control 1.2 (0.5) 1.86 (0.49) ryanodine and caffeine, in Control + ryanodine 2.9 (1.3)* 2.01 (0.54) control and DI muscle strips FIG. 3. The effects of ryanodine on spontaneous DI 3.1 (0.7)† 4.02 (1.22)† contractions in DI and normal muscle strips. DI + ryanodine 3.4 (0.8) 4.19 (1.28)† Spontaneous contractions from a DI muscle strip (a) Control 1.1 (0.5) 1.85 (0.46) and from a normal detrusor strip (b), before and Control + caffeine 0.3 (0.2)* 1.22 (0.22) *P < 0.05 vs before after exposure to ryanodine (10 mmol/L). DI 3.0 (0.6)† 4.01 (1.19)† treatment; †P < 0.05 vs a Ryanodine DI + caffeine 0.5 (0.3)* 1.22 (0.32)* control.
the spontaneous contractions in DI strips frequency (Fig. 3a) or the amplitude of 1 mN have a myogenic basis spontaneous contractions. The baseline 1 min spontaneous contractile activity before b Ryanodine To verify that nerve-mediated contractions applying ryanodine was significantly different would be eliminated by the cocktail, electrical between the DI and normal detrusor strips in 1 mN stimuli were applied to DI strips (five; Fig. 2.); frequency and amplitude (Table 1), but in the 1 min this evoked contractions with a mean presence of ryanodine, the contraction amplitude of 4.89 (1.05) mN and a mean frequency was not significantly different duration of 3.5 (0.8) s. The stimulus-evoked between the DI strips and normal detrusor strips, the mean frequency of contractions contractions almost disappeared after strips. The doubling of contraction frequency and the amplitude were reduced by caffeine applying the cocktail for 15 min, and partially induced by ryanodine in normal strips (Table 1). There was a similar response to reappeared after 15 min washout with suggests that RyRs modulate spontaneous caffeine in normal detrusor strips, where the normal physiological saline; after washout, contractions in normal conditions. It seems frequency and the amplitude were reduced stimulus-evoked contractions were possible that Ca2+ peaks released by RyRs (Table 1). Thus 10 mmol/L caffeine inhibited 2.44 (0.86) mN in amplitude and 3.1 (0.3) s in might act to decrease the whole contractile spontaneous contractions in detrusor strips in duration. Accordingly, we applied the cocktail force; interestingly, this modulation by RyRs is vitro from both normal and DI bladders. for the rest of the experiments to minimize lost in DI strips. the impact of neurogenic contractions. Ca2+ influx is necessary for maintaining Caffeine releases Ca2+ from intracellular spontaneous contractions in detrusor muscle RyRs release Ca2+ from the SR into the stores by RyRs, and caffeine-induced Ca2+ [14,17]. To test the role of Ca2+ entry via L-type cytoplasm, and ryanodine inhibits transient release is independent of carbachol-evoked Ca2+ channels, we applied the dihydropyridine Ca2+ peaks and the associated spontaneous Ca2+ release [17]. After applying 10 mmol/L inhibitor, nimodipine (0.1 mmol/L). transient outward currents in bladder muscle caffeine to DI strips, spontaneous Nimodipine abolished the rhythm of cells [13]. In normal detrusor strips, ryanodine contractions gradually attenuated (Fig. 4a), spontaneous contractions and attenuated the (10 mmol/L) increased the mean frequency of and this attenuation was reversed only slowly contractile amplitude in normal detrusor spontaneous contractions (Fig. 3b; Table 1). after the caffeine was washed out with a strips (five, Fig. 5b), but was less effective in DI The mean contraction amplitude was not fresh cocktail of physiological saline. It took a strips (five, Fig. 5a); in these, the contraction significantly affected (Table 1). In contrast, in long time (>30 min) for rehabilitation of the amplitude decreased sharply but the DI strips, ryanodine did not alter either the steady-going and regular contractions. In DI frequency was maintained. These results
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FIG. 4. The influence of caffeine (10 mmol/L) on DI FIG. 5. a Nimodipine and normal detrusor strips. a, After adding caffeine Effects of nimodipine (L-type Ca2+ in DI strips, contractions were attenuated. b, The channel blocker) on spontaneous results were similar in normal detrusor strips. contractions of detrusor muscle strips. In both DI strips (a), and a Caffeine normal detrusor strips (b), myogenic contractile activity 1 mN was largely abolished after L- 2+ 1 min 1 mN type Ca channel inhibition. b Nimodipine 1 min b Caffeine
1mN 1 mN
1 min 1 min indicate that Ca2+ entry is critical for expression and regulation of spontaneous FIG. 6. RyR protein expression in normal and DI spontaneous contractions, especially in contractions in vitro. In these experimental groups. Western blot analysis show differences in normal detrusor. conditions, spontaneous contractions in the expression of RyR protein. Equal amounts of isolated detrusor occur that do not appear to total protein (50 mg) were applied to each lane. No RyR protein expression was determined in 11 be mediated by nerves (Fig. 1); it is unclear bands were detected when the RyR channel preparations (six from the DI and five from whether they represent normal physiological antibody was absent during the blot operation. the control group). The mean intensity in each contractile activity or are an artificial normal blot was defined as 100 relative phenomenon in the condition of isolated intensity units by scanning densitometry. The preparations, but the increased frequency of RyR relative intensity was significantly lower in DI spontaneous contractions in detrusor strips samples (Fig. 6), with a mean relative intensity from DI bladder might correspond to the of 25 (20) vs 100 (15) in the normal group. uninhibited contractions identified in vivo by NormalDI Furthermore, there were no such bands in the filling cystometry. These contractions might biochemical assay when the RyR channel represent a background activity of muscle antibody was absent during the blot function that determines the overall resting required (such as T-type Ca2+ channels [25] operation. tone of the detrusor smooth muscle [23]. in DI).
DISCUSSION L-type Ca2+ channels are essential for Ca2+ sparks are caused by opening of RyRs in initiating the rise of intracellular Ca2+ that is the SR and are associated with the opening of In the present study we used a BOO-induced associated with spontaneous contractions L-type Ca2+ channels (Ca2+-induced Ca2+ model of DI in rats, which shares similar [14,17]. The contraction pathway evoked by release), and can be modulated by ryanodine, pathogenesis with DI after obstruction in various neurotransmitters (e.g. ATP and voltage, Ca2+, caffeine and the location of other animal models, and in humans in acetylcholine) or Ca2+ influx, is inhibited by events [26]. RyRs contribute high ‘local’ Ca2+ clinical practice [2,3,18]. The bladder responds dihydropyridine derivatives such as nifedipine concentrations, which are not in equilibrium to the increased afterload by hypertrophy to in a dose-dependent manner in the urinary with Ca2+ buffers and which could locally normalize wall tension, and with persistent bladder [24]. There is no doubt that an reach much higher levels than the ‘overall’ afterload, myogenic disorders appear, increase in intracellular Ca2+ concentration is Ca2+ concentrations measured during including DI. After surgically creating partial key to activating contraction in detrusor depolarization in bladder smooth muscle. In BOO in the rat, the uninhibitable rises in muscle; this increase can be due to Ca2+ influx addition, the appearance of ‘hot spots’ of Ca2+ detrusor pressure measured during filling from the extracellular space and/or Ca2+ in bladder smooth muscle cells [9] closely 2+ cystometry confirmed DI, but the precise release from intracellular stores. L-type Ca parallels the rise in KCa currents, reaching course of the pathological changes is still channels might play a pivotal role in a peak within 20 ms of the start of elusive and needs further investigation [19]. maintaining Ca2+ entry and in refilling depolarization, whereas the rise in ‘overall’ The bladder has localized micromotions in intracellular Ca2+ stores [17,24]. Nimodipine, Ca2+ is much slower. The Ca2+ ‘hot spots’ might isolation, or generalized contractions when an inhibitor of L-type Ca2+ channels, inhibited be attributed to the site of SR in the sub- the bladder fills [20,21]. The detrusor strips spontaneous contractions of detrusor muscle plasmalemma that has been called the contract spontaneously, and there is strips, but the underlying rhythm of ‘superficial SR’; unlike Ca2+-induced Ca2+ widespread activity that is independent of contractions was maintained in most DI release in cardiac muscle, that in smooth input from the CNS [22], and which persists strips, although their contraction amplitudes muscle is not tightly linked to the gating of when the actions of known neurotransmitters were too small to be analysed. To identify the L-type Ca2+ channels [10]. Meanwhile, large- 2+ 2+ + are blocked [14]. In the present study, we Ca entry pathways required for spontaneous conductance Ca -dependent K (BKCa) targeted the RyR, and observed changes in contractile activity, further investigations are channel currents are activated by Ca2+ sparks
© 2005 BJU INTERNATIONAL 431 JIANG ET AL.
