British Journal of Urology International( April 2005 )

British Journal of Urology International April 2005 - Vol. 95 Issue 6 Page i-927

i Editor's comment Online publication date: 24-Mar-2005 Comments 723 Robotic urology in the UK: establishing a programme and emerg

Prokar Dasgupta, Ashok Hemal, Kirsten Rose, the Guy's and St.

Online publication date: 24-Mar-2005 724 Laparoscopic reconstructive urology

Sravanti P. Tegavarupu, Prokar Dasgupta

Online publication date: 24-Mar-2005 726 Drug-eluting biomaterials in urology: the time is ripe

Bodo E. Knudsen, Ben H. Chew, John D. Denstedt

Online publication date: 24-Mar-2005 727 The European working-time directive: one step forward, two ste

Majid Shabbir, Peter Amoroso, Roger S. Kirby

Online publication date: 24-Mar-2005 Mini-reviews 729 Peyronie's disease: the epidemiology, aetiology and clinical eval

Christopher J. Smith, Chelsea McMahon, Ridwan Shabsigh

Online publication date: 24-Mar-2005 733 Recent advances in understanding the biology of diabetes-associ and novel therapy

Naoki Yoshimura, Michael B. Chancellor, Karl-Erik Andersson

Online publication date: 24-Mar-2005

739 Molecular prognostic factors in bladder cancer

Maurizio Buscarini, Marcus L. Quek, Parkash Gill, Guangbin Xia, David I. Quinn, John P. Stein

Online publication date: 24-Mar-2005 743 An evidence-based approach to understanding the pharmacological class effect in the management of prostatic diseases

Christopher P. Evans, Neil Fleshner, John M. Fitzpatrick, Alexander R. Zlotta

Online publication date: 24-Mar-2005 Urological Oncology 751 Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome

John F. Ward, Jeffrey M. Slezak, Michael L. Blute, Erik J. Bergstralh, Horst Zincke

Online publication date: 24-Mar-2005 757 The influence of bladder neck mucosal eversion and early urinary extravasation on patient outcome after radical retropubic prostatectomy: a prospective controlled trial

Miguel Srougi, Mario Paranhos, Kátia M. Leite, Marcos Dall'oglio, Luciano Nesrallah

Online publication date: 24-Mar-2005 761 Prostate-specific antigen (PSA) complexed to 1-antichymotrypsin improves prostate cancer detection using total PSA in Japanese patients with total PSA levels of 2.0 4.0 ng/mL

Takashi Kobayashi, Toshiyuki Kamoto, Koji Nishizawa, Kenji Mitsumori, Keiji Ogura, Yoshihiro Ide

Online publication date: 24-Mar-2005 766 A novel technique for approaching the endopelvic fascia in retropubic radical prostatectomy, based on an anatomical study of fixed and fresh cadavers

Atsushi Takenaka, Ryoei Hara, Hideo Soga, Gen Murakami, Masato Fujisawa

Online publication date: 24-Mar-2005 772 The incidence and treatment of lymphoceles after radical retropubic prostatectomy

Ruth J. Pepper, Jhumur Pati, Amir V. Kaisary

Online publication date: 24-Mar-2005

776 Testosterone recovery and changes in bone mineral density after stopping long-term luteinizing hormone-releasing hormone analogue therapy in osteoporotic patients with prostat cancer

Robin Weston, Asad Hussain, Emmanuel George, Nigel J. Parr

Online publication date: 24-Mar-2005 780 Sexual, psychological and dyadic qualities of the prostate cancer 'couple'

Cynthia T. Soloway, Mark S. Soloway, Sandy S. Kim, Bruce R. Kava

Online publication date: 24-Mar-2005 786 Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma

Vincenzo Ficarra, Orietta Dalpiaz, Najati Alrabi, Giacomo Novara, Antonio Galfano, Walter Artibani

Online publication date: 24-Mar-2005 791 A comparison of the pathology of transitional cell carcinoma of the bladder and upper urinary tract

Grant D. Stewart, Simon V. Bariol, Ken M. Grigor, David A. Tolley, S. Alan McNeill

Online publication date: 24-Mar-2005 794 The assessment of patient life-expectancy: how accurate are urologists and oncologists?

James R.M. Wilson, Michael G. Clarke, Paul Ewings, John D. Graham, Ruaraidh MacDonagh

Online publication date: 24-Mar-2005 Lower Urinary Tract 799 Towards a better understanding of involuntary detrusor activity

Helen D. Bradshaw, Stephen C. Radley, Derek J. Rosario, Christopher R. Chapple

Online publication date: 24-Mar-2005 804 The pharmacokinetics of 400 µg of oral desmopressin in elderly patients with nocturia, and the correlation between the absorption of desmopressin and clinical effect

Gitte M. Hvistendahl, Anders Riis, Jens P. Nørgaard, Jens C. Djurhuus

Online publication date: 24-Mar-2005

810 Self-assessed health, sadness and happiness in relation to the total burden of symptoms from the lower urinary tract

Gabriella Engström, Lars Henningsohn, Gunnar Steineck, Jerzy Leppert

Online publication date: 24-Mar-2005 816 Nocturia in relation to somatic health, mental health and pain in adult men and women

Ragnar Asplund, Sven-Uno Marnetoft, John Selander, Bengt Åkerström

Online publication date: 24-Mar-2005 820 Nocturia, depression and antidepressant medication

Ragnar Asplund, Susanne Johansson, Svante Henriksson, Göran Isacsson

Online publication date: 24-Mar-2005 824 Combined external urethral bulking and artificial urinary sphincter for urethral atrophy and stress urinary incontinence

Nadeem U. Rahman, Thomas X. Minor, Donna Deng, Tom F. Lue

Online publication date: 24-Mar-2005 827 Day-case sling surgery for stress urinary incontinence: feasibility and safety

Subhasis K. Giri, John Drumm, Jean A. Saunders, Jane McDonald, Hugh D. Flood

Online publication date: 24-Mar-2005 833 A stereological analysis of fibrosis and inflammatory reaction induced by four different synthetic slings

Marcelo Thiel, Paulo C. Rodrigues Palma, Cássio L.Z. Riccetto, Miriam Dambros, Nelson R. Netto Jr

Online publication date: 24-Mar-2005 838 Sacral magnetic stimulation in non-inflammatory chronic pelvic pain syndrome

Thomas Leippold, Raeto T. Strebel, Mirjam Huwyler, Hubert A. John, D. Hauri, Daniel M. Schmid

Online publication date: 24-Mar-2005

Sexual Medicine 843 Use of combined intracorporal injection and a phosphodiesterase-5 inhibitor therapy for men with a suboptimal response to sildenafil and/or vardenafil monotherapy after radical retropubic prostatectomy

Jack H. Mydlo, Rosalia Viterbo, Paul Crispen

Online publication date: 24-Mar-2005 847 The effect on erectile function of 103palladium implantation for localized prostate cancer

Anton Ponholzer, Renée Oismüller, Canatay Somay, Felix Büchler, Ulrich Maier, Robert Hawliczek, Michael Rauchenwald, Stephan Madersbacher

Online publication date: 24-Mar-2005 Upper Urinary Tract 851 Comparison of laparoscopic and open donor nephrectomy: a randomized controlled trial

Nasser Simforoosh, Abbas Basiri, Ali Tabibi, Nasser Shakhssalim, Seyed M.M. Hosseini Moghaddam

Online publication date: 24-Mar-2005 Reconstructive Urology 857 Determination of the time required for appropriate chemical de- epithelialization of an ileal segment for cystoplasty: an animal model

Jalal Bakhtiari, Hamid Reza Fattahian, Mohammad Javad Gharagozlou, Abdolmohammad Kajbafzadeh, Seyed Reza Jafarzadeh

Online publication date: 24-Mar-2005 Paediatric Urology 863 The laparoscopic management of intersex patients: the preferred approach

Francisco T. Dénes, Marcelo A.S. Cocuzza, Edison D. Schneider- Monteiro, Frederico A.Q. Silva, Elaine M.F. Costa, Berenice B. Mendonca, Sami Arap

Online publication date: 24-Mar-2005

868 Predictive factors of ultrasonographic involution of prenatally detected multicystic dysplastic kidney

Eli Armando S. Rabelo, Eduardo A. Oliveira, Guilherme Souza Silva, Isabela Leite Pezzuti, Edson Samesina Tatsuo

Online publication date: 24-Mar-2005 Investigative Urology 874 The promise of gene-expression analysis in bladder cancer: a clinician's guide

Steven C. Smith, Gary Oxford, Dan Theodorescu

Online publication date: 24-Mar-2005 881 Synergistic inhibitory effect of high-intensity focused ultrasound combined with chemotherapy on Dunning adenocarcinoma

Philippe Paparel, Laura Curiel, Sabrina Chesnais, Rene Ecochard, Jean- Yves Chapelon, Albert Gelet

Online publication date: 24-Mar-2005 886 Stereotactic electrical stimulation of the pontine micturition centre in the pig

Asger L. Dalmose, Carsten R. Bjarkam, Jens Christian Djurhuus

Online publication date: 24-Mar-2005 890 Gene transfer of vasoactive intestinal polypeptide into the penis improves erectile response in the diabetic rat

Zhou-Jun Shen, Hua Wang, Ying-Li Lu, Xie-Lai Zhou, Shan-Wen Chen, Zhao-Dian Chen

Online publication date: 24-Mar-2005 895 Assessment of microheterogeneity of blood flow in the rat urinary bladder by high-resolution digital radiography

Takahiro Kimura, Tokunori Yamamoto, Atsushi Sone, Atsushi Takenaka, Masato Fujisawa

Online publication date: 24-Mar-2005

Pharmaceutical review 899 Back to the future for urological drug development?

Michael G. Wyllie

Online publication date: 24-Mar-2005 Points of Technique 901 Modified tubularized transverse preputial island flap repair for severe proximal hypospadias

Rakesh P. Patel, Aseem R. Shukla, J. Christopher Austin, Douglas A. Canning

Online publication date: 24-Mar-2005 905 Tubeless and stentless percutaneous nephrolithotomy

Vikas Gupta, Trilok C. Sadasukhi, Krishan K. Sharma, Ram G. Yadav, Rajeev Mathur

Online publication date: 24-Mar-2005 Letters 907 The molecular staging of prostate cancer

George Yardy, Stephen McGregor, Walter Bodmer

Online publication date: 24-Mar-2005 907 Prostate size influences the outcome after presenting with acute urinary retention

Alan McNeill

Online publication date: 24-Mar-2005 908 Robotically assisted surgery

Christopher G. Eden

Online publication date: 24-Mar-2005 09 Prostate cancers in the transition zone: Part 2; clinical aspects

Joe Philip, Ramaswamy Manikandan

Online publication date: 24-Mar-2005

909 Comparative study of dartos fascia and tunica vaginalis pedicle wrap for the tubularized incised plate in primary hypospadias repair

Vemuri V.S.S. Chandrasekharam

Online publication date: 24-Mar-2005

909 Sacral ratio and fecal continence in children with anorectal malformation

Suzi Demirbag, Emre Senel, Salih Cetinkursun

Online publication date: 24-Mar-2005 Surgery Illustrated 911 Radical retropubic prostatectomy: apical preparation and curtain dissection of the neurovascular bundle

Wolfgang Horninger, Hannes Strasser, Georg Bartsch

Online publication date: 24-Mar-2005 924 Erratum Online publication date: 24-Mar-2005 925 Abbreviations Online publication date: 24-Mar-2005 926 Diary Online publication date: 24-Mar-2005

Editor’s comment

The Fourth International Symposium on Genitourinary Cancers was an excellent meeting, with presentations from many leading medical and radiation oncologists, as well as from a handful of urologists

Although there are many areas in the time for friendly discussion and informal treatment of urological cancer in which the interaction between the groups which might interests of urologists and medical or not have been possible at larger meetings. The radiation oncologists meet, it is selectively Fifth Multidisciplinary Symposium on uncommon that urologists attend oncology Genitourinary Cancers is scheduled to be held meetings, or indeed that oncologists attend in Los Angeles in January 2006, and should be urological meetings. I believe that we need to attended by urologists interested in urological have a greater understanding of each other’s cancer. approach to patient care, and this can only come from greater dialogue between the From the point of view of the BJU groups, which will inevitably lead to International, I am pleased to say that many improvements for patients. The papers from the above meeting will appear in multidisciplinary team approach now adopted print in the forthcoming months, showing our by most urology departments has been a dedication to serving the diversity of the great advance in this regard, but this must urological community. surely lead logically to more widespread attendance at each other’s academic I have decided to stop publishing Points of meetings and conferences. Technique in the BJU International; this is something that myself and the Editorial Team To ‘test the water’, I attended the Fourth have been considering for some time, and I International Symposium on Genitourinary feel that it is now the right time to change our Cancers, held in Los Angeles, and organised by policy on publishing these types of papers. Nick Vogelzang, Cora Sternberg, Arie There are several Points of Technique already Belldegrun and Richard Cote. This was an accepted and awaiting publication, so they excellent meeting, with presentations from will continue to appear in print for the next many leading medical and radiation few months before they disappear. However oncologists, as well as from a handful of from this month I would ask that they be no urologists. The opportunity to hear the latest longer submitted for consideration. pharmaceutical management of advanced urological cancer was most welcome, and I feel that the input from the urologists present was also well received. There are many very large oncology meetings, such as ASCO and AACR, which many of us attend, but this JOHN M. FITZPATRICK smaller-scale meeting allowed considerable Editor - in - Chief

Minirev Article ROBOTIC UROLOGY IN THE UK DASGUPTA et al.

KEYWORDS ROBOTIC UROLOGY IN THE UK: ESTABLISHING A PROGRAMME AND EMERGING ROLE PROKAR DASGUPTA, ASHOK HEMAL* and robotic surgery, urology, Da Vinci system KIRSTEN ROSE on behalf of the Guy’s and St. Thomas’ Robotics Group – Department of Urology, Guy’s and St. Thomas’ Hospitals and GKT School of Medicine, London, INTRODUCTION UK and the *Vatikutti Urology Institute, Henry Ford Health System, Detroit, USA

Urological surgery has embraced the use of Accepted for publication 29 October 2004 robotics since the late 1980s, when Guy’s Hospital and Imperial College London collaborated on clinical trials of a robotic the Charitable Foundation of Guy’s and St. TRAINING TURP frame [1]. Following this pioneering Thomas’. This grant was not intended only to experience by Wickham and colleagues, purchase the robot and maintain it, but also The robotics group, including surgeons and further developments in robotic urology for its scientific evaluation. Before this, nurses, were initially trained on a Da Vinci moved to the USA and mainland Europe. This funding for an AESOP voice-controlled ‘dry-lab’ and subsequently a ‘cadaveric lab’ in is possibly not only a result of surgical robotic arm and transatlantic telerobotic trials Paris. They then travelled to the Vatikutti scepticism and lack of vision, but also the using the RCM-PAKY robot came from the Institute in Detroit to observe robotic urology prohibitive initial expense of establishing a Guy’s Hospital Trust, the Guy’s and Johns in a high-throughput unit. An experienced robotic programme. In an institution such as Hopkins urology research funds, and the robotic urologist (A.K.H.) from the same the UK National Health Service, free at the Friends of Guy’s. institute mentored the initial UK operations. point of delivery, funding for a technological innovation such as robotic surgery has a CLINICAL EXPERIENCE: THE FIRST lower priority than, e.g. stroke rehabilitation BASIC SCIENCE FOUR CASES or diabetes, and rightly so. New technology does not necessarily produce durable results Investing >£1 million in clinical robotics Permission to commence clinical robotics 5–10 years later. Each development must be needed prior evidence of the effectiveness of with the Da Vinci system was obtained by supported by evidence showing it to be more robotics in a laboratory. To our knowledge the formal applications to the local clinical effective than traditional open surgery. only randomized, controlled trial of robotics governance committee, which reports to Robotic radical prostatectomy has previously in urology was the recent transatlantic study the National Institute of Clinical Excellence. been performed in the UK but results in a trial between Guy’s and Johns Hopkins. Statistical Patients were counselled about the operations with many patients are lacking. As evidence of analysis with adequate power required by surgeons and a robotics nurse, particularly its efficacy and that of other robotic a total of 304 telerobotic percutaneous that they were new procedures at our centre. procedures emerges from the Vatikutti nephrolithotomies, which could not be They were given information leaflets and Institute [2,3] there is increasing interest in ethically supported in humans and was legally shown a generic video of the Da Vinci robot in robotic urology amongst British urologists, unacceptable in animals in the UK. A specially action. many of whom enthusiastically participated designed and validated kidney model was in the first UK robotic urology symposium at used (Limbs and Things, Bristol, UK) and either The mean (range) docking time (the time Guy’s in 2004. Establishing a structured a robotic arm (152 procedures) or a urologist taken to attach the robot to the patient) was robotic urology programme involved five key (152 procedures) inserted a percutaneous 7 (5–9) min. Robotic radical prostatectomy steps: funding, basic science, training, clinical needle. Thirty remote procedures were (bilateral nerve-sparing) and robotic experience and evaluation. performed from Baltimore via four ISDN lines. cystectomy (unilateral nerve-sparing on the The trial showed the robot to be slower but side contralateral to the tumour in men) were more accurate than humans. All urologists performed using a six-port transperitoneal FUNDING made fewer needle passes while using the technique. Ileal conduit diversion after robotic arm. A crossover trial subsequently cystectomy/anterior exenteration for bladder Funding for the Da VinciTM robotic system showed that the robot can be controlled cancer was performed through a 4–5 cm (Innovative Surgical, Sunnyvale, CA) was equally well from the UK to the USA as it is in incision for delivering the bladder and lymph obtained as a competitive project grant from the opposite direction [4]. nodes in laparoscopic sacks. Robotic

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colposuspension was performed by a four- TABLE 1 The initial UK experience with the Da Vinci robotic system port extraperitoneal technique. None of the patients needed a blood transfusion, which is Procedure Sex Time, min Blood loss, mL Early outcome particularly encouraging after cystectomy. Radical prostatectomy M 185 300 Gleason 3 3; margins ve The details are shown in Table 1. + - Radical cystectomy M 340 150 G3T4a TCC margins -ve Anterior exenteration F 295 100 Extensive CIS; margins -ve Colposuspension F 140 20 Continent EVALUATION

To establish its place in urology robotics requires a rigorous scientific evaluation. A Guy’s and St. Thomas’ Robotics Group is: P Nerve-sparing robot assisted radical ‘Evaluation Steering Group’, including Dasgupta, AK Hemal, K Rose, C Wolfe, D cystoprostatectomy and urinary clinicians and scientists with expertise in the Armstrong, A MacGuire, D Probert, I Mushtaq, diversion. BJU Int 2003; 92: 232–6 area, has been set up to oversee this process. D Wilcox, C Blauth, D Cahill, MS Khan, T 4 Challacombe BJ, Kavoussi LR, Dasgupta The effects of robotic surgery on operative O’Brien, R Popert, H Patel, P Rimington, M P. Trans-oceanic telerobotic surgery. BJU times, pain control, oncological outcome and Nightingale, R Nicholson, BJ Challacombe. Int 2003; 92: 678–80 full recovery are being assessed prospectively 5 Dasgupta P, Rodriguez G. A new method in a pilot study. Robotics will then be to evaluate human-robot performance compared to traditional open surgery and REFERENCES and its application to urological robotics. pure laparoscopy, ideally in a randomized J Endourol 2004; (Suppl. WCE): MP2– controlled trial. Validated patient-satisfaction 1 Davies BL, Hibberd RD, Ng WS, Timoney 12 surveys, quality-of-life questionnaires and AG, Wickham JE. The development of a 6 Dasgupta P, Challacombe B. Robotics in disability scales are being used to obtain surgeon robot for prostatectomies. Proc urology. BJU Int 2004; 93: 247–8 objective data. The effect of robotics on Inst Mech Eng [H] 1991; 205: 35–8 7 Nedas TG, Challacombe B, Dasgupta P. hospital stay, waiting times and overall 2 Tewari A, Srivasatava A, Menon M and Virtual reality in urology. BJU Int 2004; quality of service is being assessed. A health- members of the VIP Team. A prospective 94: 255–7 economic evaluation will specifically assess comparison of radical retropubic and resource inputs and cost-benefit analysis. The robot-assisted prostatectomy: experience Correspondence: Prokar Dasgupta, ergonomics of robotic urology will be in one institution. BJU Int 2003; 92: 205– Department of Urology, 1st Floor Thomas Guy compared to laparoscopic and open surgical 10 House, Guy’s Hospital, London SE1 9RT, UK. techniques. Analytical evaluation of robotic 3 Menon M, Hemal AK, Tewari A et al. e-mail: [email protected] movements and stereoscopic vision is in progress. This was first developed for space April 2005 956 robotics and uses performance-to-resource Original Article ratios [5]. LAPAROSCOPIC RECONSTRUCTIVE UROLOGY SRAVANTI AND DASGUPTA LAPAROSCOPIC RECONSTRUCTIVE UROLOGY THE FUTURE SRAVANTI P. TEGAVARUPU and PROKAR DASGUPTA – Department of Urology, Guy’s and St. Thomas’ Hospitals and GKT School of Medicine, London, UK There has been much progress since the initial enthusiasm for urological robotics [6]. A Accepted for publication 26 October 2004 structured project in urological robotics has been established in the UK. Urological robotics has a bright future, and deserves KEYWORDS Gill et al. [1] broadly divided laparoscopic rigorous scientific evaluation. It may be reconstructive urology into ‘established’ and possible for master-slave systems to be reconstruction, laparoscopy, robotics ‘developing’; established procedures include adapted to work with a virtual-reality training pyeloplasty, bladder neck suspension, radical system. It will be possible for most surgeons prostatectomy and orchidopexy (Fig. 1). to learn from previous errors by repeating INTRODUCTION key parts of the operation in a virtual The first decade of laparoscopic pyeloplasty environment [7]. Image guidance can help in Over the last few years, the applications of has shown it to be as effective as open this, as well as during the surgical procedure laparoscopic surgery have been widely pyeloplasty, although it demands accurate in real time. extended from diagnostic to most therapeutic intracorporeal suturing skills. Operative times ablative procedures, and of late to have reduced from ª330 min in earlier series reconstructive surgery. There is emerging to ª200 min in contemporary reports. ACKNOWLEDGEMENTS evidence to show that laparoscopic Success rates of >90% have consistently been reconstructive procedures are at least as reported for both primary and secondary PUJ The Guy’s and St. Thomas’ Charitable effective as traditional open surgery but with obstruction [2]. Precise plastic repair of the Foundation, Intuitive Surgical, Mantis. The lower morbidity. PUJ appears to be the key factor for success,

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FIG. 1. The current status of the various procedures in laparoscopic reconstructive urology.

Laparoscopic reconstructive procedures

upper tract miscellaneous lower tract

established developing established developing established developing

pyeloplasty partial adrenalectomy orchidopexy sacrocolpopexy bladder neck suspension cystectomy ureterolithotomy partial nephrectomy radical prostatectomy bladder augmentation nephropexy vesico-vaginal fistula pyelolithotomy urethral sling

calyceal diverticulectomy ureteroureterostomy ureteric reimplantation

and crossing vessels, if found, can either be with 67% of the open group. In their single- the results will become equivalent. Other translocated or transposed cephalad to the centre experience the hospital stay was laparoscopic reconstructive procedures PUJ [2]. Gettman et al. [3] compared 1.2 days for robotic, 1.3 days for LRP and include bladder augmentation, nephropexy, laparoscopic with robot-assisted pyeloplasty, 3.5 days for ORP; the respective catheter vesicovaginal fistula repair, sacrocolpopexy, showing a reduction in the operating time in duration was 7, 8 and 15 days, although with renal artery aneurysm repair and urethral the robot-assisted group. However, robotics is a continuous suturing technique of sling insertion (Fig. 1). relatively new, with few data available on the urethrovesical anastomosis the catheter long-term experience. duration after robotic RP has reduced to Laparoscopic pyelolithotomy, sometimes 4 days [6], which is similar to LRP in other combined with pyeloplasty [2] and The results of laparoscopic colposuspension centres [5]. Experienced open surgeons have ureterolithotomy, have been successful in are more controversial and its effectiveness also tried to reduce the catheter duration to patients after failed ESWL or ureteroscopic was evaluated in a recent systematic review 7 days in ª75% of their patients, although manipulation. Two cases of laparoscopic of five trials comparing laparoscopic to open this is still longer than that reported after LRP ureterocalycostomy have been reported with colposuspension. Subjective cure rates at up and robotic RP. In Detroit, positive margins successful outcomes after failed pyeloplasty to 18 months of follow-up were comparable were more frequent after ORP, at 23% for [7]. Laparoscopic ileal ureter and ureteric (85–100%), while blood loss and hospital stay open and 9% for robotic surgery. In reimplantation are still developing. were shorter in the laparoscopic group [4]. comparison, expert open and laparoscopic [5] Long-term follow-up and randomized trials to surgeons have reported positive surgical Laparoscopic cystectomy and urinary assess the durability of laparoscopic margins of 12.8% and 13.7%, respectively. diversion is becoming popular because of colposuspension are necessary. the significantly lower blood loss and The laparoscopic approach to cryptorchidism hospital stay. It is an advanced procedure Guillonneau et al. [5] popularized laparoscopic traditionally consisted of the diagnostic and early outcomes indicate oncological radical prostatectomy (LRP) and reported evaluation of the impalpable testis. equivalence to open cystectomy [8]. equivalent outcomes to open surgery (ORP), Laparoscopic and needle-scopic one- and Laparoscopic ileal conduit and orthotopic with excellent operating times and minimal two-stage orchidopexy have shown complete neobladder construction are developing but blood loss. LRP can be performed both trans- success rates with almost no complications are time-consuming; thus most surgeons and extraperitoneally, and the urethrovesical [1]. currently create a laparoscopically assisted anastomosis is completed either by ileal conduit through small muscle-splitting interrupted or running intracorporeal sutures. Experienced surgeons are performing or midline incisions. In an animal study, RP is increasingly being performed laparoscopic partial adrenalectomy and the formation of an ileal conduit and robotically; in their unrandomized nephrectomy. At present the complication orthotopic neobladder by complete comparison of 200 robotic RPs with 100 ORPs, rates of laparoscopic partial nephrectomy are intracorporeal techniques took ª2.5 and the Detroit team reported similar operative somewhat higher than its open counterpart, 4.5 h, respectively [9]. With increasing times, and none of the patients needed a but with increasing experience and better experience it is anticipated that these blood transfusion after robotic RP, compared ways of achieving haemostasis it is likely that operative times will improve.