2+ 2+ from RyRs in the SR, and BKCa channels are store releasing Ca (‘hot spots’ Ca ) activates 6 Montgomery BS, Thomas PJ, Fry CH. critical in regulating bladder smooth muscle KCa currents in the plasmalemma to facilitate The actions of extracellular magnesium excitability and contractility [27]. action potential re-polarization or on isolated human detrusor muscle hyperpolarization and inhibit Ca2+ influx [9]. function. Br J Urol 1992; 70: 262–8 RyRs decreased spontaneous contractions in Moreover, caffeine increases intracellular 7 Levin RM, Kitada S, Hayes L et al. normal detrusor strips but this negative- levels of cAMP via its phosphodiesterase Experimental hyperreflexia: effect of feedback regulation was lost in DI muscle activity; cAMP causes muscle relaxation, and intravesical administration of various 2+ 2+ (Fig. 3.). It seems reasonable that Ca sparks might directly influence the [Ca ]i-tension agents. Pharmacology 1991; 42: 54–60 by RyRs would decrease excitability through relationship. If so, the latter would play a 8 Brading AF. Ion channels and control of activation of K+ channels, leading to inhibition major role [31,32]. contractile activity in urinary bladder of Ca2+ influx through voltage-dependent smooth muscle. Jpn J Pharmacol 1992; 58 Ca2+ channels. Ca2+ release by RyRs limits In conclusion, the present results indicate that (Suppl 2): 120P–127P contraction frequency in detrusor muscle, as RyR Ca2+ release plays a negative role in 9 Herrera GM, Nelson MT. Differential blocking RyRs doubled the contraction spontaneous contractile activity. The regulation of SK and BK channels by frequency. However, in DI muscle, ryanodine presumed mechanism is that RyR Ca2+ release Ca(2+) signals from Ca(2+) channels and had no significant effect on spontaneous decreases contractility by inducing the ryanodine receptors in guinea-pig urinary contractions, thus we hypothesized that RyRs activation of KCa channels [14]. The present bladder myocytes. J Physiol 2002; 541: are dysfunctional in DI muscle. RyR results indicate that the effect of this cross- 483–92 dysfunction could result from decreased talk between RyRs and ion channels might be 10 Imaizumi Y, Torii Y, Ohi Y et al. expression of RyR protein, and Western weakened in DI muscle, resulting in Ca2+ images and K+ current during blotting analysis supported this hypothesis spontaneous contraction overactivity. depolarization in smooth muscle cells (Fig. 6); RyR expression was significantly of the guinea-pig vas deferens and decreased in DI smooth muscle. Thus it seems urinary bladder. J Physiol 1998; 510: possible that the decrease of RyR expression ACKNOWLEDGEMENTS 705–19 in DI muscle results in increased contraction 11 Collier ML, Ji G, Wang Y, Kotlikoff MI. frequency; this could result from either less The authors thank Dr Gerry Herrera Calcium-induced calcium release in hyperpolarization, or from less inactivation of (University of Vermont) for helpful discussion smooth muscle: loose coupling between voltage-dependent Ca2+ channels during the and skills relating to the detrusor strip the action potential and calcium release. resting phases between bursts of action experiments. J Gen Physiol 2000; 115: 653–62 potentials. 12 Ganitkevich VY, Isenberg G. Contribution of Ca(2+)-induced Ca2+ However, RyR Ca2+ release and the sequence CONFLICT OF INTEREST release to the [Ca2+]i transients in of negative regulation are complex and under myocytes from guinea-pig urinary the control of several factors. In isolated rat Bo Song and Qian-Jun Wen have received bladder. J Physiol 1992; 458: 119–37 uterus, ryanodine had almost no effect on the funding: Source of funding: the National 13 Heppner TJ, Bonev AD, Nelson MT. spontaneous cytosolic Ca2+ or force Nature Science Foundation of China Ca(2+)-activated K+ channels regulate transients, and Ca2+-induced Ca2+ release (30371429). action potential repolarization in urinary plays little role in SR Ca2+ release [28]. The bladder smooth muscle. Am J Physiol discrepancy might also be attributed to the 1997; 273: C110–7 different tissue orientation or the absence of REFERENCES 14 Herrera GM, Heppner TJ, Nelson MT. the cocktail. Further evaluation is needed of Regulation of urinary bladder smooth different Ca2+ sparks effects between the DI 1 Brading AF. A myogenic basis for the muscle contractions by ryanodine and normal smooth muscle. overactive bladder. Urology 1997; 50 receptors and BK and SK channels. Am J (Suppl. 6A): 57–73 Physiol Regul Integr Comp Physiol 2000; Caffeine, which mobilizes intracellular Ca2+ 2 Bulmer P, Abrams P. The unstable 279: R60–8 stores via RyRs, markedly enhances detrusor. Urol Int 2004; 72: 1–12 15 Heppner TJ, Herrera GM, Bonev AD, spontaneous transient outward currents 3 Sibley GN. A comparison of spontaneous Hill-Eubanks D, Nelson MT. Ca2+ sparks caused by activating BKCa channels [29]. In and nerve-mediated activity in bladder and K(Ca) channels: novel mechanisms to both normal and DI bladder strips, caffeine muscle from man, pig and rabbit. J Physiol relax urinary bladder smooth muscle. Adv generally blocked spontaneous contractions 1984; 354: 431–4 Exp Med Biol 2003; 539: 347–57 (Fig. 4). Caffeine-induced intracellular Ca2+ 4 Kinder RB, Mundy AR. Pathophysiology 16 Tunwell RE, Wickenden C, Bertrand BM transients are independent of membrane of idiopathic detrusor instability and et al. The human cardiac muscle ryanodine potential under physiological conditions [17]. detrusor hyper-reflexia. An in vitro study receptor-calcium release channel: Some intracellular Ca2+ stores function as a of human detrusor muscle. Br J Urol 1987; identification, primary structure and superficial buffer barrier for Ca2+ influx, 60: 509–15. topological analysis. Biochem J 1996; limiting the degree of contractile protein 5 Kato K, Wein AJ, Radzinski C et al. Short 318: 477–87 activation by diverting some of the Ca2+ that term functional effects of bladder outlet 17 Wu C, Sui GP, Fry CH. The role of the L- enters the cell away from the cytosolic obstruction in the cat. J Urol 1990; 143: type Ca(2+) channel in refilling functional compartment [30]. The subplasmalemma Ca2+ 1020–5 intracellular Ca(2+) stores in guinea-pig
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detrusor smooth muscle. J Physiol 2002; Abe K, Brading AF. Ca(2+) channel dependent K+ channels in urinary bladder 538: 357–69 properties in smooth muscle cells of the smooth muscle cells of the guinea pig. Jpn 18 Sibley GN. An experimental model of urinary bladder from pig and human. Eur J Pharmacol 2001; 85: 382–90 detrusor instability in the obstructed pig. J Pharmacol 2002; 443: 19–29 30 Yoshikawa A, van Breemen C, Isenberg Br J Urol 1985; 57: 292–8 25 Sui GP, Wu C, Fry CH. Inward calcium G. Buffering of plasmalemmal Ca2+ 19 Fry CH, Sui GP, Severs NJ, Wu C. currents in cultured and freshly isolated current by sarcoplasmic reticulum of Spontaneous activity and electrical detrusor muscle cells: evidence of a T- guinea pig urinary bladder myocytes. Am J coupling in human detrusor smooth type calcium current. J Urol 2001; 165: Physiol 1996; 271: C833–41 muscle: implications for detrusor 621–6 31 Watanabe C, Yamamoto H, Hirano K, overactivity? Urology 2004; 63 (Suppl. 1): 26 Jaggar JH, Porter VA, Lederer WJ, Kobayashi S, Kanaide H. Mechanisms 3–10 Nelson MT. Calcium sparks in smooth of caffeine-induced contraction and 20 Drake MJ, Hedlund P, Harvey IJ, Pandita muscle. Am J Physiol Cell Physiol 2000; relaxation of rat aortic smooth muscle. RK, Andersson KE, Gillespie JI. Partial 278: C235–56 J Physiol 1992; 456: 193–213 outlet obstruction enhances modular 27 Herrera GM, Heppner TJ, Nelson MT. 32 Hockey JS, Wu C, Fry CH. The actions of autonomous activity in the isolated rat Voltage dependence of the coupling of metabolic inhibition on human detrusor bladder. J Urol 2003; 170: 276–9 Ca(2+) sparks to BK(Ca) channels in smooth muscle contractility from stable 21 Bristow SE, Neal DE. Ambulatory urinary bladder smooth muscle. Am J and unstable bladders. BJU Int 2000; 86: urodynamics. Br J Urol 1996; 77: 333–8 Physiol Cell Physiol 2001; 280: C481–90 531–7 22 Skehan AM, Downie JW, Awad SA. The 28 Taggart MJ, Wray S. Contribution of pathophysiology of contractile activity in sarcoplasmic reticular calcium to smooth Correspondence: Bo Song/Hai-hong Jiang, the chronic decentralized feline bladder. muscle contractile activation: gestational Urology Center, Southwest Hospital, Third J Urol 1993; 149: 1156–64 dependence in isolated rat uterus. Military Medical University, Chongqing 23 Damaser MS, Arner A, Uvelius B. Partial J Physiol 1998; 511: 133–44 400038, China. outlet obstruction induces chronic 29 Ohi Y, Atsuki K, Tori Y, Ohizumi Y, e-mail: [email protected] distension and increased stiffness of rat Watanabe M, Imaizumi Y. Imaging of urinary bladder. Neurourol Urodyn 1996; Ca2+ release by caffeine and 9-methyl-7- Abbreviations: DI, detrusor instability; RyR(s), 15: 650–65 bromoeudistomin D and the associated ryanodine receptor(s); SR, sarcoplasmic 24 Kajioka S, Nakayama S, McMurray G, activation of large conductance Ca2+- reticulum.
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Pharm review Article
Unseen forces at AUA 2005?
This time last year I was accused, even by On the basis of the data presented at the AUA, my impeccable standards, of being unduly the interest in dapoxetine is easy to cynical and negative in my assessment of the understand. Its pharmacokinetic profile, with
impact and visibility of the pharmaceutical short Tmax and half-life that rendered it industry at the AUA meeting in San Francisco, ineffective as an antidepressant, makes it near which led me to conclude that “Those ideal for ‘on demand’ use in the treatment of participants at the recent AUA meeting premature ejaculation [2]. As the NDA was looking for new and exciting disclosures submitted at the end of 2004 we (assuming from the pharmaceutical industry would approval of dapoxetine) may well be about to have been sorely disappointed. The other enter the second phase of the sexual health ª99% of attendees could have been entering revolution, i.e. the arrival of effective therapy a re-run of the previous year’s AUA in for premature ejaculation. It is almost certain Chicago, but in a more convenient downtown that other companies will be ‘dusting off’ setting and at a higher ambient temperature” their own SSRIs but dapoxetine will be [1]. So what has changed about this year’s difficult to match. In particular, the drug is AUA? As a minimum, the words ‘convenient’, effective (on demand) after a single dose, ‘higher ambient temperature’ and ‘Chicago’ whereas the ‘off label’ use generally requires can be omitted from the above quote and some degree of chronic drug exposure. once again it was what was not being reported by industry in public that was Although dapoxetine is potentially a drug ‘fit probably more interesting and important than for purpose’, i.e. the rapidity of action and fast what was. plasma clearance gives patients what they want, it may well represent the start of As would be anticipated from previous AUAs the story, as there are several unanswered (and even more so at the recent EAU), questions. The first is the identity and even the audience attendance at the pre-AUA industry- location of the 5-HT (serotonin) receptor sponsored symposia was low in both head- subtype involved in producing the acute effect count and energy level. Like many investors on of dapoxetine; the elevated synaptic 5-HT the stock market, at most symposia attendees levels produced by inhibition of the serotonin appeared to be looking for their exit strategy transporter must act via a receptor. Rest at the time of entry. In part this may be due to assured the pharmaceutical industry, using the almost universal policy of vetoing the type of animal models described by interesting questions from the audience. Or is Francois Guiliano, are actively researching this this my paranoia? Somewhat ironically, by way area. There are certainly enough 5-HT receptor of contrast, was any symposium related to the subtypes to choose from, with up to 15 having use of dapoxetine in premature ejaculation. been described so far. The other major Certainly, at least in terms of novelty of data, question is how dapoxetine will eventually be dapoxetine was the star of the show. In terms described, e.g. could we be on the cusp of a of quantity Prof. Roehrborn, with 28 description as an ejaculo-selective serotonin presentations (most of them personal), was transport inhibitor (ESSTI) [2]? well positioned but the overall prize on both the quality and quantity was the BJU This time last year, with the arrival of International’s own Georg Bartsch, with at duloxetine in the European marketplace least 39. and the entry of RO 115-1240, the a1A/L
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agonist [3], we would have expected Elsewhere within the AUA there is In many other areas, including oncology, the AUA literature to be burgeoning with considerable evidence that the although here presumably much basic information on these or mechanistically pharmaceutical industry have not lost interest research is being undertaken, beyond similar agents. Unfortunately the in a-blockers for BPH/LUTS with ‘new’ data presentations on microtubule inhibitors and development of the Roche drug has been on naftopidil and silodosin (KMD 3213) endothelin antagonists, industry is saying terminated due to unexpected toxicology emerging. Data interpretation is in general little. and the sponsors (Lilly) have removed complicated by the comparison only with a duloxetine (hopefully only temporarily) from homeopathic dose of tamsulosin (0.2 mg). None of the above in any way detracts from the FDA approval process. Otherwise, in the ‘my a-blocker is better than the value of the AUA to the urologist, only yours’ stakes, companies are concentrating on that for a variety of reasons (largely For the pharmaceutical industry duloxetine product ‘evergreening’ (i.e. patent extension) regulatory and patent) it is not a forum for would always have been a difficult act to by launching new formulations; doxazosin the pharmaceutical industry to present high follow as, with the possible exception of Karl (Cardura XL), alfuzosin (Uroxatral) and the science or early stage clinical data. Thor, no-one is really sure how it works. This TOCAS formulation of tamsulosin. merely reflects the relative complexity of Next month I will focus on combination understanding overall neurophysiological As in the case of BPH/LUTS, there appears products and ‘one drug fits all’ for the patient control mechanisms. In the case of a- to be little happening in urinary urge and his or her co-morbidities. agonists, as several companies (including incontinence (UUI)/overactive bladder Abbott, Pfizer and Roche) have failed to (OAB). We may well be at the end of the 1 Wyllie MG. It’s new and exciting- can it deliver efficacy without blood pressure road with strategies designed to reduce dry be AUA 2004? BJU Int 2004; 94: 437–8 elevation, this may represent the end of the mouth, with new generation M3-selective 2 Wyllie MG. The era of ESSTIs is slowly story. An alternative approach involving local agents and patches appearing to have little approaching? BJU Int 2005; 96: 181–2 delivery of the a-agonist is being evaluated in impact on the overall clinical profile. Few 3 Musselman DM, Ford DP, Gennevois DJ phase II studies by Plethora Solutions Ltd. GSK companies, with the possible exception of et al. A randomized crossover study to may well hold ‘pole position’ in the search for Roche, remain interested in selective evaluate RO 115-1240, a selective a1A/L effective therapy for stress incontinence; antimuscarinics. The only sign of major partial agonist, in women with stress their b3-adrenoceptor agonist (solabegron, activity is from Dynogen, who are looking incontinence. BJU Int 2004; 93: 78–83 GW 427353) being in the early stages of for alternative mechanistic strategies, development. A major issue will be whether it have a combination product in clinical MICHAEL G. WYLLIE, is possible to separate bladder and sphincter development and have identified potentially Urodoc Ltd, Maryland, Ridgeway Road, effects from obtrusive tachycardia and exploitable calcium currents in bladder Herne, Kent, CT6 7LN, UK. elevation of core temperature. sensory neurones. e-mail: [email protected]
436 © 2005 BJU INTERNATIONAL
PoT Article MODIFICATION TO THE ALBARRAN DEFLECTOR LOUGHLIN
A simple modification to the Albarran deflector enhances endoscopic control
KEVIN R. LOUGHLIN Division of Urology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA Accepted for publication 27 January 2005
INDICATIONS deflector, and the Bugbee electrode, ureteric catheter or laser fibre is placed through this The Albarran deflector is one of the oldest and cylinder or ring. most frequently used endoscopic instruments employed by urologists [1]. However, it is often cumbersome to control instruments in all planes of view through the Albarran. A COMPARISON WITH OTHER METHODS simple modification of converting the flat Albarran plate into a cylinder facilitates The cylinder or ring is no more difficult to use control of catheters, laser fibres or electrodes than the standard Albarran deflector. The placed through the instrument. ureteric catheter, laser fibre or electrode is threaded through the ring before placing the instrument into the cystoscope sheath. Using a 30° lens, the tip of any of these devices METHOD always remain in the surgeon's field of view and cannot migrate from the field of vision, as A circumferential cylinder or ring is placed can happen with the standard Albarran on the deflecting portion of the Albarran deflector (Figs 1 and 2).
FIG. 1. a, Placing the electrode through the ring, and b, the field of vision maintained as the electrode is extended.