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CONCLUSION Correspondence: Prokar Dasgupta, Abbreviations: L(O)RP, laparoscopic (open) Department of Urology, 1st Floor Thomas Guy radical prostatectomy. Laparoscopic reconstructive urology is House, Guy’s Hospital, London SE1 9RT, UK. April 2005 technically feasible but challenging. The major e-mail: [email protected] 956 limitations are prolonged operating times, Comment Article comment limited instrumentation, small working spaces KNUDSEN and ﬁxed angles at the trocar level to place et al. sutures. Robotic assistance has provided increased dexterity because of the intuitive motion, and may overcome these technical difﬁculties. Larger series with a meticulous follow-up are required to determine the place DRUG-ELUTING BIOMATERIALS IN UROLOGY: THE TIME IS RIPE of many of these developing laparoscopic BODO E. KNUDSEN, BEN H. CHEW and JOHN D. DENSTEDT – Division of Urology, reconstructive procedures. The University of Western Ontario, London, Ontario, Canada

ACKNOWLEDGEMENTS INTRODUCTION catheter with long-term resistance to We thank the Guy’s and St. Thomas’ encrustation. This would limit the need for Charitable Foundation, Geoff Koffman, Abhay Urology has a reputation for promoting regularly changing the devices. In addition, Rane and Peter Rimington. advances in technology; the development of decreased encrustation may reduce the ESWL, sophisticated minimally invasive number of UTIs that require antibiotic REFERENCES procedures and advances in robotic surgery treatment. Heparin-coated ureteric stents are a testament to urological innovation. were evaluated in a clinical study, which 1 Kaouk JH, Gill IS. Laparoscopic Naturally, in some fields of endeavour other showed that after being in situ for up to reconstructive urology. J Urol 2003; 10: medical specialists have been the pioneers. 6 weeks, heparin-coated stents remained free 1070–8 e.g. in cardiovascular disease, where the of encrustation, as opposed to uncoated 2 Adeyoju AB, Hrouda D, Gill IS. combined advances in engineering and control stents which began to encrust within Laparoscopic pyeloplasty: the first decade. interventional cardiology have lead to the 14 days [2]. Another novel attempt at BJU Int 2004; 94: 264–7 development of drug-eluting devices such decreasing encrustation was to coat silicone 3 Gettman MT, Peschel R, Neururer R, as coronary stents [1]. Urinary tract drainage disks with oxalate-degrading enzymes, Bartsch G. A comparison of laparoscopic by catheters and stents represents a produced by Oxalobacter formigenes. The pyeloplasty performed with the da Vinci fundamental aspect of urological practice. disks were implanted into rabbit bladders robotic system versus standard The time is ripe to evaluate drug-eluting and left in situ for 30 days. The disks coated laparoscopic techniques: initial clinical compounds for possible use in urological with oxalate-degrading enzyme had less results. Eur Urol 2002; 42: 453–8 biomaterials. encrustation after 30 days than uncoated 4 Pesce F. Current management of stress control disks [3]. This is a promising advance urinary incontinence. BJU Int 2004; 94 and paves the way for future clinical studies. (Suppl 1): 8–13 THE PROBLEMS 5 Guillonneau B, Rozet F, Barret E, A SOLUTION Cathelineau X, Vallancien G. Indwelling catheters and stents are plagued Laparoscopic radical prostatectomy: with three primary problems that limit their Reports from cardiology show that stents can assessment after 240 procedures. Urol function, i.e. encrustation, infection and be not only ‘coated’ with a drug, but that the Clin North Am 2001; 28: 189–202 patient discomfort. All indwelling catheters drug can be loaded directly into the bulk 6 Menon M, Hemal AK, Tewari A, and stents will eventually encrust. This can material, thereby allowing it to elute in a Shrivastava A, Bhandari A. The lead to UTIs, increased patient discomfort and controlled fashion over time [1]. Stickler et al. technique of apical dissection of the difficulties with removal. Attempts have [4] reported that triclosan (an antimicrobial prostate and urethrovesical anastomosis been made to develop devices that resist found in many products, ranging from in robotic radical prostatectomy. BJU Int encrustation but none have eliminated the mouthwash and toothpaste to children’s 2004; 93: 715–9 problem completely. Currently, treatment toys), in an artificial infected-urine model, 7 Gill IS, Cheullo EE, Steinberg AP et al. with antibiotics and analgesics is only a could prevent biofilm formation and Laparoscopic ureterocalicostomy: Initial temporizing measure; removing the device encrustation of Foley catheters. We evaluated experience. J Urol 2004; 171: 1227–30 remains the only definitive solution. triclosan-eluting stents in an infected- 8 Rimington P, Dasgupta P. Laparoscopic rabbit model [5]. Segments of stents were and robotic radical cystectomy. BJU Int Several experimental models are available to endoscopically placed into rabbit bladders 2004; 93: 460–1 evaluate the problem of encrustation. These that were infected with Proteus mirabilis. 9 Dasgupta P, Rimington P, Jones A. include ex vivo artificial urine models, animal After 7 days, 7 of the 12 rabbits implanted Intracorporeal ileal conduit and models such as the pig or the rabbit, and with triclosan-eluting stents had cleared the orthotopic neo-bladder. BJU Int 2004; 93: human studies. The primary goal of most of P. mirabilis infection, vs none of 22 with S4: P136 the work to date is to develop a stent and/or control stents. Triclosan-eluting stents also

COMMENTS

had less adherent bacteria than controls. Drug-eluting biomaterials applied to urology 4 Stickler DJ, Jones GL, Russell AD. Many urologists routinely place patients on hold considerable promise. The potential to Control of encrustation and blockage of oral antibiotics after ureteric stenting. A reduce encrustation and limit UTIs would be a Foley catheters. Lancet 2003; 361: 1435– triclosan-eluting stent may be able to reduce significant breakthrough. The discomfort of 7 the need for oral antibiotics; human trials urinary stents and catheters may be reduced 5 Chew BH, Cadieux P, Knudsen BE et al. appear warranted. by using drug-eluting biomaterials. Further Triclosan loaded ureteral stents reduce expansion of the technology to treat other proteus mirabilis 296 infection in a rabbit LUTS secondary to indwelling catheters and urological disorders also holds promise. UTI model. J Endourol 2004; 18 (Suppl. 1): stents remain a difficult problem. Numerous Clearly, future studies are required to assess A87 attempts have been made to decrease the the safety and efficacy of these devices before 6 Lingeman JE, Schulsinger DA, Kuo RL. discomfort of ureteric stents, e.g. dual- this technology becomes incorporated into Phase I trial of a temporary ureteral durometer stents and tail stents [6], but a the standard of practice, but now is the time drainage stent. J Endourol 2003; 17: 169– definitive solution to improve patient comfort for urology to take a leading position in the 71 remains elusive. Drug-eluting stents may development of drug-eluting biomaterials. 7 Beiko DT, Watterson JD, Knudsen BE represent a breakthrough in attempts to et al. A double-blinded prospective modify stent symptoms. To evaluate which randomized controlled trial assessing the pharmaceuticals may be beneficial REFERENCES safety and efficacy of intravesical agents intravesically, to mimic a drug-eluting stent, a for ureteral stent symptoms after recent study evaluated the effect of an 1 Moses JW, Leon MB, Popma JJ et al. extracorporeal shock wave lithotripsy. intravesical instillation with oxybutynin, Sirolimus-eluting stents versus standard J Endourol 2004; 18: 723–30 ketorolac or lidocaine immediately after stents in patients with stenosis in a native 8 Lazzeri M, Spinelli M, Beneforti P, placing a ureteric stent in patients coronary artery. N Engl J Med 2003; 349: Malaguti S, Giardiello G, Turini D. undergoing ESWL. Objective symptom scores 1315–23 Intravesical infusion of resiniferatoxin by showed that patients receiving ketorolac had 2 Riedl CR, Witkowski M, Plas E, Pflueger a temporary in situ drug delivery system significantly less flank pain at 1 h after the H. Heparin coating reduces encrustation to treat interstitial cystitis: a pilot study. procedure. Moreover, all drugs were safe and of ureteral stents: a preliminary report. Int Eur Urol 2004; 45: 98–102 there were no adverse effects [7]. This study J Antimicrob Agents 2002; 19: 507–10 should serve as the foundation for future 3 Watterson JD, Cadieux PA, Beiko DT Correspondence: John Denstedt, Department studies of stent comfort to evaluate drug- et al. Oxalate-degrading enzymes from of Surgery, The University of Western Ontario, eluting urinary stents. Oxalobacter formigenes: a novel device London Health Sciences Centre, 339 956 coating to reduce urinary tract Windermere Road, London ON, Canada N6A Comment Article comment There are many other potential applications biomaterial-related encrustation. 5A5. SHABBIR et al. for drug-eluting technology in urology. J Endourol 2003; 17: 269–74 e-mail: [email protected] Currently patients are treated with weekly April 2005 instillations of BCG for Ta and T1 urothelial cell cancers of the bladder. Theoretically it is THE EUROPEAN WORKING-TIME DIRECTIVE: ONE STEP FORWARD, possible that a continuous indwelling delivery TWO STEPS BACK MAJID SHABBIR, PETER AMOROSO and ROGER S. KIRBY method for BCG, or a chemotherapeutic agent – St George’s Hospital & The London Clinic, Harley Street, London, UK such as mitomycin C, might provide both a more tolerable and perhaps more effective Accepted for publication 26 November 2004 delivery system. Similarly, treating upper-tract urothelial cell cancers with BCG or chemotherapeutic agents has been INTRODUCTION some time. The effect of these changes will cumbersome, requiring either a nephrostomy alter the way we teach and practice medicine, tube or reliance on reflux with a ureteric stent We are now in a new era of medical practice; and the consequences of this law will in place. Neither method ensures prolonged the UK has finally come into line with the rest resonate long into the future. contact of the reagent with the cancer; a of the Continent and the European Working drug-eluting stent may provide such a Time Directive (EWTD), which was integrated The greatest concerns with the solution. into British law in 1998, has at last been implementation of the new working hours are extended to include the medical profession. the effects on training and the quality of Patients with interstitial cystitis remain some This directive is essentially a Health and Safety clinical care. Medicine has traditionally been of the most challenging for the urologist to law, aimed at reducing the working week to a taught by a system of apprenticeship. Less treat. Resiniferatoxin administered locally to maximum of 56 h by August 2004, and to time spent at work will undoubtedly result in the bladder continuously over 10 days via an 48 h by 2009. While no one can question the reduced training opportunities. A report from infusion pump gave positive results in such logic behind this law, concerns exist as to its the Royal College of Surgeons calculated that patients [8]. A continuous local drug delivery effect on an already strained UK National before the Calman report, the average junior via a drug-eluting biomaterial might provide Health Service (NHS). The changes needed to doctor spent ª30 000 h at work before long-term symptomatic relief in these make hospitals compliant with the EWTD have becoming a consultant. With the new changes difficult-to-treat patients. seen the greatest overhaul of the NHS for to the system this figure is set to fall to

6000–8000 h [1]. While no one wishes to go The other major area of concern with the increase in the number of consultants under back to the ‘bad old days’ of 120-h working EWTD is its potential effect on the quality of this new scheme will improve service weeks, this dramatic change will lead to clinical care. Implementation of the new provision within the speciality, and improve greater inexperience at the consultant grade. restrictions to the working week has led to patient waiting times. However, not all While surgical training has been refined to fewer staff on duty at any given time and a urologists welcome this new development ensure that essential skills are adequately subsequent increase in the development of with optimism; many feel that the new 3-year taught, nothing will account for the cross-cover between specialities. This has training programme will be too short to experience gained from high exposure to three potential problems: (i) A worrying lack develop the necessary experience and a wide variety of different conditions. In of specialist expertise available on-call; (ii) responsibility required to become a medicine not all cases are straightforward, Breakdown in the continuity of patient care, consultant, with the potential need for and the ability to deal with unusual and often with the admitting team often different from continued mentorship forming an updated unpredictable situations is best enhanced the team caring for the patient for the version of the old senior registrar post. with time. remaining admission. This increases the need Despite the criticism, the proposed changes for careful transfers and raises the possibility offer a possible solution to the EWTD at a time As well as reducing the total hours worked, of potential error; (iii) Fewer staff on call leads when options are otherwise limited. While the EWTD also limits the total continuous to an over-stretched service and a greater teething troubles are to be expected at the hours worked to 13 in a 24-h period, with the possibility of problems being detected late, start, the new system should improve patient definition of ‘work’ extended to include time often when corrective measures may be care in the long term, although its effect on in the workplace on-call, even if asleep. Most ineffective. training is yet to be established. EWTD-compliant rotas work on a full-shift system, with weeks of night duty. Current This pressure cooker environment is a The EWTD is here to stay. It is important that hospital policy means that operations are only potential breeding ground for mistakes. In the we take great care to ensure that its performed at night if the condition is life- present era of clinical governance, there is a implementation does not risk the future of threatening. This means that cases such as moral and legal duty to ensure the delivery of healthcare in the UK. The policies adopted appendicectomy, which were the bread-and- high-quality clinical care. Should we forget, now will shape the medical profession forever, butter of surgical training, are now rarely we are quickly reminded of the consequence and may well decide whether the NHS will performed on-call. The admitting surgeon at of failure by the increasingly litigious sink or swim. Every effort must be made to night is also prevented from operating the environment in which we live and work. ensure that training standards are maintained next morning, as his continued presence at Changes are therefore essential to prevent the while trying to meet the pressures of service work contravenes the new directive. To add to disintegration of the NHS, and the sooner the provision in the new restricted-hours system. the problem, the week of nights is usually better. followed by time off, which results in further REFERENCES lost opportunities with elective operating Increasing the number of doctors provides a lists. A recent study highlighted this problem, long-term solution to the reduction in 1 Phillip H, Fleet Z, Bowman K. The showing that, on average, elective surgical working hours and the need to maintain a European Working Time Directive - Interim experience was reduced by a third with high standard of clinical care. The Department Report and Guidance from the Royal directive-compliant full-shift rotas [2]. of Health has already realized this and College of Surgeons of England Working planned expansion across the grades, with a Party. London: Royal College of Surgeons, At present, the surgical trainee is under fire 25% increase in the number of surgical January 2003 and already having to fight for adequate consultants by 2004 (1100 posts), and a 2 Stephens MR, Pellard S, Boyce J et al. operative experience. The increase in staff- further proposed increase of 43% by 2010 [4]. Influence of EWTD-compliant rotas on grade doctors and nurse specialists, both with However, this is still short of the 7000 new SHO operative experience. Ann R Coll Surg an emphasis on increased provision of service, posts that the British Medical Association’s Engl 2004; 86 (Suppl.): 120–1 is diluting many training opportunities. In Junior Doctors’ Committee quoted in 2001 as 3 Howell R, Scott NA. Surgical training addition, the development of ‘treatment being necessary to meet targets. Although derailed: a view from the tracks. Ann R centres’ as part of the government’s waiting- expansion of numbers is a possible solution, Coll Surg Engl 2004; 86 (Suppl.): 264–5 list initiative is also removing the prospect of the funding required to implement this 4 Chesser S, Bowman K, Phillips H. The vital training [3]. With the additional problems strategy fully is not available at present, or European Working Time Directive and that the EWTD brings, even more care must be indeed in the near future. Recruiting more training of surgeons. BMJ 2002; 325: S69 taken to ensure that remaining compliant doctors may therefore not be the most 5 MacDonald R. More doctors is not the with the EWTD is not at the expense of effective way of using available financial answer to the European Working Time developing competently trained consultants. resources [5]. One potential solution, which is Directive. BMJ 2003; 326: 68 This is of even greater importance in urology, due to be implemented in urology, is the which is now on the brink of a new phase, development of the ‘office urologist’ post. This Correspondence: Majid Shabbir, Department with a shortened training programme aimed may indeed be the way forward, particularly of Urology, St George’s Hospital Cranmer at producing ‘office urologists’ within 3 years in a speciality where fewer patients require a Terrace, London SW17 ORE, UK. of specialist registrar training. definitive surgical procedure. The resultant e-mail: [email protected]

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2004 956

Original Article PEYRONIE’S DISEASE SMITH et al.

There is a wide variety of topics Peyronie’s disease: the epidemiology, covered in this section. The epidemiology, aetiology and clinical aetiology and clinical evaluation evaluation of the deformity in of deformity Peyronie’s disease is described, followed by a discussion of recent CHRISTOPHER J. SMITH, CHELSEA MCMAHON and RIDWAN SHABSIGH advances in the biology of Department of Urology, Columbia University, New York, New York, USA diabetes-associated bladder Accepted for publication 23 September 2004 complications. Bladder cancer and its molecular prognostic factors are KEYWORDS Of concern is the belief by some that even the presented, and the section ends most recent data underestimate the true with an in-depth presentation Peyronie’s disease, epidemiology, aetiology, prevalence of PD. Men might be reluctant of an evidence-based approach clinical evaluation to report a condition that they consider to the understanding of the embarrassing, and older men might often accept their symptoms as insignificant pharmacological class effect in the DEFINITION consequences of ageing. Many physicians management of prostatic diseases. agree that the true prevalence of PD has Peyronie’s disease (PD) is a localized become more apparent since the advent of connective tissue disorder that affects the oral sildenafil, which has seen a marked tunica albuginea of the penis. Fibrous scar improvement in community awareness of tissue, which replaces the normally elastic erectile dysfunction [1]. fibres, causes a characteristic penile deformity that is most evident during erection. This Unfortunately, the quality of epidemiological pathological process can manifest as data on PD remains erratic, with one increased curvature, indentation, shortening contributing factor being the various criteria or an ‘hourglass’ irregularity of the penis. The used by researchers to define the condition. diagnosis of PD is often preceded by painful The most accepted objective measures include erections, and can be associated with erectile the number, size and location of plaques, dysfunction and palpable areas of induration as well as induration and curvature. (plaques). Nevertheless, epidemiological data have been used to propose risk factors associated with EPIDEMIOLOGY PD. Hypertension, smoking, diabetes and hyperlipidaemia have all been suggested as While PD was once considered to be relatively risk factors, but these are more likely to be uncommon, studies now suggest that its related to erectile dysfunction in general, and prevalence is similar to that of diabetes or current research has shown no substantial urolithiasis [1]. A recent epidemiological relationship between these factors and the study reported an overall prevalence of the severity of penile curvature [3]. condition of 3.2% [2], much higher than once thought, highlighting the potential physical and psychosocial impact of the disease on society. Compounding these effects on the AETIOLOGY AND PATHOPHYSIOLOGY community are the changing demographics of the population, which are predicted to Although the exact causes of PD remain increase age-related conditions. enigmatic, recent developments in animal

SMITH ET AL.

(in vivo) and cell culture (in vitro) models have TRAUMA Dupuytren’s contracture. This raises the provided an invaluable medical platform to possibility of a common pathway leading to analyse the pathophysiology of PD. El-Sakka Trauma is reported to be the important fibrosis. Genotypic analyses have shown that et al. [4] used rats as an experimental model in initiating factor, and the ensuing chromosomal instability is significant in a causal in vivo investigation of PD. Injections inflammatory response is considered to be plaque-derived cells with fibroblasts from of cytomodulin (a synthetic heptapeptide heightened through confinement in the either foreskin or normal tunica [5]. with a similar action to TGF-b) into the penile densely packed layers of the tunica albuginea. tissue of rats consistently produced an It is proposed that the trauma originates from Profibrotic or fibrogenic cytokines increase intense fibrotic reaction in the tunica excessive physical forces inflicted on the penis fibroblast collagen production and albuginea. The study provided evidence of the during penetrative sex, which result in tunical proliferation rates. While there are many pathogenetic function of TGF-b in PD, and delamination and microhaemorrhaging into families of fibrogenic cytokines, it has been promoted the use of in vivo analysis as an the subtunical spaces [6]. The subsequent established that TGF-b1 is up-regulated in PD effective tool in the search for therapeutic formation of scar tissue in the tunica [10]. TGF-b1 also stimulates the expression of solutions. albuginea occurs where the strands of the the profibrotic cytokines, including monocyte septum are attached to the dorsal and ventral chemoattractant protein 1 and connective Mulhall et al. [5] cultured cells from plaque- aspects of the penis; these are the points tissue growth factor. Further contributing to derived tissue; this in vitro analysis showed under maximum stress when the elastic tissue this fibrogenic effect, increased levels of basic reliable phenotypic, genotypic and functional of the penis is stretched to its capacity [7]. fibroblast growth factor in plaque-derived alterations in pathological tissue compared to cell cultures cause an overproduction of normal tunica-derived or neonatal foreskin- The fibrin deposited initially as a consequence extracellular matrix by fibroblasts [11]. derived fibroblasts. While this model was not of repetitive microvascular injury is a normal able to flawlessly replicate the in vivo component of wound healing, but Cellular over-proliferation in PD is associated environment, it allowed an investigation of pathological scar tissue forms when repetitive with aberrant p53 function that allows factors upstream of TGF-b that influence the trauma leads to inadequate resolution of the damaged cells to pass through the cell cycle pathogenetic pathway. Other advantages lesion [7]. Recent research has shown that the and proliferate. This abnormal pathway has of the cell-culture model include cost and additional accumulation of collagen in the been shown in plaque-derived fibroblasts and time efficiency, reproducibility, and the tunica albuginea is disorganized, and there is indicates an absence of cell-cycle checkpoints identification of tissue cell variance between a diminished and chaotic dissemination of in these cells [12]. While a significant presence patients. elastin fibres [8]. Despite these findings, more of p53 protein has been recognized in information is needed on the cause of the pathological plaque fibroblasts, relatively low Many of the theories that seek to explain the fibrin deposition and subsequent failure of levels were found in normal control samples pathogenesis of PD have been derived from degradation. [13]. either animal or cell-culture research. While trauma is considered to be the provocative GENETIC PREDISPOSITION AND FREE RADICAL FORMATION stimulus, other theories include: failure of AUTOIMMUNE FACTORS fibrin clearance; collagen alterations; genetic Cellular antioxidants are reported to have a predisposition; autoimmune factors; free Genetic predisposition has been suggested as role in preventing plaque growth in PD; their radical production; and cytogenetic a causal factor, because of the familial ability to combat the effects of free radicals, aberrations. In 2003 Mulhall [6] described a clustering of the condition, and studies including reactive oxygen species and reactive paradigm that encompassed these different assessing human leukocyte antigen linkage nitrogen intermediates, appears to be an theories to explain plaque developmental have shown that PD is strongly associated important component in minimizing the pathogenesis in PD; an adapted version with both Dupuytren’s contractures and proposed damage caused by oxidative stress follows: human leukocyte antigen B27 [6]. Patients [14]. However, therapeutic antioxidants with PD have various degrees of (vitamin E and superoxide dismutase) have •Penile trauma in genetically susceptible autoimmunity, supporting the theory that an been used with mixed success, and given that males, leading to; autoimmune reaction after trauma might be many signalling pathways are poorly • endogenous and/or exogenous factors the cause of the additional fibrosis and understood, further research is needed to (localized autoimmune response), leading to; scarring [9]. Diverse markers of immune determine the function of free radicals in • loss of suppressor genes and activation of incompetence were reported in affected calcification and plaque formation. promoter genes, leading to; patients, but the proposed autoimmune • cell-cycle regulator dysfunction, leading to; susceptibility is believed to be localized to the Smooth muscle cells and macrophages, • biological transformation of constituent tunica albuginea. among other cell types, produce inducible cells within tunica/plaque, leading to; nitric oxide synthase when stimulated. When • cytokine over-expression, free radical CYTOGENETIC ALTERATIONS this enzyme is up-regulated, high levels of production and cytogenetic changes, leading nitric oxide generate potent free radicals, to; Chromosomal instability has been shown in which lead to oxidative stress and poor • unregulated extracellular matrix deposition fibroblasts from pathological plaques in PD, vasorelaxation. Although this process is (fibrin and collagen), leading to; and similar cytogenetic abnormalities have thought to exist in PD, some studies suggest • plaque formation. been found in samples from patients with that nitric oxide might limit tunical scarring

PEYRONIE’S DISEASE

OBJECTIVE MEASURES TABLE 1 A summary of the clinical evaluation of penile deformity in PD The objective evaluation of penile deformity in Measures Subjective Objective PD includes measurements of length, plaque Questionnaire or clinical history: Penile length: characteristics (size and location), erectile Presenting symptoms Measure dorsally from base to meatus capacity and curvature. There is currently no Duration of disease Ensure penis is at full stretch standardized approach for assessing penile Previous penile injury length, but it is recommended to measure it Risk factors for erectile dysfunction Plaque characteristics: dorsally from the base to the meatus while the Medical and sexual history Callipers or rulers most reliable penis is at full stretch [18]. It is hoped that this Level of satisfaction Ultrasonography or MRI will minimize the potential effect of proximal Psychological distress penile fat and skin variability. Unfortunately, Erectile capacity: measurements of length obtained in the Patient observations: Penile duplex ultrasonography after erectile state are difficult to reproduce. Curvature direction and degree of severity a vasoactive penile injection Girth-related changes While a reduction in plaque size has not been Penile curvature: shown to correlate with improvements in Physical examination: Protractor most reliable, recorded at point of other functional deformities, it is often Genitourinary assessment maximum erection reported as a target for treating PD [18]. Hands and feet for systemic fibromatosis Measuring the plaque size is difficult because ‘Eyeball’ curvature, length, and erection capacity of extensions through the septum and variability in thickness, with the use of callipers or rulers thought to offer the most practical solution. Ultrasonographic and contraction by restricting myoblast Sexual Functioning, and the Social Desirability techniques are useful to verify the presence of proliferation [15]. Scale. The Peyronie’s Disease Index, first any arterial or mixed vascular abnormalities, introduced by Shabsigh et al. [17], is a and can be used to identify distinguishing OTHER CAUSES questionnaire specifically designed to address plaque features including size, hypo/hyper- issues most pertinent to patients with PD. echogenicity, calcification and tunical PD is also associated with invasive procedures albuginea thickening [19]. MRI might provide on the penis, e.g. radical retropubic The aim of the initial evaluation is to provide additional information about local prostatectomy, cystoscopy and urethral information on the duration of disease, inflammation if required [20]. catheterization; genital or peritoneal trauma; recalled injury and presenting symptoms urethritis; uric acidaemia; and lipoma [16]. (curvature, length, rigidity, softening, erection Erectile capacity or rigidity is often measured Atherosclerosis has been mentioned as a pain, coitus, girth and hinge). Ideally, subjectively in standardized questionnaires, specific area of interest, as its pathological information on psychological distress and and this is important in assessing patient mechanism is similar to that of PD [5], as level of satisfaction should be obtained, as satisfaction and quality of life. However, atherosclerosis is also subject to cellular over- well as potential risk factors for erectile objective measurements can also be obtained proliferation leading to fibrotic plaque dysfunction. Strategies to elicit the patient’s using penile duplex ultrasonography after formation. assessment of curvature direction and degree administering a vasoactive penile injection. of severity might include the use of visual Other objective measurement options include analogue scales. nocturnal penile tumescence and rigidity CLINICAL EVALUATION OF monitoring, and cavernosometry, but these THE DEFORMITY The next component of subjective evaluation are poor predictors of sexually induced involves a physical evaluation. Levine and erections [18]. The accurate clinical evaluation of penile Greenfield [18] recommend that the deformity secondary to PD requires both examination should start with a routine Penile curvature is recorded at the point of subjective and objective measures (Table 1). genitourinary assessment, which is then maximum erection, and measurement by extended to involve an assessment of hands protractor is reported to be the most reliable SUBJECTIVE MEASURES and feet for indications of systemic technique. However, assessing penile fibromatosis (e.g. Dupuytren’s contracture). angulation is often inaccurate because of The initial component of a subjective Other subjective information sometimes variability in penile rigidity at the time of evaluation is often achieved using a noted on physical examination includes evaluation. Vacuum-induced erection in the questionnaire or clinical history to estimate ‘eyeball’ evaluations of penile curvature, clinic contributes to this variability, as the the degree of deformity and its effects on penile length change and differences in erection obtained is often not representative the patient’s quality of life. There are many erection capacity. Girth-related changes are of the patient’s normal erection. Measurement established questionnaires to assess sexual most commonly reported by the patients, of angulation from photographs has also been function, including the International Index of despite the recommended use of string or suggested to be inaccurate because of several Erectile Function, the Derogatis Interview for flexible rulers to measure it directly. inconsistencies [18].