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FIG. 2. More precise control of the electrode in ADVANTAGE AND DISADVANTAGES CONFLICT OF INTEREST preparation for bladder tumour fulguration. The distinct advantage of the cylinder over None declared. the deflector is that it maintains the position of any instrument placed through it in the surgeon's visual field. The cylinder is proximal REFERENCE enough that it does not block the surgeon's view of the tip of the instrument. 1 Carter HB. Basic instrumentation and cystoscopy. In Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ eds, Campbell's DIFFICULTIES AND COMPLICATIONS Urology. Philadelphia: WB Saunders, 2002: 111–21 The cylindrical ring, which is 3 mm long, is made of stainless steel. It has been used over Correspondence: Kevin R. Loughlin, Division 100 times in an ex-vivo setting and does not of Urology, Harvard Medical School, Brigham fatigue or lose its shape in any way. There has and Women's Hospital, Harvard, Boston, MA, been no damage to any catheter, electrode or USA. laser fibre placed through it. e-mail: [email protected]
438 © 2005 BJU INTERNATIONAL PoT Article MURTHI AND CUCKOW REMOVING A JJ STENT
Cystoscopic removal of a JJ stent using a suture ‘lasso’
GOVIND V.S. MURTHI and PETER CUCKOW Department of Paediatric Urology, Great Ormond Street Hospital, London, UK Accepted for publication 31 January 2005
INDICATIONS FIG. 1. The strong, stiff, monofilament Cystoscopic removal of a JJ ureteric stent in suture is kinked into a sharp, the neonate and young infant (inserted, e.g. narrow apex to fit it into the after a neonatal pyeloplasty) can present channel technical difficulties because of the small calibre of the urethra. While a Wolf 7.5 F rigid cystoscope can be passed with ease, its working channel (4 F) will not accommodate a grasping forceps with jaws large and robust enough to grasp the JJ stent (usually 3 F or 4.7 F) adequately to enable removal without slipping. Alternatives are open cystotomy or to wait for several months for the urethra to enlarge sufficiently (with the risk of infection, stone encrustation, migration, etc.). We FIG. 2. The suture is passed through the working channel of the cystoscope and the ends brought out. present a simple technique to circumvent this problem
METHOD
A strong, stiff, monofilament suture e.g., 0 polydioxanone or 0 polypropylene, is kinked into a sharp, narrow apex to fit it into the channel (Fig. 1). It is then passed through the working channel of a 7.5 F Wolf cystoscope and the ends both brought out of the cystoscope (Fig. 2). Once inside the bladder, because of the stiffness of the monofilament, advancing one limb opens up a loop inside the bladder; advancing both limbs will not open the loop. The stiffness and monofilament nature of the suture used will prevent buckling inside the working channel. Suitable positioning and gentle withdrawal of the FIG. 3. Gentle withdrawal of the suture will ‘lasso’ the J-loop onto the stent. suture will ‘lasso’ the J-loop onto the stent (Fig. 3). The loop and the stent are then pulled snug onto the tip of the cystoscope that is then withdrawn en masse.
We have used this technique successfully on several occasions and its use can be extended to the older patient when suitable grasping forceps are unavailable.
CONFLICT OF INTEREST
Correspondence: Govind V.S. Murthi, Department of Paediatric Urology, Great Ormond Street Hospital, London, UK. e-mail: [email protected]
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Correspondence Article LETTERS
WRITE TO THE EDITOR AT BJU INTERNATIONAL, 47 ECCLES STREET, DUBLIN 7, IRELAND
ANALYSIS OF HER2 EXPRESSION IN superficial bladder cancer, but also in 47% cancer and their relationship to epidermal PRIMARY URINARY BLADDER CARCINOMA and 21% of normal-appearing adjacent growth factor receptor. Br J Cancer 1996; AND CORRESPONDING METASTASES proximal and distal mucosa, respectively 73: 654–8 [6]. Moreover, in our recent article, we 4 Cianciulli AM, Botti C, Coletta AM et al. Sir, found, in 48 advanced bladder cancers, The contribution of fluorescence in situ We were interested in this recent article by chromosome 17 polysomy in 42% and hybridization to immunohistochemistry Gardmark et al. [1], in which they describe HER2 gene amplification in 15% of for the evaluation of Her-2 in breast their analysis of 90 patients with metastatic specimens. Our study strongly confirmed cancer. Cancer Genet Cytogenet 2002; TCC of the urinary bladder to evaluate “the the importance of chromosome 17 polysomy 133: 66–71 suitability of HER2 as a target in preparation in detecting HER2 amplification [7]. Evidence 5 Latif Z, Watters AD, Dunn I, Grigor K, for planned systemic therapies of HER2- from breast cancer suggests that only Underwood MA, Bartlett JM. HER2/neu positive urinary bladder carcinoma”. The tumours with HER2 gene amplification gene amplification and protein authors examined HER2 expression using respond to the anti-HER2 therapy ( Herceptin) overexpression in G3 pT2 transitional cell two different immunohistochemical stains [8]. If this were true for bladder cancer, only a carcinoma of the bladder: a role for anti- (the HerceptTest and modified HerceptTest, low proportion of patients would be suitable HER2 theapy? Eur J Cancer 2004; 40: 56– MH). for treatment. 63 6 Cianciulli AM, Leonardo C, Guadagni F According to these authors, HER2 staining In conclusion, Gardmark et al. should be more et al. Genetic instability in superficial was positive in 79% of the primary tumours careful in stating that immunohistochemical bladder cancer and adjacent mucosa: an and 62% of the metastases when the MH staining is sufficient to select HER2-targeting interphase cytogenetic study. Hum Pathol staining and target-score criteria were in patients. We suggest that it would be useful 2003; 34: 214–21 applied. Moreover, in their conclusions to re-evaluate these results using 7 Gallucci M, Guadagni F, Marzano R section, they underlined that the primary goal fluorescence in situ hybridisation, which et al. Status of the p53, 16, RB1, and HER- of the study was to analyse over-expressed permits the simultaneous assessment of the 2 genes and chromosomes 3, 7, 9, and 17 receptors for possible treatment with HER2 chromosome 17 aneusomy and HER2 gene in advanced bladder cancer: correlation targeting agents. status. with adjacent mucosa and pathological parameters. J Clin Pathol 2005; 58: 367– To that end, in our opinion, essential MICHELE GALLUCCI, 71 requisites are those of evaluating not only ROBERTA MEROLA*, 8 Slamon DJ, Leyland-Jones B, Shak S HER2 expression, but also gene amplification COSTANTINO LEONARDO, et al. Use of chemotherapy plus a and chromosome 17 aneusomy. Many studies ENZO MARIA RUGGERI† and monoclonal antibody against HER2 have evaluated HER2 protein expression and ANNA MARIA CIANCIULLI for metastatic breast cancer that gene amplification rates; they report HER2 Urology, *Clinical Pathology Cytogenetic Unit overexpresses HER2. N Engl J Med 2001; expression rates of 2–74% [2]. This variation is and †Oncology, Regina Rlena Cancer Institute, 344: 783–92 partly a result of differences in the methods Rome, Italy used to assess HER2 and variability in the reporting of data. Both overexpression with 1 Gardmark T, Wester K, De La Torre M, no gene amplification and heterogeneity in Carlsson J, Malmstrom PU. Analysis of REPLY HER2 expression are more common in bladder HER2 expression in primary urinary cancer than in breast cancer [3,4]. This is bladder carcinoma and corresponding We were very pleased to get such quick mainly explained by a high level of metastases. BJU Int 2005; 95: 982–6 response to our work and wish to comment as chromosome 17 polysomy in TCC. Latif et al. 2 Small EJ, Halabi S, Dalbagni G et al. follows. As already noted by the authors of [5], in 75 TCC classified as G3pT2, showed Overview of bladder cancer trials in the the letter, the primary goal of our work was to polysomy 17 in 97%, increased HER2 copy cancer and leukaemia group B. Cancer evaluate the HER2-receptor as a target for number in 92% and HER2 gene amplification 2003; 97: 2090–8 anti-HER2 nuclide-based treatment. We in 7% of cases examined. In our previous 3 Mellon JK, Cook S, Chambers P et al. thank the authors for an interesting update investigation, we reported that chromosome Transforming growth factor and on FISH and chromosome 17 polysomy. In our 17 aneusomy is present in 84% of examined epidermal growth factor levels in bladder case however, the reason for a high
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LETTERS expression of the receptor on the cell surface S. ASAD ABEDIN dysgenesis [4] but I think these data allow one is not important. Perhaps there may be some Research Fellow, Endocrinology and to be more positive if discussing the future confusion as to the role of trastuzumab. Our Metabolism Laboratory, Institute of risk of testicular cancer with the parents of a approach involves the antibody merely as a Biomedical Research, University of cryptorchid boy. carrier delivering the nuclide at the cell Birmingham, Birmingham, UK surface, not primarily acting alone or STEPHEN J. GRIFFIN, combined with chemotherapy, as in the 1 Lehrer S, Diamond EJ, Mamkine B, SpR Urology, West Suffolk Hospital, Bury St. treatment of breast cancer. In fact, the Droller MJ, Stone NN, Stock RG. C- Edmunds, UK. most recent work at our laboratory has reactive protein is significantly associated been with other antibodies targeting the with prostate-specific antigen and 1 Patil KK, Green JSA, Duffy PG. receptor. metastatic disease in prostate cancer. BJU Laparoscopy for impalpable testes. BJUI Int 2005; 95: 961–2 2005; 95: 704–8 TRULS GÅRDMARK and 2 Swerdlow AJ, Higgins CD, Pike MC. Risk PER-UNO MALMSTRÖM of testicular cancer in cohort of boys with Division of Urology, Department of Surgical REPLY cryptorchidism. BMJ 1997; 314: 1507–11 Sciences, Akademiska Hospital, Uppsala, 3 Forman D, Pike MC, Davey G et al. Sweden Dr. Abedin writes that we implied that the Aetiology of testicular cancer: association multiple regression we used would allow the with congenital abnormalities, age at prediction of the dependent variable, CRP, and puberty, infertility and exercise. BMJ that this would be clinically useful. We 1994; 308: 1393–9 C-REACTIVE PROTEIN IS SIGNIFICANTLY implied nothing of the sort in our article, nor 4 Martin DC. Malignancy and the ASSOCIATED WITH PROSTATE-SPECIFIC did we say anything about clinical utility. Dr. undescended testis. In Fonkalsrud EW, ANTIGEN AND METASTATIC DISEASE IN Abedin is reading into our work something Mengel W eds, The Undescended Testis. PROSTATE CANCER that simply is not there. We did feel that the r2 Chicago. London: Year Book Medical value of 0.207, contrary to Dr. Abedin's Publishers, Inc, 1981: 144–56 Sir, assertion, was useful for the reader to know I read with interest this paper [1] investigating because it shows that the PSA level explained the relationship between PSA, stage of 20.7% of CRP level; therefore, regression was prostate cancer and the important but non- the appropriate analysis to use. (Dr. Abedin THE ROLE OF URINARY URGENCY AND ITS specific inflammatory marker, C-reactive incorrectly states that the r2 value of 0.207 MEASUREMENT IN THE OVERACTIVE protein (CRP). The authors state in the final was from a multiple regression; in fact, it was BLADDER SYMPTOM SYNDROME: paragraph of their discussion: “The present from the simple regression shown in Figure 2.) CURRENT CONCEPTS AND FUTURE finding of a significant correlation of CRP and Prostate cancer and PSA levels are PROSPECTS PSA levels suggests that more study may complicated biological phenomena, poorly further illuminate the causal role of understood, and obviously do not correlate Sir, inflammation in prostate cancer.” The authors perfectly with inflammation, CRP, or, probably, I read this article [1] with interest and have used the statistical technique of multiple anything else. congratulate the eminent authors for tackling regression, as opposed to correlation. These this issue. We have in common our concern to are closely related; however, using multiple STEVEN LEHRER, MD improve the treatment for this symptom regression may have been unnecessary in this syndrome, but I may have additional insight context. The latter technique gives a precise to offer, as I suffer from it. I began research relationship between two variables, PSA and LAPAROSCOPY FOR IMPALPABLE TESTES into lower urinary tract physiology before I CRP in this instance, which is expressed as a had any urological problems, but over the regression equation. This has the implied use Sir, years my bladder has become seriously for predicting the dependent variable, CRP in I read with interest this article by Patil et al [1]. overactive, something that appears to happen this case, when the independent variables are However, their statement that orchidopexy to many who contracted poliomyelitis as known (PSA and disease stage). I would does not reduce the risk of malignant young adults. Although I can only speak for suggest that there is no use of such prediction transformation may not be entirely true. what applies to me, I find that the authors are in routine clinical use, as CRP is a commonly Swerdlow et al [2], in a retrospective cohort wrong in some of their assessments, and offer measured serum variable. The authors quote study of 1075 boys with cryptorchidism, the following observations. an r2 value of 0.207 in Figure 2, relating to showed that the relative risk of testicular the multiple regression model illustrated. cancer decreases significantly at 15 years The definition of urgency as ‘a sudden This indicates that the multiple regression after orchidopexy. Furthermore, a population- compelling desire to pass urine, which is analysis shown only explains 20.7% of the based case-control study of 794 men with a difficult to defer’ is accurate, and I agree with observations made by the authors, i.e. 79.3% testicular germ cell tumour suggested that this. However, over the issue of whether urge of the data is not modelled by the regression orchidopexy before age 10 years eliminates and urgency are a continuum, or urgency is analysis described. This suggests that the the excess risk of testicular cancer associated pathological and not experienced by normal multiple regression shown may be with undescended testis [3]. Undoubtedly people, in my experience it is the former. I inappropriate for the data. intra-abdominal testes confer a greater risk of seem to remember from childhood friends
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queuing for a lavatory, hopping around from I do not routinely use drugs to control my We were surprised that all 260 patients had one foot to the other desperate to get in, were bladder, although I may have to in the future, had bilateral PLND, irrespective of the stage of they not experiencing urgency? Certainly for but use antimuscarinics when I travel. They the disease. We would differ with the authors' me the sensation of normal urge and are extremely effective for me initially, approach and only undertake PLND in higher- compelling urgency differ only in intensity. suppressing urgency and meaning that I can risk patients, as in other centres worldwide What does differ though is that urgency now avoid leaking and cope with travelling. [3,4]. Indeed, the senior author of the paper can come on suddenly, whereas before, However, they are less effective with time, (A.V.K.) took part in a multicentre audit of normal urge if unattended to would progress although usually being reasonably effective radical prostatectomy involving 854 patients, to urgency. for ≈10 days. However, when I stop taking 701 of whom had PLND, the positive local them I have several days with very bad node metastatic rate being only 4.9% [5]. We Another thing that I disagree with is the overactivity before things settle down again. think that subjecting all patients to PLND, concept that it is not possible to defer the As a pharmacologist, this is exactly what I irrespective of the risk factors, carries extra void after an urgency episode, or that there is would expect. The body is set up to adjust the morbidity (other than lymphoceles), increases a ‘warning time’ that is measurable. For me sensitivity of receptive organs to the amount the operative time and not least the financial the most important thing is to defer voiding of stimulation received by the receptors. I burden on the health service. With such after an urgency episode, because my motor would far prefer to use a drug that did not significant morbidity, the authors made no disability means that it takes me a work through receptors, and am looking attempt to justify undertaking PLND. It would considerable time to get to the toilet, get out forward to a bladder-selective K-channel- have been helpful if they had commented on of my wheelchair, sort out garments and opening drug, if ever they develop one. the histological status of the dissected lymph prepare to void (normally into a jug). While I nodes and whether there was a higher am experiencing urgency I cannot do any of ALISON F. BRADING, incidence of positive nodes in the patients these things. Although I have several physical Oxford Continence Group, University with lymphocele, as there appears to be a and psychological strategies to suppress Department of Pharmacology, Oxford, UK greater risk of lymphocele formation in urgency (I learnt a new one from Richard patients with tumour-bearing lymph nodes Turner Warwick the other day), they do not 1 Chapple CR, Artibani W, Cardozo LD [6]. always work, and occasionally I leak urine et al. The role of urinary urgency and its before I can get up, but usually I manage to measurement in the overactive bladder AMRITH RAJ RAO and ROGER O. PLAI, suppress it. Then if I have any sense, I empty symptom syndrome: current concepts Department of Urology, Conquest Hospital, my bladder. Otherwise it may be anything and future prospects. BJU Int 2005; 95: Hastings, East Sussex, UK between a few minutes to half an hour before 335–40 I get another attack, and then I am likely to 1 Pepper RJ, Pati J, Kaisary AV. The leak. Even if I do suppress the first incidence THE INCIDENCE AND TREATMENT OF incidence and treatment of lymphoceles of urgency and get to the bathroom, I am very LYMPHOCELES AFTER RADICAL after radical retropubic prostatectomy. likely to get a second urgency episode while I RETROPUBIC PROSTATECTOMY BJU Int 2005; 95: 772–5 am sorting out garments, and more often 2 Porpiglia F, Bellina M, Tarabuzzi R et al. than not I leak some urine. This most Sir, Pelvic ultrasound monitoring of effectively stops the urgency, and I can then We read with interest this article by Pepper lymphocele in patients treated with void normally. Urgency is clearly triggered by et al [1]. on the incidence and treatment radical prostatectomy. Arch Ital Urol psychological stimuli, and by increasing of lymphoceles after radical retropubic Androl 2000; 72: 194–6 bladder volume. In my experience it is also prostatectomy and bilateral pelvic lymph node 3 Meng MV, Carroll PR. When is pelvic related to the composition of my urine; dissection (PLND). They rightly highlighted the lymph node dissection necessary before urinating into a jug gives plenty of need for suspicion of a lymphocele in such radical prostatectomy? A decision opportunity to measure volume and assess patients presenting with vague abdominal pain analysis. J Urol 2000; 164: 1235–40 the colour, and urgency comes on with small and discomfort. We would like to highlight a 4 Sullivan LD, Rabbani F. Should we volumes of concentrated urine, but larger few issues that may need clarification. reconsider the indications for ileo- volumes of dilute urine. obturator node dissection with We suggest the title should relate to localized prostate cancer? Br J Urol With reference to quality-of-life issues, the ‘symptomatic lymphoceles’, as it is well 1995; 75: 33–7 most negative feature is the leakage; urgency documented that the incidence of sub-clinical 5 Winkler MH, Khan FA, Hoh IM et al. is a nuisance, but it is the knowledge that it is lymphoceles is ≈40% [2]. Interestingly, Time trends in case selection, stage and very often associated with leakage that is the eight of the nine patients who had an prostate-specific antigen recurrence after problem. It is not easy for me to change my ultrasonographic diagnosis of lymphocele radical prostatectomy: a multicentre clothes or to deal with any damp seats. proceeded to a confirmatory CT. The ninth audit. BJU Int 2004; 93: 725–9 Currently the volumes I leak are small enough patient ‘presumed’ clinically to have a 6 Resnick MI, Kursh ED. Extrinsic to deal with using pads (I supplement these lymphocele after failure to image on obstruction of the ureter. In Walsh PC, with Sainsbury's super-absorbent clothes, ultrasonography, did not have a CT scan. We Retik A, Vaughan ED Jr, Wein AJ eds, which are easy to rinse out and re-use later). think that this patient should not have been Campbell's Urology. Vol. 1, Chapt. 10, 7th Urgency does not yet trigger a proper void – I included in the data without confirmatory edn. Philadelphia: WB Saunders Co, 1998: hope it never will. imaging. 387–422
442 © 2005 BJU INTERNATIONAL Surgery Article surgery illustrated THÜROFF et al.