SMITH ET AL.

CONCLUSION 2 Schwarzer U, Sommer F, Klotz T, Braun 12 Mulhall JP, Branch J, Lubrano T, M, Reifenrath B, Engelmann U. The Shankey TV. Perturbation of cell cycle The prevalence of PD is much greater than prevalence of Peyronie’s disease: results regulators in Peyronie’s disease. Int J previously thought, with the condition now of a large survey. BJU Int 2001; 88: 727– Impot Res 2001; 13 (Suppl. 5): S21–28 reported to affect 3.2% of the male 30 13 Martin DJ, et al. Immunoblot analysis of population. This confirms fears that it is 3 Usta MF, Bivalacqua TJ, Jabren GW p53 and cyclin D in Peyronie’s disease. Int becoming a major public health issue for et al. Relationship between the severity J Impot Res 2002; 14 (Suppl. ): S10 ageing men, with action now required to of penile curvature and the presence of 14 Sikka SC, Helstrom WJ. Role of oxidative minimize the impact on society. The comorbidities in men with Peyronie’s stress and antioxidants in Peyronie’s development of extensive screening disease. J Urol 2004; 171: 775–9 disease. Int J Impot Res 2002; 14: 353–60 programmes would offer a means for 4 El-Sakka AI, Hassan MU, Nunes L, 15 Bivalacqua TJ, Champion HC, evaluating associated comorbidities, and Bhatnagar RS, Yen TS, Lue TF. Leungwattanakij S et al. Evaluation of would provide a better understanding of the Histological and ultrastructural nitric oxide synthase and arginase in the risk factors for PD. The need for medical alterations in an animal model of induction of a Peyronie’s-like condition in practitioners to adopt a standardized Peyronie’s disease. Br J Urol 1998; 81: the rat. J Androl 2001; 22: 497–506 approach to the clinical evaluation of penile 445–52 16 Gholami SS, Gonzalez-Cadavid NF, Lin deformity will also be greater as the condition 5 Mulhall JP, Anderson MS, Lubrano CS, Rajfer J, Lue TF. Peyronie’s disease: becomes more common. T, Shankey TV. Peyronie’s disease cell a review. J Urol 2003; 169: 1234–41 culture models: phenotypic, genotypic 17 Shabsigh R, Fleming M, Pereman M, Much debate remains over the and functional analyses. Int J Impot Res Anastasiadis A. Peyronie’s Disease pathophysiological mechanisms leading to 2002; 14: 397–405 Index (PDI); a standardized patient excessive scarring and fibrosis. Recent 6 Mulhall JP. Expanding the paradigm for questionnaire. Int J Impot Res 2003; 14 refinements of cell culture and animal models plaque development in Peyronie’s disease. (Suppl. 3): S68 have enhanced understanding of what is Int J Impot Res 2003; 15 (Suppl. 5): S93– 18 Levine LA, Greenfield JM. Establishing a thought to be a multifactorial process. While 102 standardized evaluation of the man with it appears that penile trauma is the major 7 Devine CJ Jr, Somers KD, Jordan SG, Peyronie’s disease. Int J Impot Res 2003; inciting factor in the causes of PD, it is Schlossberg SM. Proposal: trauma as the 15 (Suppl. 5): S103–12 unlikely to be solely responsible, as only some cause of the Peyronie’s lesion. J Urol 1997; 19 Wilkins CJ, Sriprasad S, Sidhu PS. men are susceptible, despite having similar 157: 285–90 Colour Doppler ultrasound of the penis. sexual experiences to the rest of the 8 Akkus E, Carrier S, Baba K et al. Clin Radiol 2003; 58: 514–23 population. With further research into the Structural alterations in the tunica 20 Hauck EW, Hackstein N, Vosshenrich R pathological cascade of cellular and albuginea of the penis: impact of et al. Diagnostic value of magnetic molecular events, and an increase in Peyronie’s disease, ageing and impotence. resonance imaging in Peyronie’s disease: a community awareness of the disease, the Br J Urol 1997; 79: 47–53 comparison both with palpation and development of effective therapeutic and 9 Schiavino D, Sasso F, Nucera E et al. ultrasound in the evaluation of plaque prophylactic measures will become a realistic Immunologic findings in Peyronie’s formation. Eur Urol 2003; 43: 293–300 objective. disease: a controlled study. Urology 1997; 50: 764–8 Correspondence: Ridwan Shabsigh, CONFLICT OF INTEREST 10 El-Sakka AI, Hassoba HM, Pillarisetty Department of Urology, Columbia University, RJ, Dahiya R, Lue TF. Peyronie’s disease New York, New York, USA. None declared. is associated with an increase in e-mail: [email protected] transforming growth factor-beta protein REFERENCES expression. J Urol 1997; 158: 1391–4 Abbreviations: PD, Peyronie’s disease. 11 Mulhall JP, Thom J, Lubrano T, Shankey 1 Sommer F, Schwarzer U, Wassmer G TV. Basic fibroblast growth factor et al. Epidemiology of Peyronie’s disease. expression in Peyronie’s disease. J Urol Int J Impot Res 2002; 14: 379–83 2001; 165: 419–23

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2004 956

Minirev Article THE BIOLOGY OF DIABETES-ASSOCIATED BLADDER COMPLICATIONS YOSHIMURA et al.

Recent advances in understanding the biology of diabetes-associated bladder complications and novel therapy

NAOKI YOSHIMURA, MICHAEL B. CHANCELLOR*, KARL-ERIK ANDERSSON† and GEORGE J. CHRIST‡ Departments of Urology and Pharmacology, *Urology and McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, †Department of Clinical and Experimental Pharmacology, Lund University Hospital, Lund, Sweden, and ‡Department of Regenerative Medicine, Wake Forest University, Winston-Salem, NC, USA Accepted for publication 12 October 2004

KEYWORDS overdistension. Many animal models have be a result of an alteration in the physiology been used to elucidate this and other of the detrusor smooth muscle cell, the diabetes mellitus, detrusor, smooth muscle, questions associated with diabetic innervation or function of the neuronal nerve growth factor, urothelium cystopathy. Streptozotocin (STZ)-induced component, or urothelial dysfunction (Fig. 1). diabetic rats and sucrose-drinking rats The experimental model most often used to (sucrose induces a polyuria similar to that assess bladder complications is the STZ rat INTRODUCTION seen in diabetic patients) have generally been model. As bladder smooth muscle contraction used. Paro et al. [2] noted that alloxan- is mediated by acetylcholine released by the Diabetes mellitus (DM) is at epidemic induced diabetic rats had decreased and pelvic nerve acting on muscarinic receptors, proportions and becoming a major problem in irregular contractions, while sucrose-fed rats a series of pharmacological studies have the USA. According to the Centers for Disease had normal bladder contractions. This focused on the impact of STZ-DM on the Control and Prevention, 18 million people in suggests that in alloxan-induced DM, responsiveness of bladder strips to externally the USA have DM and the prevalence of DM contractile dysfunction is secondary to an applied muscarinic agonists. Neuronal increased from 4.9% in 1990 to 7.3% in inherent diabetic cystopathy, while bladder dysfunction may reflect a deficiency of axonal 2000 [1]. Urological complications have hypertrophy in sucrose-fed rats is an organ transport of nerve growth factor (NGF) and be increasingly become a concern in those adaptation to polyuria. Other differences important in inducing diabetic neuropathy affected by DM (both Type I and II). More than between STZ-induced diabetes and sucrose- [13–15]. The urothelium undergoes changes a quarter of diabetic patients will develop induced bladder distension include a decrease in DM; thus, in the STZ-induced DM rat model, costly and debilitating urological in noradrenaline uptake and in choline there are progressive increases in total complications, e.g. incontinence, infections, acetyltransferase activity [3], and bladder tissue, with hypertrophy of the loss of sensation and retention of urine. The cystometrographic and supraspinal reflex bladder wall and dilatation of the bladder total annual cost of diabetes in 1997 has been latencies between the groups [4]. [16,17]. Both smooth muscle and urothelium estimated at more than $98 billion (http:// have been shown to increase significantly www.diabetes.org). Clinically, the diagnosis of diabetic cystopathy with time. Thus there is strong evidence that is most readily made with urodynamic testing DM adversely affects the bladder smooth In addition to diabetic bladder dysfunction, [5,6]. The most common urodynamic findings muscle, nerves and the urothelium (Fig. 1). there is a greater incidence of asymptomatic include elevated residual urine volume, and symptomatic bacteriuria, which can impaired bladder sensation, involuntary progress to kidney infection and kidney detrusor contractions, increased cystometric DM AND DETRUSOR SMOOTH damage. This increase in infection has been capacity and decreased bladder contractility. MUSCLE FUNCTION attributed to numerous causes, from Cystometry may show detrusor areflexia, incomplete bladder emptying to changes in which is usually found in patients with an DM has been shown to alter detrusor smooth bladder wall components and immune impaired sensation of bladder filling [7–9]. muscle function in experimental animals, with dysfunction. A confounding factor for all Detrusor overactivity is also common in the vast majority of these studies conducted basic studies on the bladder is the lack of patients with DM [10]. Other aspects of the on the STZ rat model. However, because there published data on the urothelial cell, vascular, severity of DM, e.g. duration, glycaemic are no longitudinal studies conducted under neurological and smooth muscle function, control and microvascular complications similar experimental conditions, there is still and interactions in bladder tissue from resulting in damage to innervation of the uncertainty about the time course, magnitude nondiabetic sources that can be used for bladder, have been suggested as possible and mechanism of DM-related changes in comparison with the diabetic. mechanisms for incontinence [11,12]. detrusor smooth muscle cell function.

An important question is whether bladder PATHOPHYSIOLOGY STZ-DM: Pharmacological studies on isolated dysfunction is secondary to an inherent bladder strips have generated much neuropathology induced by diabetes, or The biology of DM-associated bladder confusion. While there are generally changes caused by changes associated with bladder complications is multifactorial and they can in isolated detrusor smooth muscle cell strips

Y OSHIMURA ET AL.

there is no agreement on either the FIG. 1. Three important aspects of the diabetic cystopathy that may overlap. phenomenon or the mechanism. For example, several studies documented an increase in responsiveness of DM bladder strips to externally applied muscarinic agonists [17,18] but others reported a decrease or no change in the muscarinic component [19]. There was an increase in muscarinic receptor density at Smooth Nerve both 2 and 8 weeks after STZ-induced DM muscle [20]. A recent study found an increase in the b1-receptor-mediated relaxation response in isolated detrusor smooth muscle strips from 8–10 week STZ-DM rats [21]. Moreover, there was an increased contractile response to 5- hydroxytryptamine from 4-week STZ-DM rats.

One DM-related change that most experts agree on is an increased responsiveness of Urothelium isolated rat bladder strips to electrical field stimulation (EFS) [22,23]. However, there is no consensus on the putative mechanism for this increased responsiveness to EFS. Theories include that the increased response to EFS is caused by DM-related changes in membrane lipid composition or other destabilizing membrane changes, or increased neurotransmitter release [24]. Belis et al. [25] suggested that the changes are related to associated with a decrease in neuronal of detectable effects of 6 months of DM in the increased calcium-channel activity, while transmitter release. BB/W rat on the pharmacology of isolated Waring and Wendt [23] found no evidence for detrusor (i.e. bladder body) strip contractions. altered calcium regulation, and therefore Poladia and Bauer [29] studied the changes in However, there were modest but statistically suggested that the increased responsiveness nitric oxide synthase (NOS) and reactive significant decreases in the sensitivity and may be a result of enhanced calcium nitrogen species formation during DM- magnitude of carbachol and ATP-induced sensitivity. Most recently, Bezuijen et al. [26] related bladder remodelling, using the STZ- contractions of detrusor strips when the data reported that decreased function was more DM rat model. They found early, time- were normalized for tissue weight. notable in strips from diabetic rats with dependent and cell-specific changes in the enlarged bladders. This does not elucidate the three isoforms of NOS, and region-specific Given that motility disorders are an important mechanism, but could explain some of the increases in protein nitration. Endothelial NOS component of diabetic cystopathy, it will be observed variability from previous studies. In was significantly up-regulated in the lamina critical to more precisely determine the addition, this same group recently showed propria, neuronal NOS in the urothelium, nature, time course, magnitude and that DM increases the rate of development lamina propria and in the smooth muscle mechanism for these changes (Fig. 2). of at least some aspects of bladder layer, whereas inducible NOS was up- Elucidating the contribution of detrusor decompensation in rats with partial urethral regulated only in the urothelium. They myocytes to diabetic bladder disease will be outlet obstruction [27]. Such observations suggested that changes in NO production and important to the improved understanding, further highlight the multifactorial nature of impaired NO control are early events in diagnosis and treatment of diabetic diabetic cystopathy, and the potential array of diabetic cystopathy, and that mechanisms cystopathy. To do so will require causal mechanisms and clinical symptoms leading to increased oxidative stress and multidisciplinary longitudinal studies in both that might be apparent in an ageing proteasomal activation may be key man and experimental animals, in which the population. participants leading to organ dysfunction. extent of DM is well characterized, and the effects of DM on bladder function in vivo Hashitani and Suzuki [28] found increased BB/W rat: There are only a few published documented. depolarization of myocytes in STZ-DM rat studies with the BB/W rat diabetic model bladder strips on applying acetylcholine, [14,22]. As with the STZ-rat model, the indicating enhanced muscarinic sensitivity in diabetic BB/W rat has the expected in vivo NEURONAL DYSFUNCTION IN DM the diabetic bladder. They further noted phenotypic characteristics, e.g. decreased decreased spontaneous electrical activity in overall body weight, and corresponding Although the pathogenesis of diabetic the myocytes, presumably related to altered increases in voiding volumes and voiding neuropathy is not fully clarified, it is generally purinergic transmission. These observations frequency. From a mechanistic standpoint, accepted that the cause of diabetic are consistent with the effects generally Longhurst [30] reported an apparent absence neuropathy is multifocal. Some of the

THE BIOLOGY OF DIABETES-ASSOCIATED BLADDER COMPLICATIONS

FIG. 2. Effects of DM on detrusor smooth muscle function.

Diabetes/Hyperglycemia

Urothelium Nerves Diabetes has direct and indirect effects

Smooth Muscle Cell

Diabetes-related alterations may be attributed to several mechanisms

Altered Ionic Mechanisms Pharmacological Changes Changes in cellular excitability Changes in receptor density, distribution or function (i.e., ion channels, pumps, transporters, etc.) Changes in intracellular signal transduction and/or Changes in intercellular communication

Molecular Changes (i.e., contractile filament alterations) and/or Genetic Changes (i.e., changes in gene expression)

proposals for pathogenesis include altered therapy for treating DM cystopathy [34] reduction of intercontraction intervals after metabolism of glucose, ischaemia, (Fig. 3). acetic acid instillation, were significantly superoxide-induced free-radical formation decreased in a time-dependent manner and impaired axonal transport [31]. It is also Using STZ-DM rats (65 mg/kg, intraperitoneal) during the 12 weeks after STZ injection. known that the neuropathies of DM caused by the effects of DM and gene therapy, using the metabolic derangement of the Schwann replication-defective herpes simplex virus Rat injected with HSV-NGF into the bladder cell result in segmental demyelination and (HSV) vectors encoding the NGF gene (HSV- wall 8 weeks after STZ injection had a impairment of nerve conduction. This gradual NGF) injected into the bladder wall, were significant increase in NGF levels in the process of segmental demyelination has been assessed on Ad afferent fibre-dependent bladder and L6 DRG 4 weeks after HSV-NGF confirmed histologically in the bladder and is conscious voiding and C-fibre-mediated treatment (i.e. 12 weeks after STZ injection). consistent with the observed impairment of bladder nociceptive responses. This was done DM rats injected with HSV-NGF also had a nerve conduction of the visceral afferent using metabolic cage/awake cystometry significantly smaller bladder capacity and fibres within the bladder wall. Van Poppel and cystometry with intravesical instillation postvoid residual volume than DM rats et al. [32] reported that there was less of 0.25% acetic acid under urethane injected with HSV encoding the LacZ gene acetylcholinesterase activity in bladder biopsy anaesthesia, respectively. In addition, NGF (Fig. 3). However, HSV-NGF treated rats specimens from patients with severe insulin- levels in the bladder and L6–S1 DRG were showed no significant bladder nociceptive dependent DM than in normal controls. measured by ELISA methods 3, 6, 9 and responses after intravesical acetic acid 12 weeks after STZ injection, and 4 weeks infusion [34,35]. The deficiency of axonal transport of NGF may after the HSV-NGF treatment [33]. be important in inducing DM neuropathy, These results indicate that the reduced which contributes to DM cystopathy [2,13]. In DM rats, NGF levels in the bladder and production of NGF in the bladder and/or Sasaki et al. [33] recently reported, using STZ- L6–S1 DRG significantly decreased 12 weeks impaired transport of NGF to L6–S1 DRG may DM rats, the relation between bladder after STZ injection. In cystometry and be an important mechanism inducing DM function and NGF levels in the bladder and metabolic-cage studies, bladder capacity and cystopathy, which is attributable to defects in lumbosacral dorsal root ganglia (DRG), which postvoid residual volume were significantly both Ad-fibre and C-fibre bladder afferent contain afferent neurones innervating the increased 12 weeks after STZ injection (Fig. 3). pathways. NGF gene therapy using bladder, and the feasibility of NGF gene Bladder nociceptive responses, assessed by a replication-defective HSV vectors, which

Y OSHIMURA ET AL.

restores decreased NGF expression in the FIG. 3. Cystometric analyses in an awake condition, to evaluate the efﬁcacy of HSV vector-mediated NGF bladder afferent pathways, could be effective delivery to the bladder in diabetic rats. (A) Representative traces of cystometrograms in a normal rat (upper for treating DM cystopathy [13,35] (Fig. 4). trace), an untreated diabetic rat (12 weeks after inducing DM, middle trace) and a 12-week diabetic rat injected with HSV expressing NGF gene 8 weeks after inducing DM (lower trace). (B) The mean bladder UROTHELIAL DYSFUNCTION IN DM capacity inducing voiding (upper graph) and postvoid residual volume (lower graph) (seven normal rats, six untreated diabetic rats and eight diabetic rats injected with HSV-NGF). **P < 0.01. The location of the urothelium suggests that it is important for regulating permeability, A B 40 transport and endocytosis. However, it has 3 become increasingly clear that the urothelium ** is not only a passive barrier against urea and ** ion diffusion, but that it can also function as 2 Control rat a sensor, controlling bladder function and dysfunction. The urothelium may have 1 0

receptors and ion channels similar to those in mL adder capacity, Bl O bladder nerves, and injury or inﬂammation 2 0 may alter the response of both urothelial cells 40 normal DM12W DM+NGF 4W and sensory afferents to nociceptive and other stimuli. Many mediators, e.g. ATP, NO DM 12W and prostanoids, can be released from the 0.5 urothelial cells [36,37]. Vanilloid receptors are 0.4 expressed on urothelial cells [38], and it has ** 0 been shown that ATP can potentiate the **

Intravesical pressure, cmH 0.3 response to vanilloids by lowering the 3 min threshold for, e.g. protons and capsaicin [39]. 0.2 40 mL volume, residual This means that the large amounts of ATP DM 12W 0.1 released from damaged/sensitized cells in + NGF 4W 0.0 response to injury/inﬂammation may void Post normal DM12W DM+NGF 4W inﬂuence afferent nerves and contribute to the variety of abnormalities in DM-induced bladder dysfunction. 0

In the STZ-DM rat model there are progressive increases in total bladder tissue with urothelial cells [40]. Pinna et al. [15] showed DM have bacteriuria more often than women hypertrophy of the bladder wall and dilatation that ATP evoked a phasic and tonic without. Geerlings et al. [41] showed that Type of the bladder [15,16]. Both smooth muscle contraction in bladder strips from nondiabetic 1 fimbriated Escherichia coli adhered twice as and urothelium (percentage of total tissue) rats; in preparations from DM, but not from well to diabetic as to control epithelial cells. increase significantly in a time-dependent normal animals, the tonic contraction was The receptors for these Type 1 fimbriae are manner. Pinna et al. [15] found that the abolished by removing the urothelium. glycoproteins (uroplakins), and it was epithelium from STZ-DM rat bladders was at Bradykinin evoked a long-lasting tonic proposed that diabetic uroepithelial cells have least twice as thick and heavy as that from contraction that was reduced significantly by a different glycosylation of the receptor on controls. In isolated urothelial layer removing the urothelium only in DM rat their cells, resulting in higher adherence. preparations from bladders of STZ-DM rats, bladders. Part of the effects of both ATP and the absolute amount of endogenous bradykinin on DM bladders thus seemed to prostaglandins E2 and F2a was higher than in depend on the generation and release of CONCLUSIONS corresponding preparations from control prostaglandins from the urothelium. This animals, but when prostaglandin F2a implies that both ATP (P2X) and bradykinin Although urological complications and major production was expressed as a fraction of receptors might be present in the urothelium, health problems in men and women with DM tissue weight, it was reduced in the diabetic and that these receptors may be important in, are common, data to define the expected epithelium. e.g. prostaglandin generation and release. In prevalence, incidence and risk factors, and turn, prostaglandins may sensitize sensory interventions to reduce the risk of developing ATP and bradykinin significantly increased the nerves and increase the sensitivity of bladder these complications, are limited. New research endogenous release of both prostaglandins smooth muscle to contractile stimuli, which initiatives are needed to further understand from the urothelium when compared with the may contribute to some of the bladder the basic disease mechanisms, to develop safe release under basal conditions. This increase abnormalities, e.g. detrusor overactivity, and effect prevention and treatment of the was time-dependent and was higher in observed in DM. urological complications of DM. A better diabetic than in control tissues. Bradykinin- understanding of the biology of how DM induced release of prostaglandin E2 has also The urothelium may also be important in DM- affects the muscle, nerve and urothelium of been reported in primary cultures of human related UTI. It was reported that women with the urinary bladder could lead to improved

THE BIOLOGY OF DIABETES-ASSOCIATED BLADDER COMPLICATIONS

FIG. 4. The relationship between bladder function and NGF: (i) In conditions of peripheral neuropathy such as sympathetic skin response. J Urol 1997; DM, reduced NGF production in the bladder or deficiency in NGF transport to the bladder afferent pathway 157: 580–4 is an important factor in the pathogenesis of diabetic cystopathy that induces bladder hyporeflexia and 10 Kaplan SA, Te AE, Blaivas JG. decreased sensation. NGF supplement therapy may be useful to restore bladder function in these conditions. Urodynamic findings in patients with (ii) In conditions of bladder hypertrophy induced by BOO, spinal cord injury or bladder inflammation, there is diabetic cystopathy. J Urol 1995; 153: increased NGF that can induce detrusor overactivity and bladder pain. Reducing NGF expression may be 342–4 effective in normalizing bladder function in these conditions. 11 Andersen JT, Bradley WE. Early detection of diabetic visceral neuropathy. NGF supplement An electrophysiologic study of bladder (gene therapy) and urethral innervation. Diabetes 1976; 25: 1100–5 12 Andersen JT, Bradley WE. Abnormalities of bladder innervation in diabetes (i) Neuropathy NGF Hyporeflexia mellitus. Urology 1976; 7: 442–8 (Diabetes) Areflexia 13 Sasaki K, Yoshimura N, Chancellor MB. Implications of diabetes mellitus in urology. Urol Clin North Am 2003; 30: 1–12 14 Paro M, Prashar A, Prosdocimi M, Cherian PV, Fiori MG, Sima AA. Urinary bladder dysfunction in the BB/W diabetic (ii) Hypertrophy NGF Hyperreflexia Inflammation Pain rat. effect of ganglioside treatment on functional and structural alterations. J Urol 1994; 151: 781–6 15 Pinna C, Zanardo R, Puglisi L. Prostaglandin-release impairment in the bladder epithelium of streptozotocin- NGF suppression induced diabetic rats. Eur J Pharmacol 2000; 388: 267–73 16 Pitre DA, Ma T, Wallace LJ, Bauer JA. Time-dependent urinary bladder remodeling in the streptozotocin-induced care of the diabetic patient with lower urinary contraction and relaxation mechanisms in diabetic rat model. Acta Diabetol 2002; tract dysfunction. rat urinary bladder. Diabetes 1989; 38: 39: 23–7 278–84 17 Mimata H, Wheeler MA, Fukumoto 4 Steers WD, Mackway AM, Ciambotti J, Y et al. Enhancement of muscarinic CONFLICT OF INTEREST de Groat WC. Effect of streptozotocin- receptor-coupled phosphatidyl inositol induced diabetes on bladder function in hydrolysis in diabetic bladder. Mol Cell None declared. Sources of Funding: NIH the rat. J Urol 1990; 143: 1032–6 Biochem 1995; 152: 71–6 HD397658, DK55045, NIH DK57267, 5 Chancellor MB, Blaivas JG. Multiple 18 Kanda M, Eto K, Tanabe N, Sugiyama A, DK68557, NIH DK55076, DK60037 and sclerosis and diabetic neurogenic bladder. Hashimoto K, Ueno A. Effect of ONO- DK60204 and Swedish Research Council, In Blaivas JG, Chancellor MB eds, Atlas of 2235, an aldose reductase inhibitor, on grant no. 6837. Urodynamics. Chapter 15. Philadelphia: muscarinic receptors and contractile Williams & Wilkins, 1996: 183–91 response of the urinary bladder in rats 6 Goldstein I, Siroky MB, Krane RJ. with streptozotocin-induced diabetes. Jpn REFERENCES Impotence in diabetes mellitus. In Krane J Pharmacol 1997; 73: 221–8 RJ, Siroky MB, Goldstein I eds Male Sexual 19 Malmgren A, Andersson PO, Uvelius B. 1 Mokdad AH, Bowman BA, Ford ES, Dysfunction. Boston, MA: Little, Brown, Bladder function in rats with short- and Vinicor F, Marks JS, Koplan JP. The 1983: 77–86 long-term diabetes; effects of age and continuing epidemics of obesity and 7 Ellenberg M. Development of urinary muscarinic blockade. J Urol 1989; 142: diabetes in the United States. JAMA 2001; bladder dysfunction in diabetes mellitus. 1608–14 286: 1195–200 Ann Intern Med 1980; 92: 321 20 Tong YC, Cheng JT, Wan WC. Effects 2 Paro M, Prosdocimi M, Sima AA. 8 Frimodt-Moller C. Diabetic cystopathy I. of Ba-Wei-Die-Huang-Wan on the Gangliosides improve urinary bladder A clinical study on the frequency of cholinergic function and protein

dysfunction in experimental diabetic bladder dysfunction in diabetics. Dan Med expression of M2muscaranic receptor of autonomic neuropathy. Pharmacol Res Bull 1976; 23: 267–72 the urinary bladder in diabetic rats. 1990; 22: 125–6 9 Ueda T, Yoshimura N, Yoshida O. Neurosci Let 2002; 330: 21–4 3 Kidlacz EM, Gerald MC, Wallace JL. Diabetic cystopathy: Relationship to 21 Kubota Y, Nakahara T, Mitani A, Effects of diabetes and diuresis on autonomic neuropathy detected by Maruko T, Sakamoto K, Ishii K.