Surgical Atlas Simplified orthotopic ileocaecal
10 cm 20 cm 10 cm pouch (Mainz pouch) for bladder substitution
JOACHIM W. THÜROFF, LUDGER FRANZARING, ROLF GILLITZER, MARKUS WÖHR and SEBASTIAN MELCHIOR Department of Urology, Johannes Gutenberg University, Medical School, Mainz, Germany
ILLUSTRATIONS by STEPHAN SPITZER, www.spitzer-illustration.com
INTRODUCTION is bladder cancer, when cystoprostatectomy (or cystectomy in females) allows Since the early 1980s ileocaecal segments preservation of the sphincteric urethra. have been used in the Mainz pouch technique This is generally possible in the absence for orthotopic bladder substitution to the of urothelial cancer in the prostate bladder neck or to the urethra [1–3]. The (bladder neck in females) and at the Mainz pouch provides a low-pressure surgical margins (frozen-section analysis) reservoir with good capacity [4]. In orthotopic of the transected urethra. Orthotopic bladder substitution to the urethra, functional bladder substitution to the trigone (with characteristics compare favourably with other no ureteric reimplantation) or to the types of ileal-pouch bladder substitutes [5]. bladder neck is indicated in benign conditions which nevertheless require However, the surgical technique was criticised subtotal cystectomy, e.g. interstitial cystitis for being tedious and time-consuming, or severe detrusor hyper-reflexia. Whether and that the technique of antirefluxive or not ureteric reimplantation into the pouch submucosal tunnel ureteric implantation was is preferable depends on the presence or not applicable to dilated, irradiated or short absence of vesico-ureteric obstruction and/or ureters. reflux.
In 2001 we introduced surgical modifications Patient selection is critical for the functional to simplify the construction of an orthotopic success of the procedure; in those aged Mainz pouch, and to use the same ≥70 years the results for urinary control standardized technique of ureter become less favourable. In patients with a implantation for normal, dilated and even neurogenic bladder and females, capability very short ureters, but still providing and willingness to perform transurethral antireflux protection [6]. clean intermittent self-catheterization (CISC) must be checked before surgery. In PLANNING AND PREPARATION handicapped and very obese patients catheterization of a continent abdominal Indications. The main indication for stoma might be preferable to transurethral orthotopic bladder substitution to the urethra CISC.
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SPECIFIC INSTRUMENTS AND MATERIALS • Poly GIA-75 staplers (lactomer absorbable and secondly on the surgeon’s preference. copolymer staples). In children and patients with a small • Optical loupes (¥2.5–3.5, 50 cm focal diameter of small bowel and/or caecum length); The day before surgery the bowel is cleansed and ascending colon, the standard sutured • Headlight; by administering 3 L of polyethyleneglycol technique is preferable. In all others, it • Babcock clamps; solution. During surgery antibiotics depends on the surgeon’s preference. • 4/0 glyconate monofilament sutures, (ampillicin/clavulanic acid and metronidazol) However, as the length of bowel segments double-armed with two 5/8 needles (FR 26) are administered and continued afterward for to be resected differs slightly with either for urethral anastomosis; 7–10 days. technique, this decision has to be made • 4/0 poly p-dioxanone monofilament before resecting the bowel. In the following, sutures on a 1/2 needle (HR22) for ileo- The patient is placed supine on the table, both the sutured version (Figs 1–7) and the ascendostomy, pouch suturing; allowing access to the external meatus of the stapled version (Figs 8–16) are illustrated. • 4/0 polydioxanon on a straight needle; urethra to place a transurethral catheter If ureters have to be cut short because of • 4/0 polyglytone monofilament sutures during surgery. For urethro-intestinal irradiation damage or urothelial tumours, on a 3/8 needle (P-13) for fixation of stents, anastomosis, a slight Trendelenburg position again this has to be considered before pouchostomy; is helpful. resecting the bowel segments, to allow ileal • 7/0 polyglycolic acid braided sutures on a ureteric substitution (Figs 19 and 20) by 3/8 needle (DR10) for ureteric anastomosis; resecting a somewhat longer segment of the • 6/0 glyconate monofilament sutures on a INTRAOPERATIVE DECISION-MAKING: prevalvular ileum. However, for all variations 1/2 needle (HR13) for ureteric anastomosis; SUTURING OR STAPLING THE POUCH? of pouch formation, techniques of ureteric • 6 and 8 F polyurethane/polypropylene implantation and urethral anastomosis ureteric stents; Whether suturing or stapling of the pouch is (Figs 17 and 18) are identical. • 10 F pigtail pouchostomy catheter; used depends primarily on bowel diameter
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SURGERY ILLUSTRATED
Figure 1
Sutured version, normal length ureters. The caecum and ascending colon are mobilized up to the hepatic flexure. The terminal 30 cm of ileum and 10 cm of caecum and ascending colon are isolated. A Foley balloon catheter is inserted into the ileum and the excluded bowel segments are irrigated with 1–2 L of saline. Thereafter, the proximal 20 cm of ileum is separated from the terminal 10 cm of prevalvular ileum, with transection of the superficial arcade of the mesentery only. The appendix is resected.
10 cm 20 cm
10 cm
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Figure 2
The intestinal continuity is restored by a spatulated end-to-end ileo-ascendostomy. The single-row seromuscular anastomosis is established with two running 4/0 glyconate sutures, here shown for the posterior wall.
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Figure 3
The anterior wall of the spatulated end-to- end ileo-ascendostomy has also been closed by a running suture. The separated loop of 20 cm ileum is folded into a U-shape and opened along its antimesenteric border with cautery.
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Figure 4
The posterior walls of the opened and into a U-shape arranged ileal segments are joined to each other by side-to-side anastomosis using a single row of all-layer running 4/0 polydioxanon on a straight needle. Stay sutures and Allis clamps help to align the segments. Caecum and ascending colon are opened thereafter at its antimesenteric tenia.
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Figure 5
The posterior wall of the pouch is completed by side-to-side anastomosis of colon with the opened ileum. Again, a single row of all-layer 4/0 polydioxanon running sutures on a straight needle are used and the bowel segments are aligned with stay sutures and Allis clamps.
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Figure 6
In a door-wing fashion, the bowel segments are opposed to each other and the anterior wall of the pouch is established by side-to- side all-layer running 4/0 polydioxanon sutures on a straight needle of ileum and colon.
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Figure 7
The lower and the upper aspects of the pouch are closed, again using a single row of all- layer 4/0 running glyconate sutures.
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Figure 8
Stapled version, normal length ureters. The caecum and ascending colon are mobilized up to the hepatic flexure. The terminal 25 cm of ileum and 15 cm of caecum and ascending colon are isolated. A Foley balloon catheter is inserted into the ileum and the excluded bowel segments are irrigated with 1–2 L of saline. Thereafter, the proximal 15 cm of ileum are separated from the terminal 10 cm of prevalvular ileum with transection of the superficial arcade of the mesentery only. The appendix is resected.
15 cm
15 cm 10 cm
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Figure 9
After the intestinal continuity is restored (see Figs 2 and 3), the proximal ileal segments are translocated towards the cecum and ascending colon with stay sutures.
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Figure 10
Both the separate ileum and the caecum and ascending colon must be opposed to each other at their antimesenteric borders and fixed in this position with stay sutures or Allis clamps, to allow the Poly GIA stapler to divide both bowel segments longitudinally along their antimesenteric borders.