Y OSHIMURA ET AL.

Augmentation of rat urinary bladder streptozotocin-induced diabetic rats. Br J 36 Vlaskovska M, Kasakov L, Rong W et al.

relaxation mediated by a1-adrenoceptors Urol 1996; 77: 798–804 P2X3 knock-out mice reveal a major in experimental diabetes. European J 29 Poladia DP, Bauer JA. Early cell-specific sensory role for urothelially released ATP. Pharmacol 2003; 467: 191–5 changes in nitric oxide synthases, reactive J Neurosci 2001; 21: 5670–7 22 Longhurst PA, Kauer J, Levin RM. The nitrogen species formation, and 37 Birder LA, Nealen ML, Kiss S et al. Beta- ability of insulin treatment to reverse or ubiquitinylation during diabetes-related adrenoceptor agonists stimulate prevent the changes in urinary bladder bladder remodeling. Diabetes Metab Res endothelial nitric oxide synthase in rat function caused by streptozotocin- Rev 2003; 19: 313–9 urinary bladder urothelial cells. J Neurosci induced diabetes mellitus. General 30 Longhurst PA. Urinary bladder function 6 2002; 15: 8063–70 Pharmacol 1991; 22: 305–11 months after the onset of diabetes in the 38 Avelino A, Cruz C, Nagy I, Cruz F. 23 Waring JV, Wendt IR. Effects of spontaneously diabetic BB rat. J Urol Vanilloid receptor 1 expression in the rat streptozotocin-induced diabetes mellitus 1991; 145: 417–22 urinary tract. Neuroscience 2002; 109: on intracellular calcium and contraction 31 Apfel SC. Neurotrophic factors and 787–98 of longitudinal smooth muscle from diabetic peripheral neuropathy. Eur 39 Birder LA, Nakamura Y, Kiss S et al. rat urinary bladder. J Urol 2000; 163: Neurol 1999; 41 (Suppl): 27–34 Altered urinary bladder function in mice 323–30 32 Van Poppel H, Stessens R, Van Damme lacking the vanilloid receptor TRPV1. Nat 24 Tammela TL, Briscoe JA, Levin RM, B, Carton H, Baert L. Diabetic Neurosci 2002; 5: 856–60 Longhurst PA. Factors underlying the cystopathy. Neuropathological 40 Zenser TV, Thomasson DL, Davis BB. increased sensitivity to field stimulation examination of urinary bladder biopsy. Characteristics of bradykinin and TPA of urinary bladder strips from Eur Urol 1988; 15: 128–31 increases in the PGE2 levels of human streptozotocin-induced diabetic rats. Br J 33 Sasaki K, Chancellor MB, Phelan MW urothelial cells. Carcinogenesis 1988; 9: Pharmacol 1994; 113: 195–203 et al. Diabetic cystopathy correlates with 1173–7 25 Belis JA, Curley RM, Wagner CH, Murty long-term decrease in nerve growth 41 Geerlings SE, Meiland R, van Lith EC, VN, Winter SJ, Rohner TJ. Neurogenic factor (NGF) levels in the bladder and Brouwer EC, Gaastra W, Hoepelman AI. function of the diabetic rat bladder: lumbosacral dorsal root ganglia. J Urol Adherence of type 1-fimbriated alteration by calcium channel effectors. 2002; 168: 1259–64 Escherichia coli to uroepithelial cells: Pharmacology 1991; 43: 273–81 34 Goins WF, Yoshimura N, Phelan MW, more in diabetic women than in control 26 Bezuijen MWF, Levendusky MC, de Groat WC, Glorioso JC, Chancellor subjects. Diabetes Care 2002; 25: 1405–9 Longhurst PA. Functional response of MB. Herpes simplex virus mediated nerve bladder strips from streptozotocin growth factor expression in bladder and Correspondence: Michael B. Chancellor, 3471 diabetic rats depends on bladder mass. afferent neurons: Potential treatment for Fifth Avenue, Suite 700, Pittsburgh, PA 15213, J Urol 2003; 169: 2397–401 diabetic bladder dysfunction. J Urol 2001; USA. 27 Longhurst PA, Levendusky MC, 165: 1748–54 e-mail: [email protected] Bezuijen MW. Diabetes mellitus 35 Sasaki K, Chancellor MB, Goins WF et al. increases the rate of development of Gene therapy using replication defective Abbreviations: DM, diabetes mellitus; STZ, decompensation in rats with outlet herpes simplex virus (HSV) vectors streptozotocin; NGF, nerve growth factor; obstruction. J Urol 2004; 171: 933–7 expressing nerve growth factor (NGF) in a EFS, electrical field stimulation; NOS, nitric 28 Hashitani H, Suzuki H. Altered electrical rat model of diabetic cystopathy. Diabetes oxide synthase; DRG, dorsal root ganglia; properties of bladder smooth muscle in 2004; 53: 2723–30 HSV, herpes simplex virus.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2004 956 review Article MOLECULAR MARKERS IN BLADDER CANCER BUSCARINI et al.

Molecular prognostic factors in bladder cancer

MAURIZIO BUSCARINI, MARCUS L. QUEK, PARKASH GILL*, GUANGBIN XIA*, DAVID I. QUINN* and JOHN P. STEIN Departments of Urology and *Medical Oncology, Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA Accepted for publication 11 October 2004

KEYWORDS Mutations in the H-ras gene have been On chromosome 13, Rb gene mutations are implicated in the development and found in 25–30% of bladder tumours and loss bladder neoplasms, tumour markers, progression of human bladder cancer. of heterozygosity at the Rb locus (13q14) is transitional cell Alterations involving codons 12 and 61 of the associated with an absence of Rb protein ras oncogene have been found in up to 39% expression by immunohistochemical of bladder cancers [3]. A potential prognostic techniques. INTRODUCTION role for the cH-ras oncogene was suggested by Fontana et al. [4], where overexpression of On chromosome 17, a well-recognized Cancer cells are distinguished from normal the cH-ras oncogene was correlated with chromosomal alteration involves the tumour- cells by several hallmarks, including evasion of early recurrence in patients with superficial suppressor gene at 17p13 (p53). Olumi et al. apoptosis, self-sufficiency in growth bladder cancer. Complete loss of p53 is a [11] reported the high frequency of loss of signalling, insensitivity to antigrowth signals, prerequisite for collaborating with cH-ras to heterozygosity at chromosome 17p in high- sustained angiogenesis, limitless replicative promote bladder cancer [5]. grade TCC. Genetic defects in the p53 locus potential, propensity towards tissue invasion have been shown to correspond with protein and metastasis [1]. The molecular and genetic The HER2/neu oncogene encodes a expression of the mutated p53 gene product. changes in TCC of the bladder can be broadly transmembrane glycoprotein similar to classified into three interrelated processes: (i) epidermal growth factor (EGF) receptor, CELL-CYCLE REGULATORY PATHWAYS chromosomal alterations, triggering the initial having tyrosine kinase activity [6] and the carcinogenic event; (ii) tumour proliferation, ability to stimulate cellular growth. Several Tumour proliferation depends on the caused by loss of cell-cycle regulation and studies noted an association between derangement of normal cell-cycle progression derangements in normal apoptotic turnover; HER2/neu expression and higher stage and control. Cell cycle-associated protein and (iii) metastasis, in which the initial tumours [7], tumour progression, greater complexes composed of cyclins and cyclin- tumour spreads to distant sites, bringing into incidence of metastatic disease and reduced dependent kinases regulate normal cellular play processes such as angiogenesis and loss overall survival. proliferation [11]. As previously mentioned, of cellular adhesion. several tumour-suppressor genes and their protein products (p53, pRb, p27Kip1, p16INK4A The accumulation of these successive genetic TUMOUR-SUPPRESSOR GENES and p14ARF) act at the G0/G1 checkpoint of the alterations, rather than a single genetic event, cell cycle to prevent loss of cell-cycle control, determines a tumour’s phenotype and Deletions of chromosome 9 are the most and ultimately lead to tumour progression. ultimately the patient’s clinical outcome [2]. common chromosomal abnormalities Herein we summarize recent publications on associated with bladder cancer. Given that Gene alteration may occur by mutation, some of the more promising molecular deletions of chromosome 9 are found with deletion or methylation, but in most cases, markers for prognostication in bladder cancer both superficial and muscle-invasive disease, phenotypic expression requires the alteration and comment on potential clinical this alteration may represent an early event in of both gene copies. One gene copy may applications. the molecular pathogenesis of TCC [8]. Other be inherently altered, followed by an notable chromosomal deletions have been environmental mutagen, or both copies may be detected on chromosomes 13 (at the affected by two independent somatic events, THE CARCINOGENESIS OF retinoblastoma, Rb, gene) and 17 (at the p53 leading to expression of the altered gene BLADDER CANCER gene). product. One notable exception to this ‘two-hit’ model of carcinogenesis is the tumour- ONCOGENES Most chromosome 9 deletions involve the suppressor gene p53, in which alteration of 9p21 locus (INK4a/ARF and INK4b) which only one copy is sufficient to alter function. Oncogenes are normal cellular genes that can encodes for three distinct proteins, i.e. become altered by various genetic insults, p16INK4A, p14ARF and p15INK4B. Each of these TUMOUR-SUPPRESSOR GENES resulting in a malignant phenotype, either by proteins acts as a negative cell-cycle overexpression of the normal gene product or regulator, and they are therefore considered The interaction of several tumour-suppressor by expressing a protein product with altered potential tumour-suppressor genes. genes leads to alterations in cell-cycle function [1]. Oncogenes thought to be Chromosome 9 losses occur early in bladder regulatory pathways. The Rb gene, at 13q14, important in human bladder cancer include oncogenesis and before p53 alterations or encodes for a nuclear phosphoprotein that cH-ras and HER2/neu. development of aneusomy [9,10]. normally acts at the G1/S checkpoint to

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inhibit cell cycle progression. The interaction Not all p53 mutated bladder tumours recur or normal development and physiological repair, of the Rb-encoded protein with various cell- progress. Indeed, p53 mediates its effects on this event proceeds in a tightly regulated cycle regulatory proteins allows for normal the cell cycle through regulating p21WAF/Cip1 manner [20]. Neoplastic conditions also cellular proliferation, while alterations with expression [15]. Therefore, alterations in p53 require angiogenesis (neovascularization) to these protein interactions can subsequently may lead to loss of p21WAF/Cip1 expression and maintain their malignant growth and lead to uncontrolled cell growth. Functional subsequently unregulated cell growth. metastatic potential. Therefore, inhibiting reduction of Rb is associated with progression tumour angiogenesis may provide another of bladder cancer to a more malignant and Stein et al. [16] evaluated 101 patients with avenue for therapeutic benefit. aggressive behaviour [12]. Further evidence p53-altered tumours treated with radical for this was reported from studies by Cordon- cystectomy, and found that loss of p21WAF/Cip1 Under most homeostatic conditions Cardo et al. [13], in which loss of Rb expression was associated with higher angiogenesis is an infrequent process, immunoexpression was associated with recurrence rates and lower overall survival controlled by an abundant array of inhibitory significantly shorter survival in patients with than p21WAF/Cip1-positive tumours. While signals directed at the endothelium, thereby muscle-invasive bladder tumours. several other groups have subsequently tipping the balance towards neovascular questioned the prognostic value of p21WAF/Cip1 quiescence. Therefore, within a tumour’s The p53 gene, at 17p13, encodes for a protein expression, these findings suggest that microenvironment, the balance between vital to arresting the cell cycle [14]. When p21WAF/Cip1 expression through p53- various stimulatory and inhibitory inputs to DNA damage is detected, the level of p53 independent pathways may influence cell- the endothelial cells determines its ability to protein increases, leading to cell-cycle arrest. cycle control, and that tumours with both p53 induce angiogenesis, thus providing the This necessarily allows for DNA repair and alterations and loss of p21WAF/Cip1 expression necessary nutrients for continued growth and prevents propagation of DNA defects. appear to have a poorer prognosis. These eventual metastasis. Mutations in p53 result in the production of a patients may be candidates for more dysfunctional protein product with a longer aggressive adjuvant therapeutic regimens. Several mechanisms are thought to be half-life than the wild-type protein. Because involved in tumour angiogenesis, including of this difference in protein longevity, p53- Reduced expression of p27 Kip1 and cyclins D overexpression of various inducers and loss of mutated gene products accumulate in the cell and E correlates with increased grade, stage endogenous inhibitors [21]. These factors may nucleus and can be easily detected by and mortality in bladder cancer [17]. Several be produced by the tumour cells themselves immunohistochemical methods. groups have reported data suggesting that or released from the surrounding extracellular low p27 expression with or without low cyclin matrix and tumour-associated stromal cells, Esrig et al. [15] evaluated p53 nuclear E expression is adversely prognostic in bladder or they may be products of the host immunoreactivity in 243 patients with cancer [18]. Decreased p27Kip1 expression is inflammatory cells that infiltrate the tumour. invasive bladder cancer treated uniformly prognostic in several cancers, including with radical cystectomy. Altered p53 breast, prostate and nonsmall cell lung cancer, MICROVESSEL DENSITY expression was associated with a significantly and is usually associated with increased cyclin greater risk of disease recurrence and reduced E expression. Juan and Cordon-Cardo [19] Given the role of angiogenesis in tumour overall survival than in patients with wild- recently described disruption of the growth and spread, one concept that may type p53 expression, and nuclear nucleoplasm-nucleolar shuttling of cyclin E in provide prognostic information is the accumulation of p53 was found to be an bladder cancer cell lines, suggesting that ‘microvessel density’ within and around a independent predictor of disease progression. altered intranuclear localization of cyclin E given tumour. By measuring antibodies to A prospective randomized multi-institutional rather than overexpression may be a factor VIII and CD34 that recognize immature trial is currently underway to determine the distinguishing feature of progressive bladder or new vascular endothelial cells, it is possible impact of chemotherapy in organ-confined cancer. Overexpression of a low molecular to quantify the degree of angiogenesis taking bladder cancer based on p53 status. weight cyclin E was recently reported to be a place. Microvessel density counts have been major prognostic factor in breast cancer. correlated with bladder cancer progression Given the apparent prognostic value of absent Interestingly, loss of p27Kip1 expression in and overall survival [22]. Rb expression and p53 nuclear accumulation superficial bladder cancer correlates with in bladder cancer, two independent studies disease recurrence and invasion, as does low ANGIOGENIC INDUCERS sought to determine whether combining expression of cyclin D1. Patients with low these two markers could better stratify cyclin D1, low p27Kip1 and a high proliferative Several human cancers have high levels of patients with bladder cancer. Indeed, tumours index measured by Ki67 expression had an growth factors and their receptors that can with alterations in both p53 and Rb are extremely high rate of recurrence. be used as potential therapeutic targets. associated with a poorer prognosis than Urothelial tumours overexpress tyrosine tumours with normal wild-type p53 and Rb kinase receptors such as the receptors for EGF genes. Tumours with alterations in only one of ANGIOGENESIS AND LOSS OF (ErbB-1), vascular endothelial growth factor these genes behaved in an intermediate CELL ADHESION (VEGF) and Her2/neu (ErbB-2). Systemic fashion. These studies suggest an administration of inhibitors blocks the growth independent, yet synergistic role for both p53 Angiogenesis is the process by which new of bladder cancer and enhances the activity of and Rb expression in the progression of blood vessels are formed from the conventional chemotherapy. Several trials bladder cancer. surrounding established vasculature. During are now ongoing, testing agents such as

MOLECULAR MARKERS IN BLADDER CANCER

herceptin (anti-HER2), IMC225 cetuximab, ZD EXTRACELLULAR MATRIX AND METASTASIS expression of a myriad genes in multiple 1389 Iressa and OSI-774 Tacerva (EGF tissue sites simultaneously, with linkage to receptor inhibitors). The extracellular matrix provides the outcome data and other clinical variables, scaffolding for endothelial attachment and promises to deliver a new level of VEGF is present in higher concentrations in subsequent capillary formation. Bladder prognostication and prediction for several the urine of patients with bladder cancer than cancer cells have been shown to induce the cancers. Molecular techniques will continue in controls, and VEGF levels are correlated production of the angiogenesis-inducer to develop and clinical trials testing the with tumour recurrence in patients with Ta scatter factor by the underlying stromal cells. strongest candidate markers will be necessary and T1 disease [23]. Williams et al. [24] also Matrix metalloproteinases (MMPs) are also to bring this understanding of the basic reported higher levels of VEGF in the urine of intimately involved in tumour-associated science of tumour biology to clinical decision- patients with high-grade and/or muscle- degradation of the extracellular matrix. Two making and patient care. invasive TCC than in those with prostate of these factors, MMP-2 and MMP-9, are cancer or no malignancy. In those patients elevated in the serum and urine of patients undergoing radical cystectomy, higher with muscle-invasive TCC, and correlate with CONFLICT OF INTEREST preoperative urinary VEGF was associated decreased disease-free survival. MMP-9 with a lower 3-year survival. In a series of expression was also higher in TCC than in None declared. Source of funding: American patients with locally advanced bladder cancer normal urothelium, and directly related to Italian Cancer Foundation. and undergoing cystectomy, expression of increasing tumour stage [29]. VEGF and E-cadherin was strongly related to disease-specific survival. CD44 is a widely expressed cell-surface REFERENCES adhesion molecule involved in cell–cell and Increased cyclooxygenase-2 (COX-2) cell–matrix interactions, as well as signal 1 Hanahan D, Weinberg RA. The hallmarks expression has been the focus of considerable transduction through ras in response to of cancer. Cell 2000; 100: 57–70 interest as a prognostic marker, because of hyaluronic acid. Expression of CD44 is 2 Al-Sukhun S, Hussain M. Current the potential to specifically target this pro- increased in superficial TCC, with a decrease in understanding of the biology of advanced angiogenic molecule with inhibitors [25,26]. expression at the time of muscle invasion. bladder cancer. Cancer 2003; 97: 2064– Recent experimental work suggests that COX- Recent data suggest that CD44 status is 75 2 may reduce the cytotoxic effects of prognostic in urothelial cancer [30]. 3 Buyuro N, Tigli H, Ozcan F, Dalay N. Ras chemotherapy. High expression of COX-2 is oncogene mutations in urine sediments associated with shorter survival in patients of patients with bladder cancer. J Biochem receiving chemotherapy after cystectomy. CONCLUSIONS Mol Biol 2003; 36: 399–402 Trials of COX-2 inhibitors as preventative and 4 Fontana D, Bellina M, Scoffone C et al. therapeutic agents in bladder and other The translational application of molecular Evaluation of c-ras oncogene product cancers are ongoing [27]. markers for bladder cancer prognostication (p21) in superficial bladder cancer. Eur continues to develop. A tumour’s ability to Urol 1996; 29: 470–6 ANGIOGENIC INHIBITORS grow, invade and spread depends on a 5 Gao J, Huang HY, Pak J et al. p53 multitude of complex interactions that are deficiency provokes urothelial Although several endogenous inhibitors of only now being slowly elucidated at the proliferation and synergy with activated angiogenesis exist, thrombospondin-1 (TSP-1) molecular level. It is unlikely that a single Ha-ras in promoting urothelial has been examined most in human bladder molecular marker will provide adequate tumorigenesis. Oncogene 2004; 23: 687– cancer. It was shown that normal urothelial insight into a tumour’s biological potential. 96 cells contain high levels of TSP-1, and that The ultimate application of tumour markers 6 Akiyama T, Sudo C, Ogawara H, angiogenesis, induced by VEGF and basic may involve the evaluation of numerous Toyoshima K, Yamamoto T. The product fibroblast growth factor could be inhibited by molecular endpoints in a ‘test battery’ of the human c-erbB-2 gene: a 185- TSP-1, then again reversed by a neutralizing approach. This strategy may provide a more kilodalton glycoprotein with tyrosine antibody. accurate assessment of a tumour’s kinase activity. Science 1986; 232: 1644– phenotype, including responsiveness to both 6 Grossfeld et al. [28] reported that low TSP-1 surgical and medical therapeutics. 7 Sato K, Moriyama M, Mori S et al. An expression was associated with higher immunohistologic evaluation of C-erbB-2 recurrence rates and shorter overall survival Currently, the conventional histopathological gene product in patients with urinary in patients with invasive bladder cancer. This assessment of grade and stage allows for only bladder carcinoma. Cancer 1992; 70: correlation was strongest in patients with a gross stratification of clinical outcomes for 2493 organ-confined disease. In addition, TSP-1 patients with bladder cancer. Despite 8 Cairns P, Shaw ME, Knowles MA. expression was an independent predictor of significant research in the molecular Initiation of bladder cancer may involve disease recurrence and overall survival in understanding of neoplasia, the promise of deletion of a tumour-suppressor gene on multivariate analyses. In this same cohort accurate predictions of tumour behaviour chromosome 9. Oncogene 1993; 8: 1083– of patients, tumours with low TSP-1 based on molecular markers is yet to be 5 expression had higher microvessel density realized. The recent development of 9 Ruas M, Peters G. The p16INK4a/CDKN2A counts [28]. techniques to interrogate tumours for the tumor suppressor and its relatives.

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Biochim Biophys Acta 1998; 1378: F115– 18 Kamai T, Takagi K, Asami H, Ito Y, Sakakura C. Relation between 77 Oshima H, Yoshida KI. Decreasing of p27 cyclooxygenase-2 expression and tumor 10 Dominguez G, Carballido J, Silva J et al. (Kip1) and cyclin E protein levels is invasiveness and patient survival in p14ARF promoter hypermethylation in associated with progression from transitional cell carcinoma of the urinary plasma DNA as an indicator of disease superficial into invasive bladder cancer. bladder. Cancer 2001; 92: 188–93 recurrence in bladder cancer patients. Clin Br J Cancer 2001; 84: 1242–51 27 Thun MJ, Henley SJ, Patrono C. Cancer Res 2002; 8: 980–5 19 Juan G, Cordon-Cardo C. Intranuclear Nonsteroidal anti-inflammatory drugs 11 Markl I, Salem CE, Jones PA. Molecular compartmentalization of cyclin E during as anticancer agents. mechanistic, biology of bladder cancer. In Vogelzang N, the cell cycle: disruption of the pharmacologic, and clinical issues. J Natl Scardino PT, Shipley WU eds nucleoplasm-nucleolar shuttling of cyclin Cancer Inst 2002; 94: 252–66 Comprehensive Textbook of Genitourinary E in bladder cancer. Cancer Res 2001; 61: 28 Grossfeld GD, Ginsberg DA, Stein JP Oncology. Philadelphia: Lippincott 1220–6 et al. Thrombospondin-1 expression in Williams & Wilkins, 2000: 298–309 20 Folkman J. Angiogenesis in cancer, bladder cancer. association with p53 12 Quentin T, Hencke C, Korabiwska M, vascular, rheumatoid and other disease. alterations, tumor angiogenesis, and Schlott T, Zimmerman B, Kunze E. Nat Med 1995; 1: 27–31 tumor progression. J Natl Cancer Inst Altered mRNA expression of the Rb and 21 Volpert OV, Dameron KM, Bouck N. 1997; 89: 219–27 p16 tumor suppressor genes and of CDK4 Sequential development of an angiogenic 29 Gohji K, Fujimoto N, Ohkawa J, Fujii A, in transitional cell carcinomas of the phenotype by human fibroblasts Nakajima M. Imbalance between serum urinary bladder associated with tumor progressing to tumorigenicity. Oncogene matrix metalloproteinase-2 and its progression. Anticancer Res 2004; 24: 1997; 14: 1495–502 inhibitor as a predictor of recurrence of 1011–23 22 Bochner BH, Cote RJ, Weidner N et al. urothelial cancer. Br J Cancer 1998; 77: 13 Cordon-Cardo C. Mutations of cell cycle Angiogenesis in bladder cancer. 650–5 regulators. Biological and clinical relationship between microvessel density 30 Miyake H, Eto H, Arakawa S, Kamidono implications for human neoplasia. Am J and tumor prognosis. J Natl Cancer Inst S, Hara I. Over expression of CD44V8–10 Pathol 1995; 147: 545–60 1995; 87: 1603–12 in urinary exfoliated cells as an 14 Agarwal ML, Taylor WR, Chernov MV, 23 Crew JP, O’Brien T, Bicknell R, Fuggle S, independent prognostic predictor in Chernova OB, Stark GR. The p53 Cranston D, Harris AL. Urinary vascular patients with urothelial cancer. J Urol network. J Biol Chem 1998; 273: 1–4 endothelial growth factor and its 2002; 167: 1282–7 15 Esrig D, Elmajian D, Groshen S et al. correlation with bladder cancer Accumulation of nuclear p53 and tumor recurrence rates. J Urol 1999; 161: 799– Correspondence: John P. Stein, Department of progression in bladder cancer. N Engl J 804 Urology MS#74, University of Southern Med 1994; 331: 1259–64 24 Williams SG, Feng A, Skinner DG. Urine California Keck School of Medicine, Kenneth 16 Stein JP, Ginsberg DA, Grossfeld GD levels of vascular endothelial growth Norris Jr. Comprehensive Cancer Center, 1441 et al. Effect of p21WAF1/CIP1 expression factor and its correlation with bladder Eastlake Avenue, Suite 7414, Los Angeles, on tumor progression in bladder cancer. cancer recurrence rates. J Urol 2000; 162: California 90089, USA. J Natl Cancer Inst 1998; 90: 1072–9 133 e-mail: [email protected] 17 Del Pizzo JJ, Borkowski A, Jacobs SC, 25 Kim SI, Kwon SM, Kim YS, Hong SJ. Kyprianou N. Loss of cell cycle regulators Association of cyclooxygenase-2 Abbreviations: EGF, epidermal growth factor; p27 (Kip1) and cyclin E in transitional cell expression with prognosis of stage T1 Rb, retinoblastoma (gene); VEGF, vascular carcinoma of the bladder correlates with grade 3 bladder cancer. Urology 2002; 60: endothelial growth factor; COX-2, tumor grade and patient survival. Am J 816–21 cyclooxygenase-2; TSP-1, thrombospondin- Pathol 1999; 155: 1129–36 26 Shirahama T, Arima J, Akiba S, 1; MMP, matrix metalloproteinase.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Review Article PHARMACOLOGICAL CLASS EFFECT IN MANAGING PROSTATIC DISEASES EVANS et al.

An evidence-based approach to understanding the pharmacological class effect in the management of prostatic diseases

CHRISTOPHER P. EVANS, NEIL FLESHNER*, JOHN M. FITZPATRICK† and ALEXANDER R. ZLOTTA‡ University of California, Sacramento, CA, USA, *Princess Margaret Hospital, Toronto, Canada; †Mater Hospital and Conway Institute, University College, Dublin, Ireland and ‡University Clinics of Brussels, Erasme Hospital, Brussels, Belgium Accepted for publication 5 December 2004

KEYWORDS reviews or meta-analyses of well-designed Questions have been raised as to whether randomized controlled trials (RCTs), followed study sponsorship may also introduce bias evidence-based medicine, class effect, benign by individual RCTs and well-designed non- and there are concerns that the process of prostatic hyperplasia, prostate cancer randomized studies are considered the most publication itself can lead to bias in favour of robust, reliable and therefore valuable [3]. Less positive results. robust evidence from case reports, clinical INTRODUCTION examples, or consensus meetings may also be Although many clinical trials are conducted considered. ‘blind’ to minimize observer bias, this is not Ever more alternative products are available always a realistic option. For example, in for each drug type commonly used to treat Systematic reviews integrate otherwise prostate cancer trials, it would not be prostatic diseases, i.e. a-blockers, 5a- unmanageable amounts of information from reasonable to carry out sham orchidectomy or reductase inhibitors, antiandrogens and LHRH primary investigations in a way that limits radiotherapy, and characteristic treatment agonists. Once a urologist has decided which bias and random error; meta-analyses allow effects, such as hot flushes with LHRH type of drug to use, their decision about an evaluation of consistency of findings and, agonists, can effectively ‘un-blind’ a study. which specific agent to prescribe will depend if quantitative, may increase the accuracy The more patients in a trial, the more on several factors, including dosing regimen, of estimates of treatment effects [4]. As accurately the size of a clinical effect can be delivery mechanism, speed of onset, such, both should be useful tools in clinical assessed and the less likely the result is to be treatment costs, local prescribing habits, decision-making. However, systematic a result of random chance. The amount of marketing, patient choice, personal reviews and meta-analyses are not always information needed to avoid an incorrect experience and published reports. Ideally, possible. For trials to be combined in a conclusion depends on the size of the effect evidence-based medicine (EBM) should be the systematic review or meta-analysis, there being studied and the level of certainty main factor in treatment choice. This review needs to be a sufficient number of similar required. To be valid, a trial must be of an sets out the principles of EBM and examines studies, i.e. with analogous study designs appropriate design to answer the question the best available evidence for drugs that are in patients with similar disease states and addressed; validity is based on criteria such as commonly prescribed to treat BPH or prostate assessing comparable clinically relevant use of clinically important outcomes and cancer. We consider whether a class effect can outcomes. duration of intervention and observation. be shown for any of these groups of drugs and if class effects should be accepted in Whether trials are combined in a systematic clinical practice. We focus on efficacy, but review or meta-analysis, or examined for their IS THE CLASS EFFECT EVIDENCE-BASED? tolerability can also be an important factor individual merit, their design, endpoints and when choosing between drugs of the same reporting quality need careful examination Drugs are generally considered to be in the class, and will be discussed where relevant. to determine the most appropriate and same class if they have a similar chemical robust data. Trials must be of a high quality structure and mechanism of action, and if to avoid bias, sufficiently large enough to give they confer similar pharmacological effects. PRINCIPLES OF EBM a reliable answer, of good validity, and the However, compounds with very similar population studied should allow the results to structures can have different properties. EBM has been described as the ‘conscientious, be clinically applicable. For example, dihydrotestosterone differs from explicit and judicious use of current best testosterone by only one hydrogen atom, evidence in making decisions about the care One of the most important factors is but has a much greater binding affinity for of individual patients’ [1]. For the clinician, randomization to exclude selection bias; it has the androgen receptor, resulting in different this means identifying the best available been estimated that not randomizing can lead effects on gene expression. Consequently, the evidence from a vast number of published to an overestimation of treatment effect by notion of a pharmacological ‘class effect’ medical reports, assessing whether it is 40% [5]. Other factors (and their percentage should be considered with caution. Indeed, applicable to the individual patient and then overestimation) include small trials (30%), there is no universally accepted definition. using it in clinical practice [2]. Of the types of poor reporting quality (25%), duplicate A class effect is usually taken to mean that published evidence available, systematic reporting (20%), and lack of blinding (17%). drugs in a class have similar therapeutic

EVANS ET AL.

effects and similar safety and tolerability, includes tamsulosin, terazosin, alfuzosin, compared and no definitive conclusions can both in nature and extent [3]. If such a class doxazosin and prazosin, which have different currently be drawn about any differences effect exists, it would be likely that the least selectivity for the a1-adrenoceptor subtypes. between them. While dutasteride is said to costly agent in each class would be the first Systematic reviews have been published for inhibit serum 5a-reductase to a greater choice. However, it is clear that no matter how tamsulosin and terazosin, and a pooled extent than finasteride, the significance of strong the pathophysiological rationale or analysis for alfuzosin (Table 1) [6–8]. These this may be limited, as it is prostatic stromal indirect evidence, the efficacy and safety of a reports, in agreement with an earlier meta- intracellular 5a-reductase that mediates gene new drug must be established in clinical analysis by Djavan and Marberger [9], transcription for growth factor genes. outcome studies, and the equivalency of conclude that the a-blockers are effective Therefore, although the data support the untested drugs even in a well-established and consistently improve LUTS and urinary efficacy of both finasteride and dutasteride in ‘class’ should be considered unconfirmed. flow compared with placebo. BPH, there is as yet insufficient evidence to address the question of whether a class effect For some products routinely used in prostate a-Blockers have been directly compared in a exists for the 5a-reductase inhibitors. medicine, comparative data are limited, but few small trials (involving 50–256 patients) prescription is still widespread based on the [9–12]. A review of trials directly comparing a-BLOCKERS COMBINED WITH assumption of a class effect. To take an tamsulosin with terazosin found that these 5a-REDUCTASE INHIBITORS evidence-based approach to establishing a agents are equally effective in improving class effect, RCTs of direct comparisons of symptoms [7,8]. No definitive conclusions The long-term efficacy of the a-blocker drugs within the class are needed [3]. about differences in efficacy can be made doxazosin and the 5a-reductase inhibitor However, this level of evidence is rarely from these studies; all a-blockers, whether finasteride, as monotherapy or combined, was available. selective or not, seem to have similar efficacy evaluated in a randomized, long-term, in short-term trials [9]. The data suggest that double-blind placebo-controlled trial [15]. The next best level of evidence includes a1-blockers, such as terazosin or doxazosin, While each agent reduced the risk of overall indirect comparisons across two or more give similar improvements as subtype- clinical progression, combined therapy was placebo-controlled trials. In this case, only selective a1a-blockers, like tamsulosin, in peak significantly more effective than either proportional effects such as the relative risk urinary flow rates and symptom scores after monotherapy. This trial was of excellent reduction can be compared. A class effect is 4 weeks of treatment. From these studies it design, yet raises several interesting issues considered to be present when drugs with might be concluded, on the basis of efficacy, about the class effect. For example, is it similar mechanisms of action generate that there possibly is a class effect. However, appropriate to extrapolate the role of relative risk reductions (or odds ratios) that there are differences in tolerability, with doxazosin to other a-blockers? The trial are similar in direction and magnitude [3]. tamsulosin better tolerated than doxazosin, was designed for an intent-to-treat analysis, However, such comparisons are less useful in prazosin and terazosin, as measured by which in theory mimics ‘real-world clinical determining whether one drug is more withdrawals from treatment [9]. These may be medicine’, but 27% of patients in the effective than another, because the related to different pharmacokinetic doxazosin arm could not tolerate even comparison is between different cohorts of properties and adrenoceptor subtype 4 mg and were withdrawn from therapy. patients and the advantages of randomization selectivity, and contradict the concept of a In clinical practice these patients would are lost [3]. Decisions about the level of class effect. probably have been switched to an a1a- evidence necessary to establish a class effect subtype-selective drug such as tamsulosin. are, necessarily, individual choices, which take 5a-REDUCTASE INHIBITORS Examining the number of side-effects that into account local circumstances and occurred statistically significantly more often personal comfort levels [3]. For the last decade, finasteride, which acts on than with placebo, there were five with the type-2 isoenzyme of 5a-reductase, has doxazosin, three with finasteride and nine been the only available 5a-reductase with combined therapy. However, only 18% BPH inhibitor. A recent systematic review of of patients in the combined arm discontinued finasteride included 19 placebo-controlled treatment. Potential explanations for this In BPH, relief from symptoms is the key aim, trials of 3–48 months’ duration (14 729 include the possibility that the better efficacy with medical therapy being the first-line patients) [13]. The studies were of high resulted in patients tolerating an increase in treatment for most men with symptomatic quality, most were ≥ 1 year in duration, and side-effects, or it may have been the case that BPH. The two drug classes commonly used are most of the larger trials showed benefits in patients had to discontinue both drugs to be a-blockers and 5a-reductase inhibitors, symptom score, maximum urinary flow rate counted as ‘off treatment’. Thus, the intent- which aim to reduce LUTS by decreasing and prostate volume for finasteride over to-treat concept, drug tolerability and smooth muscle tone in the prostate and placebo (P < 0.01; Table 1) [13,14]. definition of discontinuation are potentially bladder, or by reducing prostate size, contributing to the outcomes reported. respectively. Dutasteride, which inhibits both isoenzymes Assuming a class effect, a clinician may of 5a-reductase, was launched in the USA in deduce that tamsulosin, with lower a-BLOCKERS 2003. The results of three large, double-blind discontinuation rates than doxazosin, RCTs of dutasteride including 4325 men were would be better for combined therapy. This The a-blockers are the most frequently used recently reported (Table 1) [14]. Dutasteride reasoning, while deductive, is not actually prescription medication for BPH; the class and finasteride have not been formally evidence-based.

PHARMACOLOGICAL CLASS EFFECT IN MANAGING PROSTATIC DISEASES

TABLE 1 Systematic reviews and pooled analyses of a-blockers and 5a-reductase inhibitors in the treatment of patients with LUTS suggestive of BPH

Ref Treatment(s) Study (N men) Duration of study Efficacy a-blockers [8] Tamsulosin vs placebo SR including 6 RCTs (2758) 6–17 weeks USS significantly improved vs placebo in 5/6 studies: % decreases in USS 20–48% for tamsulosin vs 18–28% for placebo. Significant improvement in peak urine flow in 5/6 studies: mean change 1.2–4 mL/s for tamsulosin and -0.1–1.4 mL/s for placebo [7] Terazosin vs placebo SR including 10 RCTs (3941) 8–52 weeks USS significantly improved vs placebo in 6/10 studies: % decreases in USS 31–69% for terazosin vs 10–58% for placebo. Significant improvement in peak urine flow in 8/9 studies: mean improvement 2.2 mL/s for terazosin and 1.1 mL/s for placebo [6] Alfuzosin vs PA including 11 RCTs (1470) 1–6 months Significant reduction in PVR: at 6 months, 36.8 mL (28%) placebo for alfuzosin vs 22.6 mL (16%) for placebo (P = 0.01) [7,8] Tamsulosin vs SR including 4 trials 4–9 weeks Mean IPSS improvement from baseline 41% for tamsulosin terazosin (492) vs 40% for terazosin. Peak urine flow increased by 29% for tamsulosin vs 25% for terazosin [9] Alfuzosin, terazosin, Meta-analysis of data from 21 1–12 months Total USS improved 30–40% and maximum urinary flow doxazosin, placebo-controlled studies and rate by 16–25% with a-blocker treatment. No efficacy tamsulosin 4 comparative studies comparisons between the different agents 5a-reductase inhibitors [13] Finasteride vs placebo SR including 19 RCTs (14 729) 3–48 months Most large trials* showed that finasteride was better than placebo for USS (3.7 points less for finasteride vs 2.3 for placebo at 1 year), maximum urinary flow rate (+1.3 mL/s finasteride vs 0.8 mL/s placebo at 2 years) and prostate volume (25% less for finasteride vs 4% less for placebo at 2 years) [14] Dutasteride vs placebo Combined results of three 24 months Statistically significantly better vs placebo at 2 years in: USS double-blind RCTs of identical (4.5 points less for dutasteride vs 2.3 for placebo, design (4325) P < 0.001); maximum urinary flow (+2.2 mL/s dutasteride vs 0.6 mL/s placebo, P < 0.001); and prostate volume (26% less dutasteride vs 2% more placebo, P < 0.001)

SR, systematic review; USS, urinary symptom score; PA, pooled analysis; PVR, postvoid residual; IPSS, International Prostate Symptom Score; *Except a study that included men with small prostates.

PROSTATE CANCER LHRH AGONISTS rate showed a small difference favouring triptorelin (97.0% vs 90.5%, P = 0.033), but a Survival is recognized as a key endpoint in There have been few direct comparisons of longer follow-up is required. This study trials of anticancer agents, and in contrast to LHRH agonists, and from which no definitive highlights that similar levels of testosterone endpoints in trials in other fields, differences in conclusions can be made. One randomized suppression do not necessarily indicate outcome of just 2–3% may be of considerable study of reasonable size (≥40 patients per similar levels of clinical efficacy, and that use clinical importance. However, detecting arm) was conducted, comparing the efficacy, of castrate levels of testosterone as a statistically significant differences at this level safety and testosterone pharmacodynamics surrogate marker for survival may not be requires clinical trials involving many patients of 1-month formulations of triptorelin appropriate. A further point is that the and, commonly, studies are not powered well (3.75 mg) and leuprorelin (7.5 mg) [16]. Men monthly dose of leuprorelin licensed for use enough to detect such small differences. In the with advanced prostate cancer (stage C or D) in most countries is 3.75 mg, in contrast to case of a highly prevalent disease such as in the intent-to-treat population received the dose of 7.5 mg used in that study; prostate cancer, differences in the 2–3% range either triptorelin (137 men) or leuprorelin therefore, conclusions made on the basis of can result in a large gain in life across the (140 men) for 9 months. Triptorelin induced that study may not reflect true clinical population. If such differences are observed castrate levels of testosterone at a slower rate practice in many parts of the world. between agents within the same class this than leuprorelin, but maintained castration as could be sufficient to suggest that a class effectively [16]. There was no evidence that As there are few direct comparative data, effect should not be assumed, but that agents the slower onset of castration with triptorelin indirect evidence from RCTs comparing should be assessed on individual merits. was deleterious, indeed the 9-month survival the various LHRH agonists with other

EVANS ET AL.

TABLE 2 RCTs comparing LHRH agonists vs orchidectomy or DES or CPA in the treatment of prostate cancer

N men randomized, vs orchidectomy or LHRH agonist Follow-up, Ref LHRH agonist other dosing interval years Survival, % (P) vs orchidectomy [17] Goserelin 148 vs 144 Monthly 2 (median) 42 vs 36 (NS, 0.23) [18] 138 vs 145 Monthly 4 (minimum) 29 vs 33 (NS, 0.42) [19] Buserelin 113 vs 118 vs plus CPA 111 Daily 5.7 (median) 13 vs 10 vs 14 (NS, not available) [20] 72 vs 46 vs oestrogens 22 Daily 1 (NS, 0.40) [21] Triptorelin 55 vs 49 Monthly 2 Mean 16 vs 13 months (P not given) Leuprorelin No comparative studies vs DES [27] Goserelin 124 vs DES 126 Monthly >3 32 vs 36 (0.88) [22] Buserelin 111 vs DES/orch 56 or MTX + DES/orch (98) Daily >2 No difference among groups by log-rank analysis [23] 105 vs DES 41/orch 14 Daily >2 No difference among groups by log-rank analysis [25] Leuprorelin* 92 vs DES 94 Daily 1 87 vs 78 (0.17) Triptorelin No comparative studies vs DES vs CPA [26] Goserelin 175 vs CPA 175 Monthly 4 (maximum) Not reported. Median TTP (days) 346 vs 225 (0.016) [24] 152 vs CPA 71 Monthly 2 Median 132 vs 130 weeks (NS) Buserelin No comparative studies with CPA Triptorelin Leuprorelin

*The dose was 1.0 mg daily, compared with the currently licensed doses of 3.75 mg or 7.5 mg per month. NS, not signiﬁcant; MTX, methotrexate; orch, orchidectomy; TTP, time to progression.

treatments need to be considered. Historically, with orchidectomy or DES, the overall hazard RCTs of adjuvant hormonal therapy after orchidectomy has been the ‘gold standard’, ratio (HR) for survival with LHRH agonists radiotherapy or radical prostatectomy with the synthetic oestrogen diethylstilbestrol relative to orchidectomy suggested that (Table 3) [29–35]. Adjuvant hormonal therapy (DES) and the steroidal antiandrogen LHRH agonists are essentially equivalent with goserelin significantly improved survival cyproterone acetate (CPA) providing to orchidectomy in terms of survival [4]. in the radiotherapy setting and in node- treatment alternatives. Although DES and CPA Although none of these trials directly positive men after radical prostatectomy, have not become well established treatments compared the three LHRH agonists, indirect and this is good evidence on which to base because of tolerability problems and a lack of comparison of seven goserelin studies (1137 treatment decisions. However, the optimum benefit in terms of overall survival, LHRH men), four buserelin studies (308 men), and timing and duration of therapy remain to be agonists have been compared with all three of one leuprorelin study (94 men) found that clarified. these treatments in RCTs. Studies that HRs for survival with the individual agents compare LHRH agonists with orchidectomy relative to orchidectomy were similar. are shown in Table 2 [17–21]; in each there Neoadjuvant therapy was no significant survival difference Adjuvant therapy between treatments. The rationale for neoadjuvant hormonal There have been no systematic reviews of therapy is to directly improve outcomes or RCTs with ≥40 patients per arm that LHRH agonists as adjuvant therapy. A recent enhance the primary therapy, e.g. by reducing compared LHRH agonists with DES or CPA are analysis of published studies suggested that the dose of radiation or field size, thereby also shown in Table 2 [22–27]. In comparisons differences in drug regimen, duration and minimizing the adverse effects of radiation. with DES, none of the studies showed a timing of treatment in trials of adjuvant or The only randomized study of an LHRH significant survival difference between neoadjuvant LHRH agonist therapy mean that agonist neoadjuvant to radiotherapy is treatments. Studies of LHRH agonists vs CPA pooling these trials for meta-analysis would with goserelin, which, combined with have only been conducted with goserelin and, not be possible [28]. However, in individual flutamide, was associated with a significant while no survival data were reported, Thorpe studies one LHRH agonist, goserelin, has improvement in overall survival compared et al. [26] reported a benefit in time to shown a consistent benefit in terms of with radiotherapy alone [36] (Table 3). progression favouring goserelin over CPA delaying progression and improving survival, Comparison of hormonal therapy (goserelin (P = 0.016; Table 2). as summarized below. plus flutamide) neoadjuvant or adjuvant to radiotherapy, found no significant difference In a meta-analysis that included 12 trials Goserelin is the only LHRH agonist studied as in progression-free or overall survival [37] comparing LHRH agonist monotherapy monotherapy in large (≥40 patients per arm) (Table 3). Although neoadjuvant hormonal

PHARMACOLOGICAL CLASS EFFECT IN MANAGING PROSTATIC DISEASES

TABLE 3 RCTs of adjuvant and neoadjuvant treatment with LHRH agonists in the treatment of prostate cancer

Median follow-up, Ref LHRH agonist, study Treatment (N patients randomized) years Survival, % (P) Adjuvant [29,31] Goserelin, EORTC 22863 RT + goserelin 3 years (207) vs RT alone + 5.5 5-year, 78 vs 62 (<0.001) goserelin after relapse (208) [32] Goserelin, RTOG 85–31 RT plus goserelin (488) vs RT alone + goserelin 7.3 10-year, 53 vs 38 (<0.0043) after relapse (489) [33] Goserelin, RTOG 92–02 Flutamide + goserelin for 2 months before and 5.8 5-year, 80 vs 79 (NS, 0.73) For patients with for 2 months during RT then randomized to Gleason score of 8–10 (337), 5-year survival 2 years of goserelin (753) or no further was 81 vs 71 (0.044) treatment (761) [34,35] Goserelin, ECOG 7887/ RP + immediate goserelin or orchidectomy (47) 10 10-year, 72 vs 49 (0.025) EST3886 or RP alone (51)* [30] Goserelin/leuprorelin RT + flutamide and either goserelin (10) or 4.5 5-year, 88 vs 78 ( 0.04) leuprorelin (88) for 6 months vs RT alone (104) Buserelin No comparative studies Triptorelin Neoadjuvant [36] Goserelin, RTOG 86–10 Goserelin + flutamide 2 months before 6.7 At 8 years, statistically significant and during RT (226) vs RT alone (230) improvement in local control (42 vs 30) (0.016), reduction in the incidence of distant metastases (34 vs 45) (0.04), PFS (33 vs 21) (0.004), PSA PFS (24 vs 10) (<0.001) and prostate cancer mortality (23 vs 31) (0.05) [37] Goserelin, RTOG 94–13 1295 randomized to 4 treatment arms: 5 No significant difference in 4-year PFS or neoadjuvant goserelin + flutamide for overall survival in patients treated with 2 months before and during RT (whole pelvis neoadjuvant vs adjuvant therapy [Arm 1] or prostate only [Arm 2]) or adjuvant goserelin + flutamide for 4 months after RT (whole pelvis [Arm 3] or prostate only [Arm 4])

*An additional two patients were randomized but found to be ineligible. EORTC, European Organization for the Research and Treatment of Cancer; ECOG, Eastern Cooperative Oncology Group; NS, not signiﬁcant; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group; RP, radical prostatectomy; PFS, progression-free survival; PSA, prostate-speciﬁc antigen.

therapy with radical prostatectomy ANTIANDROGENS draw conclusions about any class effect. significantly decreases the positive margin Similarly, to date, no comparative rate, randomized studies have shown no Steroidal and nonsteroidal antiandrogens monotherapy trials of nonsteroidal improvement in overall survival [38]. are not members of the same class. These antiandrogens have been conducted. In the two groups of agents differ in structure absence of direct comparative data, there are and mechanism of action. Steroidal too few RCTs relating to antiandrogen Summary: LHRH agonists antiandrogens, e.g. CPA, chlormadinone monotherapy to draw any conclusions about acetate and megestrol acetate, have mixed a class effect in this setting. The prevailing data suggest equivalent agonistic and antagonistic activities, while survival between LHRH agonists and nonsteroidal antiandrogens, e.g. bicalutamide, Combined therapy orchidectomy. It is apparent that within the flutamide and nilutamide, have a pure anti- LHRH agonist class, the vast majority of androgenic effect. Despite numerous trials investigating available data are for goserelin, which is combined therapy (medical or surgical associated with benefits in several settings. Monotherapy castration plus an antiandrogen, otherwise The amount and quality of evidence that known as maximal androgen blockade), only compares goserelin with other members of There have been no direct RCTs comparing one randomized, double-blind trial compared the class, or that compares LHRH agonists steroidal antiandrogens, and there are combined therapies directly [39]. Of 813 with other treatments, is insufficient to minimal clinical data with chlormadinone patients, 404 were assigned to bicalutamide establish a class effect. acetate and megestrol acetate from which to combined with an LHRH agonist, and 409 to

EVANS ET AL.