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Figure 11
Both branches of a Poly GIA 75 stapler are inserted separately into each bowel lumen and thereafter closed in exactly that position, which clamps the antimesenteric borders of the bowel segments to each other. Before the stapler is released by advancing the (blue) slide with the thumb, care must be taken that no other tissue, such as mesentery, is interposed between the bowel segments. With advancing the slide of the stapler, in a one- step procedure both bowel segments are stapled side-to-side to each other in an inverting manner by placing two double staggered rows of lactomer absorbable staples and simultaneously divided along their antimesenteric borders between the two double rows of staples.
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Figure 12
As the maximum length of the active stapling device is 75 mm, only part of the anastomosis has been established by the first application of a stapler. At the end of the incision, both rows of staples from either side of the anastomosis are unified, so that the anastomosis remains closed at its end.
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Figure 13
Before the second stapler can be applied, the pouch has to be everted using Babcock clamps along the rows of staples. The blind end of the incision is cut open exactly in between the staple rows with Metzenbaum scissors over a distance of ª0.5 cm.
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Figure 14
The branches of the second stapler are inserted in the same manner into each bowel lumen exactly between the first staple rows at their cut-open blind end, closed and released in the same manner as described above.
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Figure 15
Again, with the help of Babcock clamps along the staple rows, the pouch is further step- wise everted for the third identical stapler application. The gaps between the staple rows of the first and second stapler application from cutting open the dead end are shown here. They are closed by running 4/0 glyconate sutures (see insert).
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Figure 16
The upper and lower aspects of the pouch are sutured by all-layer running 4/0 glyconate sutures. The insert shows that in the stapled version the pouch is constructed from caecum and one loop of ileum only, compared with the two ileal segments of the sutured version. A counter-clockwise 180∞ rotation around the insertion of the ileocolic artery brings the ileocaecal valve into a cranial position and the ascending colon deep into the true pelvis. A tension-free urethro- intestinal anastomosis has been possible in every case, even in very obese patients.
Rotation 180°
Coecum
Ileum
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Figure 17
At the deepest aspect of the pouch, a 20 F excision of the seromuscularis is made for urethro-intestinal anastomosis. The incised mucosa is everted and fixed by 4/0 polyglytone sutures. The anastomosis is established with the eight pre-placed double- armed 4/0 glyconate sutures. The ureter is implanted into the prevalvular ileum using a Nesbit technique for the right ureter and a Wallace technique for the left ureter. Before that, the left ureter must be pulled through the mesentery below the duodenum and above the inferior mesenteric artery into the right retroperitoneum. Ureteric stents must be inserted before ureteric implantation through the pouch wall and pulled through the ileocaecal valve. Optical magnification is used for the ureteric anastomosis. For either ureter, three 7/0 polyglycolic sutures are used for the spatulation, and the remainder of the anastomosis is completed by using 6/0 glyconate sutures. The ureteric stents are secured with 4/0 polyglytone sutures. In addition, a 10 F pigtail pouchostomy catheter is inserted through the anterior pouch wall and secured with a 4/0 polyglytone suture.
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Figure 18
The urethral anastomosis is completed over a 20 F silicon Foley catheter.
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Figure 19
Short ureters. If ureters had to be cut short because of irradiation damage or urothelial cancer involvement, the terminal prevalvular ileum can be used as an ileal ureter substitute for both ureters. The length of the terminal prevalvular ileum, which is used as ureteric substitute, must be chosen according to the length of the ureter defects.
15 cm
15 – 20 cm
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Figure 20
For ureteric substitution, prevalvular ileum can be used up to the renal pelvis. Again, the right ureter is implanted in a Nesbit technique and, for Wallace anastomosis of the left ureter, the proximal segment of the prevalvular ileum is pulled through the mesentery below the duodenum and above the inferior mesenteric artery into the left retroperitoneum.
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POSTOPERATIVE CARE In very obese patients with a fat mesentery, Alternatively, urethroscopy may be used for colonic mobilization up to the right flexure is transurethral placement of a 8 F ureteric Medication. Antibiotics (ampillicin/clavulanic the key to success, allowing a tension-free catheter over which, as a guide, coaxial acid and metronidazol) are started before anastomosis with the urethra after 180∞ placement of an open-end 20 F balloon surgery and continued until 7–10 days counter-clockwise rotation of the pouch. catheter (Integral® nephrostomy silicone afterward. For postoperative drainage of the However, care must be taken not to harm the catheter, Uromed) can be done safely. Early stomach, we prefer intraoperative insertion of right colonic vein when deep incision of the loss of the pouchostomy catheter usually has a 12 F balloon gastrostomy catheter as colonic mesentery is necessary. If this no sequelae and no attempts should be made compared to a nasogastric tube. Patients are happens and the right colonic flexure turns to reinsert or replace it. mobilized as early as 1–2 days. Gravity drains dark blue, resection is advised and an ileo- in the small pelvis and at the ureteric transversostomy must be performed rather implantation site are removed as soon as the than the ileo-ascendostomy. REFERENCES amount of drainage is <50 mL/24 h. Ureteric stents are removed at 10 and 11 days after If previously undetected polyps are found 1 Thüroff JW, Alken P, Engelmann U, surgery. When a pouchogram at 12 days when opening the caecum/ascending colon, Riedmiller H, Jacobi GH, Hohenfellner shows no extravasation the transurethral usually they are benign and should be excised R. The Mainz-Pouch (mixed augmentation catheter is removed and voiding initiated. At and submitted to frozen section analysis. This ileum and cecum) for bladder the time of pouchogram and catheter is not an indication to abandon the planned augmentation and continent urinary removal, in ª85% of patients, the ileocaecal procedure. diversion. Eur Urol 1985; 11: 152–60 valve is able to prevent poucho-ureteric 2 Thüroff JW, Alken P, Riedmiller H, reflux. When the pouch capacity increases If there is leakage from the pouch and Engelmann U, Jacobi GH, Hohenfellner with time and pressures become lower, the associated symptoms after catheter removal, R. The Mainz-pouch (mixed ileocaecal valve gains in competence and this might be from the opening of the augmentation ileum and cecum) for prevents reflux in >90% of patients. However, pouchostomy tube. Usually the problem is bladder augmentation and continent the pouchostomy catheter remains in place solved by reinserting a transurethral Foley urinary diversion. J Urol 1986; 136: and is used to check for residual urine. When catheter for ª10 days. The problem may be 17–26 the postvoid residual is <50 mL the prevented by reinserting the transurethral 3 Thüroff JW, Alken P, Riedmiller H, pouchostomy catheter is removed. Pelvic floor Foley catheter before planned removal of the Jacobi GH, Hohenfellner R. The MAINZ- exercises are started as soon as the pouchostomy tube. Leakage from the site of Pouch for augmentation or substitution transurethral catheter is removed, and the ureteric anastomosis usually requires of the bladder and continent diversion. continued until complete continence is percutaneous nephrostomy drainage. If Semin Urol 1987; 5: 69–79 achieved. antegrade stenting is not possible this will 4 Thüroff JW, Alken P, Riedmiller H, most likely result in stricture at the Jacobi GH, Hohenfellner R. 100 cases of implantation site, requiring later surgical MAINZ-Pouch: Continuing experience revision. Early loss of ureteric stents usually and evolution. J Urol 1988; 140: 283–8 SURGEON TO SURGEON has no sequelae. When this occurs, the upper 5 Leißner J, Stein R, Hohenfellner R et al. tract should be checked by ultrasonography Radical cystoprostatectomy combined In determining the appropriate indication for and attempts to reinsert a stent and/or with Mainz pouch bladder substitution to orthotopic substitution, the most difficult nephrostomy catheter should be used only if the urethra: long-term results. BJU Int part is to predict whether and how fast there is a clinical need. 1999; 83: 964–70 urinary continence will be achieved in the 6 El-Mekresh M, Franzaring L, Wöhr M, elderly. Patients with cerebrovascular sclerosis However, early loss of the transurethral Melchior SW, Hohenfellner M, Thüroff are better with a continent cutaneous catheter mostly results in extravasation and JW. Simplified orthotopic ileocecal pouch diversion or even an incontinent conduit anastomotic stricture. Thus reinserting a (Mainz pouch) for bladder substitution. diversion. Furthermore, females who are very transurethral catheter is advisable. In the Akt Urol 2003; 34: 226–30 obese or have difficulties in using CISC are male, this can be difficult. Transrectal better using intermittent catheterization of guidance of the catheter tip and radiographic e-mail: [email protected] an abdominal stoma. control of the catheter position are advised. mainz.de [email protected]
© 2005 BJU INTERNATIONAL 465 Erratum ADDENDUM ADDENDUM
In [1], a number of values were incorrectly REFERENCE submitted in Figure 1 on page 1304. The values in the main body of the text were 1 Carson CC, Hatzichristou DG, Carrier S correct. et al. Erectile response with vardenafil in sildenafil nonresponders: a multicentre, The correct version of Figure 1 is displayed double-blind, 12-week, flexible-dose, below. placebo-controlled erectile dysfunction clinical trial. BJU Int 2004; 94: 1301–9
Patients screened n = 584
Patients randomized n = 463
Vardenafil Placebo n = 233 n = 230
Safety analysis 231 Safety analysis 226 Intent-to-treat analysis 229 Intent-to-treat analysis 225 Per-protocol analysis 192 Per-protocol analysis 185
Completed study Withdrawn Completed study Withdrawn n = 207 n = 26 n = 188 n = 42
Insufficient therapeutic effect 5 Insufficient therapeutic effect 17 Consent withdrawn 8 Consent withdrawn 10 Noncompliance 3 Noncompliance 7 Adverse event 5 Adverse event 3 Lost to follow-up 3 Lost to follow-up 3 Protocol violation 2 Protocol violation 2
466 © 2005 BJU INTERNATIONAL | 96, 466 | doi:10.1111/j.1464-410X.2005.05756.x Abbreviations
Authors may use the abbreviations in this list, without definition when within the main text, but defined when in the Summary. Other abbreviations must be defined on first mention, both in the Summary and in the main text. Abbreviations of units should be those defined by SI.