flutamide plus an LHRH agonist. There was no to efficacy considerations, also encompasses analysis of eleven controlled studies with significant difference between groups in differences between agents in safety/ alfuzosin. Urology 2001; 57: 459–65 survival. Beyond this one comparative RCT, tolerability profiles. Although a class effect is 7 Wilt TJ, Howe W, MacDonald R. the currently available data relating to the commonly assumed in prostate medicine by Terazosin for treating symptomatic efficacy of combined therapy shed no light on some urologists, on the whole this is not benign prostatic obstruction. a systematic whether a class effect exists for supported by the evidence. For example, in review of efficacy and adverse effects. antiandrogens. the case of LHRH agonists, particularly for BJU Int 2002; 89: 214–25 adjuvant therapy, the vast majority of data 8 Wilt TJ, MacDonald R, Nelson D. Tolerability come from studies of goserelin. In contrast, Tamsulosin for treating lower urinary there is less clinical evidence for other LHRH tract symptoms compatible with benign The efficacy evidence is insufficient to show a agonists in the adjuvant setting, because there prostatic obstruction. a systematic review class effect for the antiandrogens but there are too few RCTs. This raises doubt as to of efficacy and adverse effects. J Urol are differences between nonsteroidal whether a class effect for LHRH agonists is 2002; 167: 177–83 antiandrogen monotherapies in terms of proven by existing clinical data across all stages 9 Djavan B, Marberger M. A meta-analysis tolerability. Pharmacological effects of hormone-responsive prostate cancer. on the efficacy and tolerability of alpha1- associated with androgen receptor blockade, Similarly, a class effect has not been proven for adrenoceptor antagonists in patients with such as gynaecomastia and breast pain, have other classes of agent that have been reviewed lower urinary tract symptoms suggestive been reported with similar ranges of here. Urologists recognize the value of of benign prostatic obstruction. Eur Urol incidence for monotherapy with bicalutamide evidence-based practice, and on this basis, 1999; 36: 1–13 (38–66% and 13–73%, respectively), should not assume a class effect when making 10 Kirby RS. A randomized, double-blind flutamide (21–80% and 22–69%, respectively) treatment choices for prostatic disease. crossover study of tamsulosin and and nilutamide (gynaecomastia 50%, breast controlled-release doxazosin in patients pain data not available) [40]. Gastrointestinal CONFLICT OF INTEREST with benign prostatic hyperplasia. BJU Int effects (e.g. diarrhoea) have also been 2003; 91: 41–4 reported with all three agents, but occur more C. Evans is a paid consultant and study 11 Tsujii T. Comparison of prazosin, often with flutamide than bicalutamide investigator funded by sponsor. N. Fleshner is terazosin and tamsulosin in the treatment or nilutamide [40]. In contrast, visual a study investigator funded by sponsor. A.R. of symptomatic benign prostatic disturbances and alcohol intolerance have Zlotta is a paid consultant to sponsor. Source hyperplasia: a short-term open, been reported only with nilutamide [40]. There of funding: AstraZeneca. randomized multicenter study. BPH were also tolerability differences between Medical Therapy Study Group. Benign treatments in the study by Schellhammer REFERENCES prostatic hyperplasia. Int J Urol 2000; 7: et al. [39]; e.g. the incidence of haematuria 199–205 was significantly higher for the bicalutamide 1 Sackett DL, Rosenberg WMC, Muir Gray 12 Okada H, Kamidono S, Yoshioka T et al. plus LHRH agonist group than for the JA, Haynes RB, Scott Richardson Y. A comparative study of terazosin and flutamide plus LHRH agonist group (12% vs Evidence based medicine. what it is and tamsulosin for symptomatic benign 6%, P = 0.007) and there was a significantly what it isn’t. BMJ 1996; 312: 71–2 prostatic hyperplasia in Japanese patients. higher incidence of diarrhoea (26% vs 12%, 2 Evans CP. Evidence-based medicine for BJU Int 2000; 85: 676–81 P < 0.001) with flutamide than bicalutamide. the urologist. BJU Int 2004; 94: 1–2 13 Edwards JE, Moore RA. Finasteride in 3 McAlister FA, Laupacis A, Wells GA, the treatment of clinical benign prostatic Summary: antiandrogens Sackett DL. Users’ guides to the medical hyperplasia: a systematic review of literature. XIX. Applying clinical trial randomised trials. BMC Urol 2002; 2: Available efficacy data are insufficient to results B. Guidelines for determining 1–17 draw conclusions about the existence of a whether a drug is exerting (more than) 14 Roehrborn CG, Boyle P, Nickel JC, class effect for either steroidal or nonsteroidal a class effect. JAMA 1999; 282: 1371–7 Hoefner K, Andriole G. Efficacy and antiandrogens. On the basis of tolerability 4 Seidenfeld J, Samson DJ, Hasselblad safety of a dual inhibitor of 5-alpha- data for nonsteroidal antiandrogens, it is clear V et al. Single-therapy androgen reductase types 1 and 2 (dutasteride) in that drugs in this class have different suppression in men with advanced men with benign prostatic hyperplasia. characteristics, suggesting that it is not prostate cancer. a systematic review and Urology 2002; 60: 434–41 appropriate to assume a class effect. meta-analysis. Ann Intern Med 2000; 15 McConnell JD, Roehrborn CG, Bautista 132: 566–77 OM et al. The long-term effect of CONCLUSIONS 5 Bandolier Professional. On quality doxazosin, finasteride, and combination and validity. Available at http:// therapy on the clinical progression of As outlined herein, there is a substantial www.msdforphysicians.co.uk/bandolier/ benign prostatic hyperplasia. N Engl J Med amount of evidence that should be considered, qvs.pdf 2003 Accessed 2 March 2004 2003; 349: 2387–98 together with clinical experience, so that 6 McNeill SA, Hargreave TB, Geffriaud- 16 Heyns CF, Simonin MP, Grosgurin P, urologists and their patients may make Ricouard C, Santoni J, Roehrborn CG. Schall R, Porchet HC. Comparative informed choices about the treatment of Postvoid residual urine in patients with efficacy of triptorelin pamoate and prostatic disease. It is clear that the issue is lower urinary tract symptoms suggestive leuprolide acetate in men with advanced multifactorial and complex which, in addition of benign prostatic hyperplasia: pooled prostate cancer. BJU Int 2003; 92: 226–31

17 Kaisary AV, Tyrrell CJ, Peeling WB, and Treatment. Paris June 27–29 1990: 34 Messing EM, Manola J, Sarosdy M, Griffiths K, on behalf of Study Group. 53–5 Wilding G, Crawford ED, Trump D. Comparison of LHRH analogue (Zoladex) 25 The Leuprolide Study Group. Leuprolide Immediate hormonal therapy compared with orchiectomy in patients with versus diethylstilbestrol for metastatic with observation after radical metastatic prostatic carcinoma. Br J Urol prostate cancer. N Engl J Med 1984; 311: prostatectomy and pelvic 1991; 67: 502–8 1281–6 lymphadenectomy in men with node- 18 Vogelzang NJ, Chodak GW, Soloway 26 Thorpe SC, Azmatullah S, Fellows GJ, positive prostate cancer. N Engl J Med MS et al. Goserelin versus orchiectomy in Gingell JC, O’Boyle PJ. A prospective, 1999; 341: 1781–8 the treatment of advanced prostate randomised study to compare goserelin 35 Messing E, Manola J, Sarosdy M, cancer: final results of a randomized trial. acetate (Zoladex®) versus cyproterone Wilding G, Crawford ED. Immediate Urology 1995; 46: 220–6 acetate (Cyprostat®) versus a combination hormonal therapy compared with 19 de Voogt HJ, Studer U, Schroder FH, of the two in the treatment of metastatic observation after radical prostatectomy Klijn JG, De Pauw M, Sylvester R. prostatic carcinoma. Eur Urol 1996; 29: and pelvic lymphadenectomy in men with Maximum androgen blockade using LHRH 47–54 node positive prostate cancer: results at agonist buserelin in combination with 27 Waymont B, Lynch TH, Dunn JA et al. 10 years of EST 3886. J Urol 2003; 169: short-term (two weeks) or long-term Phase III randomised study of Zoladex 396, A1480 (continuous) cyproterone acetate is versus stilboestrol in the treatment of 36 Pilepich MV, Winter K, John MJ et al. not superior to standard androgen advanced prostate cancer. Br J Urol 1992; Phase III Radiation Therapy Oncology deprivation in the treatment of advanced 69: 614–20 Group (RTOG) trial 86–10 of androgen prostate cancer. Final analysis of EORTC 28 Bandolier. LHRH analogues in prostate deprivation adjuvant to definitive GU Group Trial 30843. European cancer. An overview of randomised trials, radiotherapy in locally advanced Organization for Research and Treatment with perspectives on possible meta- carcinoma of the prostate. Int J Radiat of Cancer (EORTC) Genito-Urinary Tract analysis. Available at www.ebandolier.com Oncol Biol Phys 2001; 50: 1243–52 Cancer Cooperative Group. Eur Urol 1998; 2003 Accessed 26 January 2004 37 Roach M III, DeSilvio M, Lawton C et al. 33: 152–8 29 Bolla M, Collette L, Blank L et al. Long- Phase III trial comparing whole-pelvic 20 Bruun E, Frimodt-Moller C. The effect term results with immediate androgen versus prostate-only radiotherapy and of buserelin versus conventional suppression and external irradiation in neoadjuvant versus adjuvant combined antiandrogenic treatment in patients patients with locally advanced prostate androgen suppression: Radiation Therapy with T2–4NXM1 prostatic cancer. A cancer (an EORTC study): a phase III Oncology Group 9413. J Clin Oncol 2003; prospective, randomized multicentre randomised trial. Lancet 2002; 360: 21: 1904–11 phase III trial. The ‘Danish Buserelin Study 103–8 38 Scolieri MJ, Altman A, Resnick MI. Group’. Scand J Urol Nephrol 1996; 30: 30 D’Amico AV, Manola J, Loffredo M, Neoadjuvant hormonal ablative therapy 291–7 Renshaw AA, DellaCroce A, Kantoff before radical prostatectomy: a review. Is 21 Parmar H, Edwards L, Phillips RH, Allen PW. 6-month androgen suppression plus it indicated? J Urol 2000; 164: 1465–72 L, Lightman SL. Orchiectomy versus radiation therapy vs radiation therapy 39 Schellhammer PF, Sharifi R, Block NL long-acting D-Trp-6-LHRH in advanced alone for patients with clinically localized et al. Clinical benefits of bicalutamide prostatic cancer. Br J Urol 1987; 59: 248– prostate cancer: a randomized controlled compared with flutamide in combined 54 trial. JAMA 2004; 292: 821–7 androgen blockade for patients with 22 Huben RP, Murphy GP. A comparison of 31 Bolla M, de Reijke ThM, Zurlo A, advanced prostatic carcinoma: final diethylstilbestrol or orchiectomy with Collette L. Adjuvant hormone therapy in report of a double-blind, randomized, buserelin and with methotrexate plus locally advanced and localized prostate multicenter trial. Urology 1997; 50: diethylstilbestrol or orchiectomy in newly cancer: three EORTC trials. Front Radiat 330–6 diagnosed patients with clinical stage D2 Ther Oncol 2002; 36: 81–6 40 Fourcade R-O, McLeod D. Tolerability cancer of the prostate. Cancer 1988; 62: 32 Pilepich MV, Winter K, Lawton C et al. of antiandrogens in the treatment of 1881–7 Phase III trial of androgen suppression prostate cancer. Urooncology 2004; 4: 23 Klioze SS, Miller MF, Spiro TP. A adjuvant to definitive radiotherapy. 5–13 randomized, comparative study of Long term results of RTOG study 85–31. buserelin with DES/orchiectomy in the Proc Am Soc Clin Oncol 2003; 22: 381, Correspondence: Christopher P. Evans, treatment of stage D2 prostatic cancer A1530 Department of Urology, University of patients. Am J Clin Oncol 1988; 11 (Suppl. 33 Hanks GE, Pajak TF, Porter A et al. Phase California, Davis School of Medicine, 4860 Y 2): S176–S182 III trial of long-term adjuvant androgen St, Suite 3500, Sacramento CA 95817, USA. 24 Osborne DR, Moffat LEF, Kaisary A, deprivation after neoadjuvant hormonal e-mail: [email protected] Rees DLP, Weaver JP. A comparison of cytoreduction and radiotherapy in locally Zoladex, cyproterone acetate and advanced carcinoma of the prostate: the Abbreviations: EBM, evidence-based stilboestrol in the treatment of patients Radiation Therapy Oncology Group medicine; RCT, randomized controlled trial; with advanced prostatic cancer. Recent Protocol 92–02. J Clin Oncol 2003; 21: DES, diethylstilbestrol; CPA, cyproterone Advances in Urological Cancers Diagnosis 3972–8 acetate.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article RADICAL PROSTATECTOMY FOR CLINICALLY ADVANCED PROSTATE CANCER WARD et al.

In the first paper in this section, Radical prostatectomy for clinically authors from the Mayo Clinic describe their experience and 15- advanced (cT3) prostate cancer since year outcomes in the controversial the advent of prostate-specific subject of radical prostatectomy in patients with clinical T3 prostate antigen testing: 15-year outcome cancer. The findings were interesting in many respects, but JOHN F. WARD, JEFFREY M. SLEZAK*, MICHAEL L. BLUTE†, ERIK J. BERGSTRALH* and HORST ZINCKE† the authors concluded that radical Division of Urology, Naval Medical Center, Portsmouth, VA, *Division of Biostatistics, and prostatectomy as part of †Department of Urology, Mayo Clinic, Rochester, MN, USA multimodal treatment for patients Accepted for publication 2 December 2004 with clinical T3 disease offers cancer control and good survival OBJECTIVE receive neoadjuvant therapy (27%) were rates. clinically over-staged (pT2) and most men To report a long-term experience with with pT3 disease (78%) received adjuvant extirpative surgery in patients presenting with therapy. The mean time to adjuvant therapy There follows a series of papers on locally advanced (cT3) prostate cancer, as the after RP was not significantly different both prostate cancer and bladder best management of such patients remains a between men with cT3 and cT2 disease (4.0 problem. and 4.3 years). Pathological grade (≥7), cancer, but the final paper in this positive surgical margins, and nondiploid section from the UK attempts to PATIENTS AND METHODS chromatin were all independently associated define the accuracy of urologists with a significant risk for clinical disease and oncologists in assessing patient In a single-institution retrospective study recurrence, while preoperative PSA level had identifying 5652 men who had radical little effect on outcome. Complications and life-expectancy. Using various prostatectomy (RP) for histologically continence rates after RP in patients with cT3 methods they found that, rather confirmed prostate cancer since the advent mirrored those in patients with cT2 disease. disappointingly, doctors were poor of prostate-specific antigen (PSA) testing at predicting 10-year survival, (1987–97), 15% (842) had RP for cT3 disease. CONCLUSIONS The median follow-up of these men was leading to the possible outcome 10.3 years. Cancer-specific, overall and Significantly many patients with cT3 prostate that some patients may be denied disease-free survival was plotted and cancer are overstaged (pT2) in the PSA era. treatment after a pessimistic compared with those of patients having RP as part of a multimodal treatment strategy RP for cT2 disease during the same period. assessment of life-expectancy. for patients with cT3 disease offers cancer Perioperative morbidity, continence and control and survival rates approaching those erectile function rates were examined, with a achieved for cT2 disease. Pathological grade, multivariate analysis for risk factors of disease ploidy and margin status are all significant recurrence. predictors of outcome after RP. Complications and incontinence rates in patients with cT3 RESULTS disease mirror those after RP for cT2 disease.

Freedom from local or systemic disease at 5, KEYWORDS 10, and 15 years after RP for cT3 disease was 85%, 73% and 67%; the respective cancer- prostatic neoplasm, prostatectomy, treatment speciﬁc survival rates were 95%, 90% and outcome, staging 79%. Signiﬁcantly many men who did not

W ARD ET AL.

INTRODUCTION 60 FIG. 1. Clinical stage migration of 5652 The presentational characteristics of prostate 50 newly diagnosed prostate cancers cancer have changed dramatically within the (T1c, green bars; T3-4, red) since USA in the last few years, coincident with the 40 the advent of PSA testing widespread use of PSA testing as a screening (1987–2001). tool. At our institution, where we have % 30 advocated radical prostatectomy (RP) for 20 patients with cT3 prostate cancer for over 20 years [1,2], the proportion of RPs in men with 10 cT3 disease has declined significantly, from 25.3% in 1987 to 2.8% in 2001 (Fig. 1). While 0 we hope that stage migration in this period 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 has accounted for much of this decline, Year lingering biases about the best management of cT3 disease may also be skewing the referral of such patients. It was reported that when the effect of upstaging in patients Median (25–75th percentile) TABLE 1 undergoing RP is excluded from the Variable cT2 cT3 Comparison of all patients Surveillance, Epidemiology and End Results N4810 841 undergoing RP during the database, the number of those presenting Age at RP, years 66 (61–70) 66 (61–70) 11-year investigation with cT3 disease has remained remarkably Pre-op PSA, ng/mL 7.2 (4.4–11.9) 10.2 (4.7–23.7) period stable for 20 years [3]. Clinical grade 6 (5–7) 7 (6–7) Clinical grade ≥7, % 31 54 The best management of patients with Neoadjuvant therapy 5 23 clinically advanced prostate cancer remains controversial. At this stage the tumour appears to extend beyond the prostatic capsule, but distant metastases are not yet discretionary. No patient with confirmed system. The lymph nodes were totally detectable. In the USA, surgery rates are 30% distant metastasis underwent RP. embedded for histological evaluation. for patients with newly diagnosed cT1–2 disease, while only 6% of patients staged cT3 Locally advanced prostate cancer (cT3) with The median (range) follow-up was 10.3 undergo RP [4]. Even in men with prolonged no distant metastasis, pelvic side-wall (0.1–16.7) years. To date, adjuvant (£90 days life-expectancy the RP rates are ª67% for the extension or involvement of the trigone was after RP) or salvage (>90 days after RP) youngest with cT1–2 prostate cancer but only present in 841 (15%) of the identified therapies were administered to 48% and 41% 19% for the youngest with cT3 disease [4]. patients. The clinical characteristics of all of patients with cT3, and 21% and 22% of Thus we present our retrospective single- patients in the study period (cT2 and cT3) are patients with cT2 disease. institution experience with RP as primary presented in Table 1. There was a significant therapy for patients with cT3 prostate cancer. difference between these groups in Clinical progress was assessed at regular preoperative PSA and biopsy grade. intervals either at our institution or by the PATIENTS AND METHODS Neoadjuvant therapy was given to 23% and referring physician, from the time of surgery 5% of those staged cT3 and cT2, respectively. throughout the follow-up. Clinical failure was Conduct of this study was approved by the defined as a serum PSA level of ≥0.4 ng/mL Institutional Review Board (#1989–02) and The excised prostate glands were evaluated at after RP, or demonstrable metastatic disease constitutes a minimal-risk investigation. the time of surgery by a standardized, limited- or local disease, or the initiation of salvage Consent for the use of medical records for sampling protocol using frozen-section therapy (radiotherapy or hormonal therapy, research was obtained from all patients techniques. The following day the prostates HT) >90 days after RP. Disease outcome, before starting this analysis. A single- were evaluated using haematoxylin and perioperative and late treatment institution retrospective study was conducted eosin-stained permanent sections. The apex complications were retrieved by extensive using the referral-based longitudinal Mayo and base of the prostate were amputated record review and maintained within the Clinic Prostate Cancer Registry. Men (5662) and submitted as en fasce margins, followed registry. who had RP with pelvic lymph node by serial sectioning perpendicular to the dissection during the 11-year (1987–97) long axis of the gland from apex to the tip The primary endpoints were times to death, period since the advent of PSA testing were of the seminal vesicles. On average, 14 prostate cancer death, clinical recurrence and identified. Clinical staging consisted of a prostate blocks were examined per patient. biochemical failure (defined as a PSA of DRE by two clinicians, and defined using the Pathological extraprostatic extension ≥0.4 ng/mL). Survival curves were generated 1997 American Joint Committee on Cancer was defined as tumour extending into using the method of Kaplan and Meier. guidelines. Bone scintigraphy, CT of the pelvis extraprostatic tissue (pT3). The primary Univariate and multivariate assessment of and cysto-urethroscopy before RP was tumour was graded according to the Gleason survival associations was conducted using the

RADICAL PROSTATECTOMY FOR CLINICALLY ADVANCED PROSTATE CANCER

in all but 6% of patients who had higher TABLE 2 Histological characterization of extirpated prostates for cT3 prostate cancer pathological grade disease. There was a significant difference in the chromatin HT before surgery, % (n) content between patients with pT2 and pT3 Group All No Yes P disease (diploid, tetraploid, aneuploid, 71%, Pathological stage (841) 0.064 22%, 7% vs 51%, 35%, 14%, respectively). pT2 27 (223) 27 (174) 27 (49) pT3/4 46 (391) 49 (326) 36 (65) Neoadjuvant HT was administered to 21% of TxN+ 27 (227) 24 (161) 37 (66) patients (Table 2); rates of organ confinement Pathological Gleason score (738) 0.037 (27%) and negative surgical margins (44%) £641 (305) 42 (249) 38 (56) were identical regardless of the preoperative 741 (305) 42 (250) 37 (55) administration of HT. Patients receiving ≥8 18 (128) 15 (91) 25 (37) neoadjuvant HT had a higher rate of Chromosome content (816) 0.022 pathological Gleason ≥8 (25% vs 15%), N+ Diploid 51 (420) 53 (332) 46 (88) disease (37% vs 24%) and aneuploid DNA Tetraploid 35 (284) 35 (218) 35 (66) content (19% vs 12%) than patients not Aneuploid 14 (112) 12 (76) 19 (36) receiving HT. Surgical margins 0.97 Positive 56 (471) 56 (361) 56 (110) The perioperative morbidity in patients with Negative 44 (371) 44 (284) 44 (87) cT3 disease (Table 3) was similar to that previously reported for patients with cT2 disease undergoing RP at our institution [5]. There was a parallel decrease in hospitalized Complication Rate, % (n) TABLE 3 blood transfusions in patients with cT2 or cT3 Rectal injury 1.6 (14) Morbidity associated with over the study period. After RP, 75% of the Intraoperative haemorrhage 1.8 (15) RP in patients with cT3 reporting patients had no erectile function, Hospitalized blood transfusion 29.0 (241) disease reflecting the infrequent use of a nerve- Hernia 2.6 (22) sparing technique (12% bilateral, 14% Bladder neck contracture 11.2 (93) unilateral nerve preservation, 74% wide Lymphocele 1.0 (8) excision of both neurovascular bundles) [6]. Urethral stricture 3.2 (27) Urinary continence (completely dry or Deep vein thrombosis 8.0 (15) security pad seldom moist) at 1 year was Pulmonary embolism 1.2 (10) achieved in 79% of men staged cT3 (84% cT2), Erectile dysfunction 75.3 (532 of 706 known) with few (6%) patients having severe incontinence (≥2 pads/day) and 0.5% requiring an artificial urinary sphincter. TABLE 4 Adjuvant and salvage therapies administered to patients with cT3 prostate cancer after RP, Of patients staged cT3 and cT2, 78% and 41% segregated by pathological stage received HT, radiotherapy or both at some point after RP (Table 4). There was no Pathological HT, n (%) Radiotherapy, n (%) significant difference in the time (mean, stage (n) Adjuvant† Salvage‡ Adjuvant† Salvage‡ median) to initiate secondary therapy T2N0 (223) 64 (28.7) 40 (17.9) 24 (10.8) 27 (12.1) between cT3 (4.0, 3.5 years) and cT2 (4.3, T3/4N0 (391) 149 (38.1) 128 (32.7) 73 (18.7) 75 (19.2) 3.5 years). TxN+ (227) 216 (95.2) 51 (22.5) 36 (15.9) 23 (10.1) Total (841)¶§ 429 (51.0) 219 (26.0) 133 (15.8) 125 (14.9) At 5, 10 and 15 years after RP for cT3 disease, 85%, 73% and 67% of patients were free of *1997 TNM Revision. †Adjuvant therapies were initiated £ 90 days after RP. ‡Salvage therapies were local or systemic disease recurrence. initiated > 90 days after RP. ¶5.2% of cT3 patients received both HT and radiotherapy at some time after Figure 2A compares this outcome with RP. §13.2% of cT3 patients received adjunctive therapy before and after RP. patients undergoing RP during the same period for cT2 disease. Freedom from biochemical recurrence for cT3 and cT2 at 5, log-rank test and Cox proportional hazard cT3 disease who did not receive neoadjuvant 10 and 15 years had a similar relationship models. HT, 27% were clinically over-staged, (58%, 43% and 38% for cT3, vs 74%, 61% and harbouring organ-confined prostate cancer 52% for cT2). The overall (90%, 76%, 53%) RESULTS (pT2). Nodal metastases (TxN+) were present and cancer-specific survival (CSS) (95%, 90%, in 27% of patients (37% after neoadjuvant HT, 79%) for patients with cT3 disease at 5, 10 The characteristics of the extirpated prostates 27% without). The biopsy grade reviewed at and 15 years was only moderately lower than are detailed in Table 2. Of the 661 men with the Mayo concurred with pathological grade that in patients with cT2 disease (95%, 82%

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and 61%, and 99, 96% and 92%, respectively) TABLE 5 Multivariate analysis with hazard rates for clinical disease recurrence after RP in patients with during the same period (Fig. 2B). Stratified by cT3 prostate cancer (systemic or local disease) pathological stage (Fig. 3), patients staged cT3 had a statistically significantly different CSS, Variable Hazard ratio (95% CI) P but those staged pT3/4 had a 10- and 15-year Pathological grade 7 1.27 (1.03–1.56) 0.026 CSS of 89% and 80% with adjuvant therapy. ≥ Pre-op PSA (doubling) 1.13 (0.96–1.34) 0.154 Ploidy (non-diploid) 1.85 (1.18–2.91) 0.008 The multivariate analysis of risk factors for Positive surgical margin 1.77 (1.12–2.79) 0.015 clinical disease recurrence after RP for cT3 Seminal vesicle invasion 1.49 (0.92–2.43) 0.108 prostate cancer is shown in Table 5. Pathological grade (≥7), positive surgical margins and nondiploid chromatin content were all independently associated with a FIG. 2. A, The time free of local or systemic failure FIG. 3. The CSS for patients with cT3 disease significant risk of clinical recurrence, while and B, CSS (segregated by clinical stage; cT2 green; segregated by final pathological stage (green solid preoperative PSA level had little impact on cT3, red) after RP for patients with prostate cancer. line T2N0; red dotted line, T3-4N0, and light green this endpoint. dashed line, TxN+). A DISCUSSION 100 90 80 100 Within this cohort of patients presenting to a 70 90 60 80 single referral centre with cT3 prostate cancer, 50 70 clinical over-staging occurred in a significant 40 60 30 50 proportion of hormone-naïve patients (27%); 20 40 10 30 for these men, monotherapy with RP was 0 20 potentially curative. Consistent with previous Clinical progression free, % 10 0 studies of the effect of neoadjuvant HT in B 051015 patients with cT3 prostate cancer, HT given to % Not dead from prostate cancer, Years after RP 21% of the study cohort had little effect on 100 grade, stage or rates of margin positivity, and 90 80 did not influence progression-free or CSS. The 70 improve survival over delayed HT in patients morbidity of RP in these patients was no 60 with N+ disease [7]. 50 greater than that reported by us and others 40 30 with RP for cT2 prostate cancer. However, the 20 Opponents of surgical treatment have cited maintenance of erectile function was low in 10 a lack of benefit if the prostate is not 0 the present men (25% whose status was 051015 completely excised [8], an increased incidence known), reflecting the wide resection of one % Not dead from prostate cancer, Years after RP of micrometastasis [1], and increased surgical or both neurovascular bundles in 88% of morbidity [9]. Wide-field irradiation has patients. Nonetheless, this erectile therefore become the standard accepted dysfunction rate compares favourably to treatment. However, as a monotherapy, those after RT for cT3 disease. For patients management of cT3 prostate cancer, with a radiotherapy has had limited long-term with cT3 disease, RP was part of a multimodal long-term follow-up (15 years) unmatched by success. approach to disease eradication or control, any other therapy. Eliminating the prostate which included HT or radiotherapy at some reduces the potential for late dissemination of Prostate biopsy studies after radiotherapy time after RP in 58% and 27%, respectively. radioresistant prostate cancer cells and showed persistent prostate cancer in 14–91% Interestingly, the median time from surgery to simplifies the use of serum PSA levels in the of patients [10,11]. Coen et al. [12] evaluated secondary therapy for patients with cT3 follow-up. For a quarter of patients who are 1469 men with biopsy-confirmed prostate disease was not significantly different from over-staged clinically, it eliminates the cancer treated with radiotherapy, and found those with cT2. This probably reflects the overtreatment of organ-confined disease not only an independent association between biology of prostate cancer at the time of RP, with combined hormonal and radiotherapy, delayed metastasis and the local persistence regardless of clinical stage. As part of this which is the current standard treatment for of the cancer on biopsy, but also a temporally multimodal approach to patients who once cT3 disease. With close follow-up and serial increasing hazard rate. They postulated that a felt doomed to die from the disease, RP PSA measurements, the remaining patients biologically altered prostate cancer after achieved CSS rates which approach those in harbouring pT3 disease may avoid castration radiotherapy resulted in a late wave of patients with cT2 disease undergoing RP (90% and the deleterious effect that this has on metastatic seeding, possibly worsening the vs 96% at 10 years and 79% vs 92% at 15 quality of life, until the PSA becomes outcome. years). detectable. On the other hand, patients with N+ disease, which unless bulky is difficult to To improve the problem of local control with This series represents the largest single- detect with modern imaging techniques, can radiotherapy, radiotherapists have used a institution experience of the surgical initiate early HT, which has been found to multimodal approach (radiotherapy and HT)

RADICAL PROSTATECTOMY FOR CLINICALLY ADVANCED PROSTATE CANCER

for treating cT3 prostate cancer. Laverdière examined 55 patients staged cT3 who accrual goal of 700 men during a 48-month et al. [13] conducted a prospective study of received 4-months of neoadjuvant total period has been set. The primary study patients with cT2-cT4 prostate cancer, androgen blockade (goserelin + flutamide) endpoint is a decrease in 5-year recurrence randomly assigning patients to one of three with RP [16]. The 5-year progression-free and rates, with secondary outcomes comparing treatment arms, i.e. radiotherapy alone, CSS estimate in this group, reported at a safety, tolerability and the impact of neoadjuvant HT and radiotherapy, or median follow-up of 6.1 years, was 70% and neoadjuvant therapy on the pathological neoadjuvant HT + radiotherapy + adjuvant HT. 90%, respectively. Similarly, Gleave et al. [17] specimen. Results of this study are not As a monotherapy, radiotherapy inadequately found a 75% progression-free survival in such expected until after 2011. controlled the cancer, with two-thirds of patients treated with 8-months of total prostate biopsies 2 years after treatment androgen blockade followed by RP. Because of While long-term progression-free and CSS is positive for residual prostate cancer. However, the infrequent use of neoadjuvant and the ultimate goal of any treatment strategy, with HT, the rate of positive biopsies improved frequent use of adjuvant HT within the preventing the significant morbidity of local to less than a third for neoadjuvant HT + present study we were unable to discern an prostate cancer progression (bleeding, radiotherapy, and <5% in the three-treatment effect of neoadjuvant HT. However, urethral/ureteric obstruction, pain) is also arm. neoadjuvant HT did not affect the surgical necessary. Within the present patients, none margin status, which, with tumour ploidy, was had any symptoms associated with local Bolla et al. [14] conducted a prospective, the most significant predictor of clinical tumour recurrence or progression. Tomlinson randomized trial comparing radiotherapy disease recurrence. et al. [21] assessed patients with newly alone vs radiotherapy + 3 years of adjuvant diagnosed cT3 prostate cancer treated HT in men with advanced prostate cancer The optimum treatment strategy for high- with either extirpative (perineal RP, 24) or (367 cT3/cT4, 34 T1/T2 Grade 3, 14 N+). With a risk/locally advanced prostate cancer remains less than extirpative surgery (TURP, 26) or median follow-up of 5.5 years, the combined unknown. However, definitive local simple RP (two). Non-extirpative surgery arm had better clinical disease-free (74% vs treatments as monotherapy cure only a failed to ameliorate the local morbidity of 40%) and overall survival (78% vs 62%, minority of patients in both radiotherapy and in-situ tumour progression and 75% later P < 0.001) than the radiotherapy-only arm. RP series. Multimodal therapy which includes developed BOO. Also, ureteric obstruction The clinical disease-free survival rate androgen suppression and RP or radiotherapy (40%), infection (80%) and gross prospectively achieved for combined clearly improves the outcome in men with haematuria (45%) were more frequent in treatment compares with the 85% rate in the locally advanced prostate cancer. Although the nonextirpative groups than in those present retrospective study of RP and the optimum timing of HT is not clear, short patients undergoing RP (4%, 26%, and 9%, secondary therapy for cT3 disease. courses appear inferior to long-term therapy respectively). [18]. However, the effects of HT on quality of Finally, the Radiation Therapy Oncology Group life are not insignificant. Over a quarter of the Finally, a quarter of the present patients with (RTOG 86–10) reported the results of a 15- present men (pT2) would have been cT3 were N+; we have long advocated the year, prospective, randomized investigation of unnecessarily exposed to the adverse effects early introduction of HT for this stage of radiotherapy vs radiotherapy with 4 months of HT if empirically treated. Another two- disease [7,22]. However, the ability to closely of adjuvant HT in 471 men with cT3 prostate thirds of cT3 prostate cancers examined monitor serum PSA after RP for pT3 prostate cancer (± lymph node involvement) [15]. At a contained grade ≥7 cancer, a pattern for cancer, with our increased awareness of the median follow-up of 6.7 years, patients with which radiotherapy ± HT regimens were less quality-of-life issues surrounding HT, means Gleason score £6 prostate cancer receiving effective. that we now closely observe patients with combined therapy had better local and distant pT3N0 disease and initiate salvage therapy disease control. However, there was no While HT has been the mainstay of combined only after the patient has had a significant significant advantage to combined therapy therapy, recent efforts have focused on the PSA doubling time after RP (<1 year) or (locoregional, distant metastasis or survival) delivery of chemotherapy and/or HT around clinical evidence of disease recurrence [23]. in patients with Gleason 7–10 carcinomas. RP. Konety et al. [19] conducted a phase I/II This is identical to our practice for patients While the cancer grading for the RTOG study study evaluating 36 patients with high-risk with pT2N0 disease. was based on a review of needle-biopsy prostate cancer (cT3/4, cT1/2 with Gleason specimens, we found a concordance between 8–10 and/or PSA >20 ng/mL) who received As presented here, the CSS and overall final pathological Gleason score and biopsy neoadjuvant HT and four cycles of paclitaxel/ survival was excellent using this strategy in Gleason score in the present surgically treated carboplatin/estramustine before RP. Although patients once considered incurable. However, patients (6% up-graded). With nearly two- the effect of this therapy on clinical this report has many limitations, beginning thirds of the present patients with cT3 having progression-free survival is not yet known, with its retrospective view, and an Gleason ≥7 disease, the findings of RTOG the morbidity of such therapy was low and uncontrolled bias for the initiation and timing 86–10 are worrisome. the positive surgical margin rate lower than in of adjuvant therapy before and/or after the present study (22% vs 56%). surgery. Second, as a tertiary centre, there was The use and outcome of neoadjuvant HT probably referral-pattern selection bias, which followed by surgery has been examined The Cancer and Leukaemia Group B is prevents an assessment of all men with newly prospectively but with significantly fewer conducting a prospective trial (CALGB-90203) diagnosed cT3 prostate cancer. Clinical trials patients than radiotherapy studies. The comparing RP with estramustine and comparing surgery or radiotherapy as part of South-west Oncology Group (SWOG-9109) docetaxel before RP [20]. An ambitious a multimodal treatment regimen which

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includes HT and/or chemotherapy are needed. positive prostate cancer. N Engl J Med SL, Jones EC, Bruchovsky N, Sullivan Until then, the findings of this and other 1999; 341: 1781–8 LD. Long-term neoadjuvant hormone surgical series suggest that RP when 8 Steinberg GD, Walsh PC. Expanding role therapy prior to radical prostatectomy. combined with adjuvant HT compares in the management of patients with evaluation of risk for biochemical favourably with current radiotherapy/HT adenocarcinoma of the prostate. recurrence at 5-year follow-up. Urology strategies. Problems Urol 1990; 4: 408–19 2000; 56: 289–94 9 Moul JW. The role of radical surgery in 18 Horwitz EM, Winter K, Hanks GE, the management of radiation recurrent Lawton CA, Russell AH, Machtay M. CONFLICT OF INTEREST and large volume prostate cancer. Cancer Subset analysis of RTOG 85–31 and 86–10 1991; 68: 1265–71 indicates an advantage for long-term None declared. 10 Crook JM, Perry GA, Robertson S, Esche vs. short-term adjuvant hormones BA. Routine prostate biopsies following for patients with locally advanced radiotherapy for prostate cancer: results nonmetastatic prostate cancer treated REFERENCES for 226 patients. Urology 1995; 45: 624– with radiation therapy. Int J Radiat Oncol 31 Biol Phys 2001; 49: 947–56 1 Zincke H, Fleming TR, Furlow WL, 11 Zietman AL, Westgeest JC, Shipley WU. 19 Konety BR, Eastham JA, Reuter VE Myers RP, Utz DC. Radical retropubic Radiation-based approaches to the et al. Feasibility of radical prostatectomy prostatectomy and pelvic management of T3 prostate cancer. after neoadjuvant chemohormonal lymphadenectomy for high-stage cancer Seminars Urologic Oncol 1997; 15: 230–8 therapy for patients with high risk or of the prostate. Cancer 1981; 47: 1901– 12 Coen JJ, Zietman AL, Thakral H, Shipley locally advanced prostate cancer: results 10 WU. Radical radiation for localized of a phase I/II study. J Urol 2004; 171: 2 Lerner SE, Blute ML, Zincke H. Extended prostate cancer. local persistence of 709–13 experience with radical prostatectomy for disease results in a late wave of 20 Eastham JA, Kelly WK, Grossfeld GD, clinical stage T3 prostate cancer. outcome metastases. J Clin Oncol 2002; 20: 3199– Small EJ, Cancer and Leukemia Group B and contemporary morbidity. J Urol 1995; 205 (CALGB) 90203. A randomized phase 154: 1447–52 13 Laverdiere J, Gomez JL, Cusan L 3 study of radical prostatectomy alone 3 Ries LA, Eisner MP, Kosary CL et al. SEER et al. Beneficial effect of combination versus estramustine and docetaxel before Cancer Statistics Review, 1973–99. hormonal therapy administered prior radical prostatectomy for patients with Bethesda, MD: National Cancer Institute, and following external beam radiation high-risk localized disease. Urology 2003; 2002 therapy in localized prostate cancer. Int J 62 (Suppl. 1): 55–62 4 Meltzer D, Egleston B, Abdalla I. Radiation Oncol Biol Phys 1997; 37: 247– 21 Tomlinson RL, Currie DP, Boyce WH. Patterns of prostate cancer treatment by 52 Radical prostatectomy. Palliation for stage clinical stage and age. Am J Public Health 14 Bolla M, Collette L, Blank L et al. Long- C carcinoma of the prostate. J Urol 1977; 2001; 91: 126–8 term results with immediate androgen 117: 85–7 5 Zincke H, Bergstralh EJ, Blute ML et al. suppression and external irradiation in 22 Zincke H, Lau W, Bergstralh E, Blute Radical prostatectomy for clinically patients with locally advanced prostate ML. Role of early adjuvant hormonal localized prostate cancer. long-term cancer (an EORTC study): a phase III therapy after radical prostatectomy for results of 1,143 patients from a single randomised trial. Lancet 2002; 360: 103– prostate cancer. J Urol 2001; 166: 2208– institution. J Clin Oncol 1994; 12: 2254– 6 15 63 15 Pilepich MV, Winter K, John MJ et al. 23 Ward JF, Zincke H, Bergstralh EJ, Slezak 6 Ward JF, Zincke H, Bergstralh EJ, Slezak Phase III radiation therapy oncology J, Blute ML. Prostate specific antigen JM, Myers RP, Blute ML. The impact of group (RTOG) trial 86–10 of androgen doubling time subsequent to radical surgical approach (nerve bundle deprivation adjuvant to definitive prostatectomy as a prognosticator of preservation versus wide local excision) radiotherapy in locally advanced outcome following salvage radiotherapy. on surgical margins and biochemical carcinoma of the prostate. Int J Radiation J Urol 2004; 172: 2244–8 recurrence following radical Oncol Biol Phys 2001; 50: 1243–52 prostatectomy. J Urol 2004; 172: 1328– 16 Powell IJ, Tangen CM, Miller GJ et al. Correspondence: John F. Ward, 620 John Paul 32 Neoadjuvant therapy before radical Jones Circle, Portsmouth, VA 23708, USA. 7 Messing EM, Manola J, Sarosdy prostatectomy for clinical T3/T4 e-mail: [email protected] M, Wilding G, Crawford ED, carcinoma of the prostate: 5-year Trump D. Immediate hormonal followup, Phase II Southwest Oncology Abbreviations: RP, radical prostatectomy; therapy compared with observation Group Study 9109. J Urol 2002; 168: CSS, cancer-specific survival; HT, hormonal after radical prostatectomy and pelvic 2016–9 therapy; RTOG, Radiation Therapy Oncology lymphadenectomy in men with node- 17 Gleave ME, La Bianca SE, Goldenberg Group.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article BLADDER MUCOSAL EVERSION AFTER RADICAL RETROPUBIC PROSTATECTOMY SROUGI et al.

The inﬂuence of bladder neck mucosal eversion and early urinary extravasation on patient outcome after radical retropubic prostatectomy: a prospective controlled trial

MIGUEL SROUGI, MARIO PARANHOS, KÁTIA M. LEITE, MARCOS DALL’OGLIO and LUCIANO NESRALLAH Division of Urology, Federal University of São Paulo, São Paulo, Brazil Accepted for publication 7 December 2004

OBJECTIVE sclerosis and the rate of urinary incontinence after surgery was followed by same rate of BN (more than one pad/day) was assessed by sclerosis and urinary continence as in patients To evaluate the role of bladder neck (BN) double-blind interviews at 2 days, 2 months with no urinary extravasation. mucosal eversion during retropubic radical and 6 months after catheter removal, and the prostatectomy (RRP) on the rate of BN incidence of BN sclerosis was also assessed sclerosis and urinary incontinence, with the after 12 months. CONCLUSION hypothesis that BN mucosal eversion is not essential to improve the clinical outcome RESULTS BN mucosal eversion before vesico-urethral after RRP. anastomosis during RRP is not essential to In the groups with or with no BN mucosal reduce the frequency of BN sclerosis or PATIENTS AND METHODS eversion, 48 and 47 patients, respectively, urinary incontinence. Early radiological fulﬁlled the selection criteria. Urinary leakage urinary extravasation at the vesico-urethral One hundred patients with stage T1c–T2c after vesico-urethral anastomosis was more anastomosis did not increase the risk of BN prostate cancer had RRP by the same common after mucosal eversion (33% vs sclerosis or urinary incontinence. surgeon and were randomly divided in two 21%), but not signiﬁcantly (P = 0.251). BN equal groups; one had a vesico-urethral sclerosis occurred in only one patient, with no anastomosis with and one with no BN mucosal eversion. The rate of urinary KEYWORDS mucosal eversion. The patients were assessed continence was similar in both groups at by retrograde cysto-urethrography 4 days 2 days (69% vs 68%, respectively), 2 months prostatectomy, surgical technique, urinary after surgery to evaluate the presence of (90% vs 87%) and 6 months (92% vs 92%) incontinence, bladder neck obstruction, urinary leakage. The occurrence of BN after surgery. Urinary extravasation at 4 days stenosis.

INTRODUCTION bleeding, resulting in better surgical vesico-urethral reconstruction. Most remove outcomes. Moreover, better understanding of the Foley catheter at an earlier stage, and that The use of the PSA assay in medical practice local anatomy decreased the number of does not seem to be followed by a greater and in screening programmes has enabled the positive surgical margins while increasing the incidence of BN sclerosis or urinary fistula earlier diagnosis of prostate cancer; currently chances of complete tumour eradication. The [7,8]. Moreover, the drawbacks of everting the it is possible to identify most tumours at frequency of erectile dysfunction and mucosa in bowel reconstruction have been stages T1 and T2, which has led to an increase significant urinary incontinence, which were stressed since the beginning of the last in the number of radical prostatectomies extremely high with the classical techniques century, and were based on the fact that (RPs) [1–3]. Because of the complexity of of RP, decreased, respectively, to ≈40% and eversion increases the incidence of local pelvic anatomy and the difficulty in surgical ≈10% with the use of techniques that fistula in entero-enteric anastomosis [9,10]. access, RP was followed (until recently) by preserved the neurovascular bundles and the Kostic [11] concluded that extravasation of significant side-effects, and therefore it was distal urethral sphincter [6]. These advances the ileal content at the site of anastomosis is not widely adopted. During the 1980s, studies have made RP more acceptable and widely the major cause of morbidity in this surgery, by Walsh gave a more accurate description of practised. indicating that this complication is related to the anatomy of the cavernosal neurovascular poor healing caused by mucosal extrusion. In bundles and of the periprostatic blood vessels Walsh’s original description [5] included 1990, Hardy [12] presented historical reports of the male pelvis [4,5]. These new findings closure of the bladder neck with mucosal from Lembert, Kocher, Halsted and Ravich, enabled changes in the technique of RP, eversion to prevent bladder neck (BN) comparing intestinal mucosal eversion and which improved the preservation of the sclerosis, but recent observations suggest that inversion techniques during entero-enteric urethral sphincteric apparatus and the mucosal eversion might not be necessary for anastomosis, and concluded that the clinical cavernosal neurovascular bundles, and success. Surgeons skilled in laparoscopic RP surgical outcome is better when techniques enabled better control of perioperative do not use mucosal eversion at the time of are used that prevent eversion.

SROUGI ET AL.

All these data indicate that mucosal eversion continence was evaluated using a standard FIG. 1. BN reconstruction with (A) and without (B) in vesico-urethral anastomosis during RP questionnaire, presented by an interviewer mucosal eversion. might not be necessary, and it could even be unaware of the treatment group (M.P.). Both deleterious if it increases the risks of urinary groups were then compared for two primary A fistula and excessive local fibrosis. Thus we endpoints, i.e. contrast medium extravasation devised this study to determine if bladder at the anastomosis at 4 days after RP, and the mucosal eversion in RP is relevant to the rates of urinary continence and BN sclerosis outcome compared with the technique of at 48 h, 2 and 6 months after RP. The vesico-urethral anastomosis with no mucosal incidence of BN sclerosis was also assessed eversion. after a year. Those patients wearing more than one pad per day were classified as incontinent. At the same time, patients PATIENTS AND METHODS complaining of weak urinary stream had cysto-urethrography and cystoscopy to In a randomized controlled study between identify any BN sclerosis. October 2001 and June 2003 two groups of patients who had RP were compared; all The chi-squared test was used to define B patients gave informed consent, as approved uniformity between the groups, considering by the Medical Ethics Committee of the age, tumour stage, PSA level and Gleason Federal University of São Paulo. In all, 100 score, and to compare the rates of contrast patients with T1 and T2 prostate cancer medium extravasation at 4 days. Fisher’s exact (median age 63 years, range 46–76) were test was used to compare the frequency of BN recruited; patients were excluded if they sclerosis and urinary incontinence at 48 h, 2 had had: previous TURP, suprapubic and 6 months. In all tests, P > 0.05 was prostatectomy or local radiotherapy; a history deemed to confirm the null hypothesis. of neurological diseases; surgical pathology specimens that showed positive margins at the BN. RESULTS

The participants were randomly assigned by Among the patients recruited for the study, computer into two equal groups undergoing four were excluded as they were lost to RP with or with no bladder mucosal eversion follow-up and one was excluded after failing although the rates were the same at 2 and before vesico-urethral reconstruction. All to undergo the radiological study 4 days after 6 months (P = 0.402). procedures were performed by the same RP. For the final analysis the two groups surgeon (M.S.) who used a modified Walsh included 48 (eversion) and 47 patients (no technique, with an attempt at bilateral nerve- eversion), respectively. Table 1 shows the DISCUSSION sparing whenever feasible [13]. In patients patient distribution for age, tumour stage, having mucosal eversion, the bladder mucosa PSA level and Gleason score. The data show To decrease the morbidity of retropubic RP, was pulled and attached to the external that both groups were similar, which validates attempts have been made to refine the bladder surface with six circumferential the comparisons. surgical technique [6,7]; in the present study sutures of 4/0 plain catgut (Fig. 1A). In both we assessed the issue of bladder mucosal groups the BN was anastomosed directly to Table 1 also shows the incidence of contrast eversion before vesico-urethral anastomosis. the urethra with eight 3/0 polyglactin medium extravasation at 4 days after RP; the The outcome was similar for rates of BN interrupted sutures (Fig. 1B). The retropubic rates of extravasation were similar for both sclerosis and urinary continence after vesico- area was drained with a Penrose drain, and a groups (P = 0.251). Table 1 also compares urethral anastomosis with or with no mucosal urethral Foley catheter maintained in the both techniques for the frequency of BN eversion. Furthermore, there was a bladder until 13 days after RP. All surgical sclerosis; there was no difference between the progressive improvement in urinary specimens were evaluated histologically, groups (P = 0.495). Table 1 also shows the continence in both groups at the later follow- according to a previous method and that rates of urinary continence at 48 h, 2 and up. There was also a greater trend for urinary included a careful examination of the surgical 6 months after RP; the rates were similar in extravasation at 4 days after RP with mucosal margins at the bladder neck [14]. both groups (P = 0.856). eversion, although this was not statistically significant. At 4 days after RP all patients had retrograde Table 2 shows the correlation between cysto-urethrography with contrast medium urinary extravasation and the occurrence of When the present study was designed we injected around the Foley catheter under both BN sclerosis and urinary continence; proposed that there might be a greater risk of gravity; any contrast medium or extravasation extravasation had no effect on the occurrence urinary extravasation after BN reconstruction at the vesico-urethral anastomosis was noted. of BN sclerosis, but there was a higher with mucosal eversion, a question raised after At 48 h after removing the Foley catheter, and incidence of urinary incontinence at 48 h repeated observations in gastrointestinal at 2 and 6 months after surgery, urinary among patients with urinary extravasation, surgery [9,12]. In patients undergoing entero-

BLADDER MUCOSAL EVERSION AFTER RADICAL RETROPUBIC PROSTATECTOMY

anastomosis is unnecessary; this should Variable Eversion No eversion P TABLE 1 reassure surgeons who perform laparoscopic N4847Patient distribution for age, RP, where this step is usually omitted [19]. Age, years 0.999 tumour stage, serum PSA, Moreover, omitting this stage simplifies the >60 29 28 and Gleason score in both procedure in open RP. <60 19 19 groups Clinical stage 0.535 This prospective randomized study shows that T1 30 26 it is possible to evaluate aspects of surgical T2 18 21 technique with a sound scientific basis, Serum PSA, ng/mL 0.999 contrary to what often occurs when surgical <10 40 39 points are discussed empirically. We are >10 8 8 convinced that other technical aspects of RP Gleason score 0.102 can be evaluated using similar trial designs, 2–6 19 27 allowing advances in surgery and patient care 7–10 29 20 based on a scientific rationale [13]. N (%) Urinary extravasation 0.251 Yes 16 (33) 10 (21) CONFLICT OF INTEREST No 32 (67) 37 (79) BN sclerosis 0.495 None declared. Yes 0 1 (2) No 48 (100) 46 (98) Urinary continence at: 0.856 REFERENCES 48 h 33 (69) 32 (68) 2 months 43 (90) 41 (87) 1 Jemal A, Tiwari RC, Murray T et al. 6 months 44 (92) 43 (92) Cancer statistics . CA Cancer J Clin 2004; 54: 8–29 2 Olsson CA, Goloboff ET. Detection and treatment of prostate cancer: perspective reconstruction, as evaluated here. There are of the urologist. J Urol 1994; 152: 1695– TABLE 2 Correlation between the presence of no data on this issue probably because of the 9 urinary extravasation and the rates of BN generally accepted concept that eversion of 3 Catalona WJ, Smith DS, Ratliff TL. sclerosis and urinary continence the bladder mucosa is necessary to prevent Measurement of prostate-specific antigen BN sclerosis [5]. We consider that the present in serum as a screening test for prostate Urinary extravasation results are reliable, as they were obtained in a cancer. New Engl J Med 1991; 324: 1156– Variable, n (%) yes no randomized and prospective trial, with all RPs 61 N patients 26 69 by the same surgeon. This differs from other 4 Walsh PC, Donker PJ. Impotence BN sclerosis published studies in which surgical technique following radical prostatectomy. insight 2 months 26 (100) 68 (99) and patient outcome were usually evaluated into etiology and prevention. J Urol 1982; 6 months 0 1 (1) retrospectively, and the procedures often 128: 492–7 Urinary continence performed by different surgeons from the 5 Walsh PC, Lepor H, Eggleston JC. 48 h 14 (54) 51 (74) same institution [15,16]. Radical prostatectomy with preservation 2 months 23 (88) 61 (88) of sexual function: anatomical and 6 months 24 (92) 61 (91) Several practical implications arise from the pathological considerations. Prostate study. First, urinary extravasation seems to 1983; 4: 473–85 have no deleterious effect, as was thought 6 Catalona WJ, Carvalhal GF, Mager DE, enteric anastomosis, mucosal eversion can previously, when extravasation was Smith SS. Potency, continence and have a deleterious effect, as it increases the considered to increase the chances of urinary complications rate in 1870 consecutive risk of extravasation of enteric contents. incontinence or BN sclerosis after RP. This radical retropubic prostatectomies. J Urol The same effect at the vesico-urethral concept arose from studies showing that 1999; 162: 433–8 anastomosis could lead to excessive scarring ≈15% of patients who had RP had urinary 7 Guillonneau B, Vallancien G. of the area and possibly to BN sclerosis. From extravasation at ≈4 days after surgery, and of Laparoscopic radical prostatectomy: the the present results, this does not occur after these ≈11% developed BN sclerosis [17,18]. Montsouris technique. J Urol 2000; 163: vesico-urethral reconstruction with no However, the present results are corroborated 1643–9 mucosal eversion, contrary to what was by Schatzl et al. [14], who showed that urinary 8 Turk I, Deger S, Winkelmann B, initially suggested by Walsh [5]. extravasation does not compromise the rate Schonberger B, Loening SA. of urinary continence. Another practical Laparoscopic radical prostatectomy. Reviewing current reports we found none on implication of the present study is that technical aspects and experience with 125 the role of mucosal eversion during BN mucosal eversion before vesico-urethral cases. Eur Urol 2001; 40: 46–52

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9 Neckell T, Welter E, Neckell M. Single- 16 Zhang Y, Glass A, Bennet N, Oyama KA, EDITORIAL COMMENT layer digestive sutures (manual and Gehan E, Gelmann EP. Long-term mechanical). Observations after 20 years. outcome after radical prostatectomy The authors are to be congratulated on their Chirurgia 1996; 45: 311–2 performed in a community based health efforts to bring some science to the art of RP. 10 Schumacher I, Lorenz D. Historical maintenance organization. Cancer 2004; Randomized studies are the only way to development of the intestinal suture. 100: 300–7 establish the truth behind the assertions of Chirurg 1991; 62: 71–4 17 Patel R, Lepor H. Removal of experienced surgeons, who tend to eulogise 11 Kostic LL. Sutures in digestive surgery. urinary catheter on postoperative their particular way of accomplishing RP Acta Chir Iugosl 1994; 41 (Suppl. 2): 211– day 3 or 4 after radical retropubic without subjecting their theories to rigorous 20 prostatectomy. Urology 2003; 61: testing. This study suggests that mucosal 12 Hardy KJ. A view of the development of 156–60 inversion may not reduce either anastomotic intestinal suture. Part I. From legend to 18 Nadu A, Salomon L, Hoznek A et al. Early leakage or bladder neck contracture. However, practice. Aust N Z J Surg 1990; 60: 299– removal of the catheter after laparoscopic there were relatively few patients, and when 304 radical prostatectomy. J Urol 2001; 166: assessing a relatively uncommon 13 Srougi M, Nesrallah LJ, Kaufmann 1662–4 complication like bladder neck contracture, a JR, Nesrallah A, Leite KR. Urinary 19 Vallancien G, Guillonneau B, larger series of patients may be required. continence and pathological outcome Cathelineau X, Baumert H, Doublet JD. Another point is that the process of mucosal after bladder neck preservation during Localized prostatic cancer: treatment with eversion may also help to achieve radical retropubic prostatectomy: a laparoscopic radical prostatectomy: study haemostasis at the bladder neck. Other randomized prospective trial. J Urol 2001; with 841 cases. Bull Acad Natl Med 2002; important technical questions, e.g. the 165: 815–8 186: 117–23 duration of urethral catheterization, and the 14 Schatzl G, Madersbacher S, Hofbauer J pros and cons of laparoscopic and robotic et al. The impact of urinary extravasation Correspondence: Miguel Srougi, Division of approaches, also need to be assessed in a after radical retropubic prostatectomy on Urology, Federal University of São Paulo, Rua similar comparative manner in large series. It urinary incontinence and anastomotic Peixoto Gomide, 2055/81, 01409–003 São is to be hoped that this paper stimulates strictures. Eur Urol 1999; 36: 187–90 Paulo, SP, Brazil. others to undertake such endeavours. 15 Begg CB, Riedel ER, Bach PB et al. e-mail: [email protected] Variations in morbidity after radical ROGER KIRBY prostatectomy. New Engl J Med 2002; Abbreviations: RP, radical prostatectomy; BN, 346: 1138–44 bladder neck.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article PSA-ACT IN MEN WITH A PSA OF 2.0–4.0 ng/mL KOBAYASHI et al.