AIDS acquired immune deficiency syndrome IVU intravenous urography ANOVA analysis of variance LHRH luteinizing hormone-releasing hormone AUA American Urological Association LUTS lower urinary tract symptoms BAUS British Association of Urological Surgeons MAG mercapto-acetylglycine BCG bacille Calmette-Guérin MAG3 mercapto-acetyltriglycine BPH benign prostatic hyperplasia MHC major histocompatibility complex BSA bovine serum albumin MRI magnetic resonance imaging BOO bladder outlet obstruction NHS National Health Service CI confidence interval NSAIDs nonsteroidal anti-inflammatory drugs CNS central nervous system PAGE polyacrylamide gel electrophoresis CT computed tomography PBS phosphate buffered saline DMSA dimercapto-succinic acid PCR polymerase chain reaction DRE digital rectal examination PSA prostate-specific antigen DTPA diethylene-triamine-penta-acetic acid PTFE polytetrafluoroethylene EDTA ethylenediamine tetra-acetic acid PUJ pelvi-ureteric junction ELISA enzyme-linked immunosorbent assay PUV posterior urethral valves ESWL extracorporeal shock wave lithotripsy RCC renal cell carcinoma FSH follicle-stimulating hormone SD standard deviation GFR glomerular filtration rate SDS sodium dodecyl sulphate GnRH gonadotrophin-releasing hormone TCC transitional cell carcinoma GP general practitioner TGF transforming growth factor hCG human chorionic gonadotrophin TNF tumour necrosis factor HIV human immunodeficiency virus TNM Tumour-Node-Metastasis HPLC high-pressure liquid chromatography TRUS transrectal ultrasonography ICS International Continence Society TURP transurethral resection of the prostate IGF insulin-like growth factor UTI Urinary tract infection
IgXz immunoglobulin (class X, subclass z) VUR vesico-ureteric reflux IPSS International Prostate Symptom Score WHO World Health Organization
© 2005 BJU INTERNATIONAL | 96, 467 467 august 26| september 1 september 15|17 september 21|24 35th Annual Meeting of the PSA: Past, Present and Future Milan, 57° Kongress der Deutschen Gesellschaft International Continence Society, Italy. für Urologie Düsseldorf, Germany. Montreal, Canada. Contact: Emilia Viaggi Contact: Kongress-Sekretariat, Monika T +1 847 605 0850 Langer, Gabriele Schwarzmann, Kongress- Sekretariat DGU 2005, Urologische Klinik, E [email protected] T +39 051 235 993 Städt.Klinikum Karlsruhe gGmbH, Moltkestr. W http://www.icsoffice.org F +39 051 291 4455 90, D-76133 Karlsruhe, Germany E [email protected] W http://www.emiliaviaggi.it/site/ T +49 0721 974-4102 evcm_congresso/pg-20/num-34 F +49 0721 974-4149 E [email protected] W http://www.urologenportal.de/580.html
september 29|october 1 september 30 | october 1 october 5|8 SIU Meeting on Prostatic Disease: 4th Biennial World Congress on Men’s 10th Biennial Meeting of the Asia Recent Advances and New Health & Gender (WCMH), Vienna, Austria. Pacific Society for Sexual & Technologies. Llao Llao Resort, Organization: WCMH Health & Impotence Research(APSSIR) Cairns, Bariloche, Patagonia, Argentina. Congressmanagement, Lazarettgasse 9/5, Australia. 1090 Vienna, Austria Contact: Promaco Conventions Pty Ltd., Contact: SIU Congress Office, 1155 E [email protected] P.O. Box 890, Canning Bridge, Western University Street, Suite 1155, Montreal, W http://www.wcmh.info Australia 6153 Quebec, Canada H3B 3A7 Congress Office: PROCON Conference, Incentive & Event Management, T + 61 8 93 32 29 00 T +1 514 875 5665 Odoakergasse 34-36/3, 1160 Vienna, Austria F + 61 8 93 32 29 11 F +1 514 875 0205 E [email protected] E [email protected] E [email protected] F +43 1 486 40 40 46 W http://www.promaco.com.au/ W www.siu-urology.org/bariloche W http://www.proconference.at conference/2005/apssir/
october 27|30 october 31|november 4 november 9|11 5th Meeting of the International Urology Specialist Registrars’ Spinal 4th Annual Meeting of the Society for the Study of Women’s Injuries Course. Twice Annually. Mediterranean Association of Sexual Health (ISSWSH), Las Vegas, Sheffield/Wakefield, UK. Andrology (AMA) Alexandria, Egypt. Nevada, USA. Contact: Carole Gregory (secretary to Mr Contact: Dr Ashraf Samir, P.O. Box 125, Contact: ISSWSH, 1111 N. Plaza Drive, P R Tophill, Consultant Urological Ibrahimia, Alexandria, Egypt Suite 550, Schaumburg, IL 60173, USA Surgeon), Princess Royal Spinal Injuries Unit, Northern General Hospital, Herries T +20 3 35 95 043 T +1847 517 7225 Road, Sheffield, S5 7AU, UK F +20 3 35 95 044 F +1847 517 7229 E [email protected] E [email protected] T 0114 271 5645 W http://www.isswsh.org F 0114 271 5649 E [email protected]
468 2005/2006 november 17|18 november 17|19 december 1|4 Comprehensive Urological Laparoscopy: An First World Congress on Hypospadias Fall 2005 Joint SBUR-ESUR Meeting Intermediate Level Training Course and Intersex Disorders, Istanbul, Miami Beach, FL, USA. incorporating ‘Different Techniques of organised by the ISHID International Nephrectomy’. Course Director: Mr A. Society on Hypospadias and Intersex T 847 517 7225 Rané. Venue: Aesculapium, Tuttlingen, Disorders. F 847 517 7229 Germany. E [email protected] Convenor: Seref Etker, MD Organizer and further information: W http://sbur.org/meetings/ Aesculap Akademie GmbH, Am Aesculap Platz, program2005december.asp 78532 Tuttlingen, Germany W http://www.ishid.org W http://www.hypospadias-intersex.org T + 49 7461 95 2001 E [email protected] W www.aesculap-academy.com
december 1|5 december 4|7 january 25|27 VIII Congress of the Latinamerican 8th Congress of the European Society 14th Copenhagen Symposium on Society for Sexual and Impotence for Sexual Medicine (ESSM), Endoscopic Urological Surgery in Research, Punta del Este, Uruguay, Dr Copenhagen, Denmark. Copenhagen Denmark. Miguel Alfredo Rivero VIII Congress President, Dr Luiz Otavio Torres SLAIS Contact: CPO Hanser Service, Zum T +45 4488 3644 President. Ehrenhain 34, 22885 Barsbüttel, E [email protected] Germany W www.seus2006.dk T 54 11 4325 1273/4325 1290 F 54 11 4326-8517 T +49 40 67 08 820 E [email protected] F +49 40 67 03 283 W www.slais2005.org E [email protected] W http://www.essm.org/index.cfm
february 9|12 june 21|24 november 12|16 The 5th World Congress on The Aging IASR – International Academy of Sex 28th Congress of the Société Male, Salzburg, Austria. Research 2006, Amsterdam, The Internationale d’Urologie, Cape Town Netherlands. International Convention Centre, Cape Contact: 17 Rue du Cendrier, P.O. Box Town, South Africa. 1726, Ch-1211, Geneva 1 Switzerland Contact: PCO: Status Plus BV Contact: SIU Congress Office, 1155 T +41 22 908 0488 T +31 343 443888 University, Suite 1155, Montreal, F +41 22 732 2850 F +31 343 442043 Quebec, H3B 3A7, Canada E [email protected] W http://www.statusplus.nl T +1 514 875-5665 F +1 514 875-0205 E [email protected] W www.siu2006.com
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