Prostate-speciﬁc antigen (PSA) complexed to a1-antichymotrypsin improves prostate cancer detection using total PSA in Japanese patients with total PSA levels of 2.0–4.0 ng/mL

TAKASHI KOBAYASHI, TOSHIYUKI KAMOTO*, KOJI NISHIZAWA, KENJI MITSUMORI, KEIJI OGURA and YOSHIHIRO IDE† Departments of Urology and †Surgical Pathology, Hamamatsu Rosai Hospital, Hamamatsu, and Urology, *Kyoto University Graduate School of Medicine, Kyoto, Japan Accepted for publication 8 November 2004 Presented in part at the 98th Annual Meeting of AUA, Chicago, Illinois, April 26–May 1, 2003

OBJECTIVE prostate volume-adjusted density were and benign disease in men with PSA levels evaluated by receiver operating characteristic of 2.0–4.0 ng/mL was PSA-ACT density (area To assess the utility of prostate-specific (ROC) analysis. under the curve 0.852) which provided 66% antigen (PSA) complexed to a1- specificity at a sensitivity of 90%. antichymotrypsin (PSA-ACT) in prostate RESULTS cancer screening in Japanese men with a total CONCLUSIONS PSA level of 2.0–4.0 ng/mL, as improving Of 1003 men enrolled, 547 met the biopsy cancer detection in men with these total PSA criteria and a biopsy was taken in 315 (57.6%) PSA-ACT is better than total PSA and levels is a challenge for clinical urologists. patients. The area under the ROC curve for equivalent to the free-to-total ratio for PSA-ACT (0.679) was significantly greater detecting prostate cancer in men with PSA PATIENTS AND METHODS than that for total PSA (0.601, P = 0.04) and levels of 2.0–4.0 ng/mL, and is thus useful for equivalent to that for the free-to-total ratio reducing the number of unnecessary biopsies. Total PSA and PSA-ACT were prospectively (0.686, P = 0.911) in 116 men, including assessed and prostate biopsy recommended 27 with cancer with total PSA levels of KEYWORDS for patients who met either of two thresholds, 2.0–4.0 ng/mL. PSA-ACT was more specific i.e. a total PSA of ≥2.0 ng/mL or a PSA-ACT of than the free-to-total ratio at a sensitivity PSA-ACT, diagnosis, prostatic ≥1.5 ng/mL. The diagnostic ability of total PSA of 95% (36% vs 18%, P < 0.05). The best adenocarcinoma, unnecessary biopsy, receiver and PSA-ACT, and free-to-total PSA ratio and variable for discriminating between cancer operating characteristic analysis

INTRODUCTION from BPH in men with PSA levels of and free PSA and PSA-ACT were simultaneous <10.0 ng/mL. on the same serum sample, which was PSA is an extremely useful tumour marker, obtained by venepuncture before with a high sensitivity for the early detection There have been a few studies on the utility of manipulation of the prostate, then of prostatic carcinoma and for the follow-up PSA-ACT for detecting prostate cancer in men immediately frozen at -70∞C and assessed after treatment. Although using a low PSA with PSA levels of <4.0 ng/mL [11] but the prospectively within 3 days. Total and free threshold for prostate biopsy improves the utility of PSA-ACT in screening in Japanese PSA were quantiﬁed using the Tandem-R PSA treatment outcome [1,2], lowering the men with total PSA levels of 2.0–4.0 ng/mL Assay (Hybritech Inc., San Diego, CA), a solid- threshold results in more unnecessary has yet to be elucidated. Herein we report a phase two-site immunoradiometric assay biopsies. prospective study on the diagnostic ability of using two murine monoclonal antibody PSA-ACT compared with total PSA. preparations speciﬁc for distinct sites on the Serum PSA occurs in several molecular forms, PSA molecule. PSA-ACT was determined as i.e. an unbound free form and complexed PATIENTS AND METHODS described previously [12] with a two-site forms bound to a1-antichymotrypsin enzyme immunoassay (Markit-M, Dainippon (PSA-ACT), a2-macroglobulin, protein C The patients enrolled in the study were men Pharmaceutical Co. Ltd, Suita, Japan), in inhibitor, a1-antitrypsin, and inter-a-trypsin aged £ 79 years who presented mainly for which standard PSA-ACT and its titre as PSA inhibitor [3,4]. Recent reports show that LUTS and were screened for prostate cancer are adjusted by the Stanford reference [13]. measuring some molecular forms, including between April 2001 and June 2003. The PSA complexed to a1-protease inhibitor clinical evaluation comprised a measurement A TRUS-guided prostatic needle biopsy was [5], complex PSA [6–8] and PSA-ACT [9,10], of prostate volume by TRUS, a DRE and serum recommended in patients with either a total improve the discrimination of cancer PSA measurement. The three assays for total PSA level of ≥2.0 ng/mL or PSA-ACT of

KOBAYASHI ET AL.

≥1.5 ng/mL. Abnormal DRE ﬁndings were also TABLE 1 The clinical characteristics of the 315 patients undergoing prostate biopsy, stratiﬁed by PSA considered an indication for biopsy. After levels written informed consent was obtained, a 6–10-core biopsy was taken. Between April Serum PSA (ng/mL) 2001 and October 2002, a 10-core biopsy Characteristic 2.0–4.0 4.1–10.0 10.1 (four core, lateral-mid and lateral-base, in ≥ addition to the conventional sextant sites) N116138 61 was taken in patients with prostate volumes Median (range): age, years 69 (50–79) 69 (51–79) 71 (46–79) of ≥50 mL. Thereafter, every patient had a 10-core biopsy and consequently, 158 of prostate volume, mL 36.1 (13.9–98.6) 40.4 (13.9–156.0) 42.0 (15.6–105.9) 254 (62.2%) patients with a PSA level of Abnormal DRE, % 2.6 4.3 36.1 2.0–10.0 ng/mL had a 10-core biopsy n (%) biopsy cores (Table 1). The biopsies were examined by one 6 46 (39.7) 50 (36.2) 25 (41.0) pathologist, and specimens reported as an 10 70 (60.3) 88 (63.8) 36 (59.0) atypical gland or prostatic intraepithelial Cancer detection rate, % 23.3 26.8 67.2 neoplasia were scored as negative for all further analyses.

The diagnostic utility of PSA-associated and intermediate PSA groups was 23.3 (27 of FIG. 1. Scatter plots for total PSA and PSA-ACT variables for detecting cancer was evaluated 116) and 26.8% (37 of 138), respectively. showing a close linear correlation (0.713 ¥ total PSA using the area under (AUC) the receiver – 0.12). The solid line is the regression and the dotted operating characteristic (ROC) curve, the In the ROC analysis of the 116 patients in the line that for equivalence. curves being traced using appropriate low PSA group, the AUC for PSA-ACT was software. All tests were two-sided and significantly larger than that for total PSA 10 statistical significance was indicated at (Fig. 2A; Table 2), whereas there was no 8 P < 0.05. significant difference in the 138 of the intermediate and the 31 of the high PSA 6 RESULTS group (Fig. 2B,C). The proportional variables 4 were comparable in both the low and During the 26-month period, 1003 Japanese intermediate PSA groups (Table 2). Sole use of ng/mL PSA-ACT, 2 men (mean age 67.1 years, SD 8.0, range PSA-ACT had an almost equivalent AUC to 46–79) were enrolled in the study, and all had free/total ratio (P 0.911). Of all PSA- 0 = 0246810 total and free PSA and PSA-ACT measured. associated variables, PSA-ACT density was the Total PSA, ng/mL There was a significant linear correlation strongest predictor in both the low and between PSA-ACT and total PSA (r = 0.96; intermediate PSA groups, although the Fig. 1), whereas the correlation between total difference from total PSA density was not and free PSA was weak (r = 0.24; 0.131 ¥ total statistically significant (Table 2). False-negative results from sampling error PSA + 0.226). There were only seven (0.7%) could influence the cancer detection rate, cases in which the value of PSA-ACT was PSA-ACT gave significantly better specificities particularly in patients with a six-core biopsy. greater than that of total PSA. for avoiding an unnecessary biopsy than total The cancer detection rate in the 46 patients PSA in the low-PSA group, whereas its ability who had six cores taken was 22%, compared Of the 1003 men, 544 (54.2%) and 506 was not significantly different from total PSA with 24% in the remaining 70 assessed with a (50.4%) met the threshold criteria of total PSA in the intermediate-PSA group (Table 2). At 10-core biopsy (Table 3; P = 0.825, Fisher’s (≥2.0 ng/mL) and PSA-ACT (≥1.5 ng/mL). 95% sensitivity, the specificity of PSA-ACT exact test). These results may be explained by There were 44 (4.4%) cases in which only one was 36% compared with 18% for the free-to- the difference in prostate volume of the of the two assays was a positive result at the total ratio (P < 0.001, Fisher’s exact test). In patients in the two groups. The median thresholds chosen for biopsy (43 PSA and the low-PSA group, 2.5 biopsies were prostate volumes were 30.4 mL in the six-core one PSA-ACT). Of these 44 men, 19 who had necessary to diagnose one cancer using PSA- and 41.3 mL in the 10-core group (P < 0.001, positive result for only total PSA had a biopsy ACT, whereas four biopsies were necessary Mann–Whitney U-test). In addition, although and cancer was diagnosed in only one (5%). using total PSA. Using PSA-ACT density, which both total PSA and PSA-ACT were higher provided 66% specificity at a sensitivity of in the six-core than in the 10-core group, Of the 547 patients who met at least one of 90% (Table 2), only 1.5 biopsies would be there was no significant difference in the the two criteria, 315 (57.6%) had a prostate necessary to diagnose one cancer. The AUCs proportion of PSA-ACT to total PSA (Table 3). biopsy (Table 1); of these, 116, 138 and 61 had for PSA-ACT and the difference from those of total PSA levels of 2.0–4.0 (low PSA), 4.1–10.0 total PSA tended to be greater as the PSA level DISCUSSION (intermediate) and ≥10.1 ng/mL (high PSA), decreased (Table 2). As serum PSA decreased, respectively. Cancer was diagnosed in 105 of the ratio of free PSA to PSA-ACT and its SD Whether PSA-ACT is more useful for the early the 315 men (overall cancer detection rate increased significantly (Fig. 3, P < 0.001, detection of cancer than variables associated 33%) and the cancer detection rate in the low ANOVA). with total PSA combined with free PSA or

PSA-ACT IN MEN WITH A PSA OF 2.0–4.0 ng/mL

FIG. 2. Comparison of ROC curves between total PSA TABLE 2 Speciﬁcities of PSA-associated variables related to sensitivity (green dashed line) and PSA-ACT (solid red line) at a total PSA of 2.0–4.0 (A), 4.1–10.0 (B) and ≥10.1 ng/ Speciﬁcity (%) at sensitivity of (threshold) mL (C) for discriminating prostate cancer from BPH. PSA group ng/mL (n) 95% 90% 80% AUC The line of equivalence is black. 2.0–4.0 (116) A Total PSA 22.5 (>2.3) 25.8 (>2.4) 28.1 (>2.5) 0.601* 100 PSA-ACT 36.0 (>1.6) 40.4 (>1.7) 52.8 (>1.8) 0.679* PSA-ACT/total PSA 38.2 (>0.595) 40.4 (>0.609) 50.6 (>0.645) 0.643† 80 Free/total PSA 18.0 (<0.292) 37.1 (<0.241) 50.6 (<0.203) 0.686† Free/PSA-ACT 28.1 (<0.447) 31.5 (<0.428) 53.9 (<0.300) 0.698† 60 Total PSA density 43.8 (>0.071) 52.8 (>0.073) 74.2 (>0.087) 0.832† PSA-ACT density 59.6 (>0.049) 66.3 (>0.053) 79.8 (>0.064) 0.852† 40 4.1–10.0 (138) Sensitivity, % Total PSA 7.9 (>4.2) 18.8 (>4.5) 22.8 (>4.7) 0.553† PSA-ACT 8.9 ( 2.7) 18.8 ( 3.0) 30.7 ( 3.3) 0.596† 20 > > > PSA-ACT/total PSA 7.9 (>0.527) 28.7 (>0.609) 38.6 (>0.644) 0.626† Free/total PSA 18.8 (<0.231) 37.6 (<0.196) 68.3 (<0.149) 0.782† 0 Free/PSA-ACT 27.7 (<0.344) 56.4 (<0.249) 66.3 (<0.214) 0.769† B Total PSA density 26.7 (>0.100) 32.7 (>0.105) 60.4 (>0.146) 0.768† 100 PSA-ACT density 19.8 (>0.057) 24.8 (>0.067) 65.3 (>0.105) 0.774† ≥10 (61) 80 Total PSA –––0.529† PSA-ACT –––0.595† 60 *P = 0.04. †P > 0.05. 40 Sensitivity, %

20 FIG. 3. Changes in the ratio of free PSA to PSA-ACT previously [9,14–16]. There appears to be a 0 in relation to the total PSA range. The ratio and the growing consensus that PSA-ACT is slightly SD tended to be significantly greater in the lower PSA better than total PSA but not statistically C ranges. The total number of patients in the figure is significantly so in this PSA range. Free PSA 100 not identical to that of the study because patients may be important in explaining why the AUCs with a free PSA level of <0.1 ng/mL (the minimum for PSA-ACT tend to be greater at lower PSA 80 limit of detection) were excluded. level. That the ratio of free PSA to PSA-ACT was greater at lower PSA levels indicates that 60 0.7 free PSA has a greater effect on total PSA at 0.6 P < 0.001 (ANOVA) lower PSA levels, resulting in PSA-ACT being 40 0.5 more specific than total PSA, which is Sensitivity, % 0.4 theoretically independent of the variation in 20 0.3 free PSA that might be greater at lower PSA ranges. 0.2 0 Free-to-ACT ratio 0.1 020406080100 Some investigators have reported that early 0 cancer detection with a low PSA level 100-Specificity, % 0 1.9 2.0 4.0 4.1 10 10 - - - ≥ improves the positive surgical margin rate in N 348 250 211 75 Total PSA range, ng/mL radical prostatectomy [1] or lowers clinical prostate volume remains controversial stage, resulting in improved prognoses [2]. [9–11,14–16]. In the present ROC analysis However, using a low PSA threshold for biopsy (Fig. 2) the AUC for PSA-ACT was significantly newly developed marker with a similar ability results in more unnecessary biopsies. Using greater than that for total PSA in the low PSA to the combination of free and total PSA, it is PSA-ACT, the specificity improved from 25.8% group (Table 2). The tendency was similar in possible that PSA-ACT may be more cost- to 40.4% at a sensitivity of 90%, and the patients with a normal DRE, in which PSA- effective, although this requires further study. number of biopsies required to detect one derived variables are more important (data cancer decreased from 4 to 2.5 (Table 2). If a not shown). In addition, the sole use of For men with an intermediate PSA level threshold for PSA-ACT of >1.7 ng/mL (at 90% PSA-ACT gave an equivalent AUC to the (4.1–10.0 ng/mL) there was no statistically sensitivity) had been applied, 36 of 105 free/total PSA ratio in this PSA range. When significant difference between total PSA and biopsies would have been spared, whereas a considering the possible role of PSA-ACT, a PSA-ACT on ROC analyses, as reported threshold for total PSA of >2.4 ng/mL would

KOBAYASHI ET AL.

have avoided only 25. Thus using only PSA- TABLE 3 Total PSA and PSA-ACT in 1003 patients ACT was better than using the free-to-total ratio; the specificity of PSA-ACT was better Biopsy cores than that of the free-to-total ratio both at Median (range) 610P 95% (36% vs 18%) and 90% (40% vs 37%) sensitivity. PSA-ACT density had the greatest N4670 AUC on ROC analysis (0.852, Table 2), similar Total PSA, ng/mL 3.2 (2.1–4.0) 2.9 (2.0–4.0) 0.048 to results in previous reports [9,10]. PSA-ACT, ng/mL 2.2 (1.1–3.3) 1.8 (1.0–3.5) 0.043 ACT/total ratio 0.667 (0.393–0.914) 0.680 (0.462–0.90) 0.389 From the present study, for diagnosing Prostate volume, mL 30.4 (13.9–49.0) 41.3 (16.7–98.6) <0.001 prostate cancer in Japanese patients with Cancer detection rate, % 21.7 24.3 0.825 serum PSA levels of 2.0–4.0 ng/mL, PSA-ACT is more specific than total PSA, and as specific as the free-to-total PSA ratio throughout the sensitivity range. PSA-ACT was more specific The number of biopsy cores was not constant relatively older (median 69 years) than for a than free-to-total ratio at a sensitivity of in the present study, but the analysis in population being screened by PSA for prostate 95%, around which the threshold values Table 3 suggests that it is less likely that the cancer. As noted above, the thresholds for should be set. limited number of biopsy cores caused a biopsy were slightly too high in relation to age significant bias for the difference between of the men. Another reason for the high For detecting prostate cancer in men with a total PSA and PSA-ACT. proportion of men with a high PSA level is low PSA level some authors have reported the that they were referred with LUTS to a usefulness of complexed PSA [17,18] or pro- Another limitation is that patients with urological clinic. The median prostate volume enzyme PSA [19]. In these reports the PSA abnormal findings on DRE were included. was ª40 mL (Table 1). For prostate cancer molecular forms improved cancer detection However, the proportion of patients with such detection, men referred to urological clinics and were useful for sparing unnecessary findings decreased with decreasing total PSA with LUTS should be considered as distinct biopsies. There have been few reports in which and PSA-ACT (Table 1). Indeed, at a PSA of from a screening population with no these new markers were directly compared. 2.0–4.0 ng/mL, there were only three (2.6%) symptoms; they have a higher PSA level, Unfortunately, other molecular forms of PSA cases with an abnormal DRE, in which the larger prostates and higher cancer incidence were not measured in the current study and biopsy results were all negative for cancer. [21]. Therefore, the results of the present this remains for future research. According to Therefore, this issue seems to have less study should not be directly translated into an recent studies on complexed PSA, and the influence on the main aim of the study, to extensive screening programme for prostate present study, PSA-ACT seems to be as useful assess whether PSA-ACT is a good predictor cancer in which the subjects would be as complexed PSA in having a better for cancer detection in patients with PSA younger men with no LUTS, and further specificity than total PSA and equivalent to levels of 2.0–4.0 ng/mL. studies are warranted. However, PSA-ACT the free-to-total PSA ratio [20]. seems to be promising in that it is more useful The relatively low proportion of patients who in men with a low PSA level than conventional There are some limitations of the present had a biopsy of those who met the biopsy total PSA, and has high specificity. study. In retrospect, the predetermined criteria could create a verification bias. The thresholds for biopsy may be questionable. biopsy rate was 57.6% (315/547) overall and The total PSA threshold of 2.0 ng/mL seems 45.8% (116/253) in men with total PSA levels ACKNOWLEDGEMENTS very low, especially considering that the of 2.0–4.0 ng/mL. Biopsy was uniformly median age of the present men was 67 years. recommended to all men who met the criteria The authors thank Dainippon Pharmaceutical Although we attempted to enrol younger in principle, and depended on the patient’s Co. Ltd, Suita, Osaka, Japan, for laboratory patients and considered the threshold of preference of whether to have a biopsy. There assistance. This study was funded by a 2.0 ng/mL appropriate, the threshold should was no significant difference in median age medical research grant from the Japanese have been higher, or age-related thresholds (68 vs 70 years, P = 0.09, Mann–Whitney U- Labour Welfare Corporation, 2002. used. Indeed, the cancer detection rate in men test) and free-to-total ratio (0.191 vs 0.185, with PSA levels of 2.0–2.4 ng/mL was only 8% P = 0.343) between men who had a biopsy (two of 25). For PSA-ACT, although we and those who did not, whereas total PSA (3.1 CONFLICT OF INTEREST determined the threshold of 1.5 ng/mL to be vs 2.7 ng/mL, P < 0.001) and PSA-ACT (2.0 vs equivalent to that of total PSA based on a 1.8, P = 0.018) differed. This might result in a None declared. Source of funding: medical previous study [10], the present regression significant selection bias and is thus a research grant from the Japanese Labour analysis predicted a PSA-ACT of 1.3 ng/mL at limitation of the study. Welfare Corporation, 2002. a total PSA of 2.0 ng/mL. As one of the aims of the study was to determine appropriate In addition, the proportion of men with a total thresholds for biopsy, provisional values had PSA level of >2.0 ng/mL was 54% (544/1003) REFERENCES to be a little lower, and the thresholds should and greater than expected in a prostate be corrected appropriately as a result of the cancer screening programme. One possible 1 Berger AP, Volgger H, Rogatsch H et al. present study. explanation for this is that the patients were Screening with low PSA cutoff values

results in low rates of positive surgical Prostate specific antigen complexed to specific antigen alpha1-antichymotrypsin margins in radical prostatectomy alpha-1-antichymotrypsin in patients complex for the detection of prostate specimens. Prostate 2002; 53: 241–5 with intermediate prostate specific cancer in patients with a PSA level of 2 Kubota Y, Ito K, Imai K, Yamanaka H. antigen levels. Cancer 2002; 94: 1685–91 4.1–10.0 ng/mL: comparison with PSA- Effectiveness of mass screening for the 10 Kobayashi T, Kamoto T, Isogawa Y et al. related parameters. Int J Urol 2001; 8: prognosis of prostate cancer patients in Ratio of prostate specific antigen minor 589–93 Japanese communities. Prostate 2002; molecular forms to total prostate specific 17 Okihara K, Cheli CD, Partin AW et al. 50: 262–9 antigen is constant regardless of the Comparative analysis of complexed 3 Christensson A, Laurell CB, Lilja H. pathological condition of the prostate. prostate specific antigen, free prostate Enzymatic activity of prostate-specific J Urol 2003; 169: 121–4 specific antigen and their ratio in antigen and its reactions with 11 Zhu L, Leinonen J, Zhang WM, Finne P, detecting prostate cancer. J Urol 2002; extracellular serine proteinase inhibitors. Stenman UH. Dual-label immunoassay 167: 2017–23 Eur J Biochem 1990; 194: 755–63 for simultaneous measurement of 18 Horninger W, Cheli CD, Babaian RJ et al. 4 Lilja H, Christensson A, Dahlen U et al. prostate-specific antigen (PSA)-alpha1- Complexed prostate-specific antigen for Prostate-specific antigen in serum occurs antichymotrypsin complex together with early detection of prostate cancer in men predominantly in complex with alpha 1- free or total PSA. Clin Chem 2003; 49: 97– with serum prostate-specific antigen antichymotrypsin. Clin Chem 1991; 37: 103 levels of 2–4 nanograms per milliliter. 1618–25 12 Kuriyama M, Abrahamsson PA, Urology 2002; 60: 31–5 5 Finne P, Zhang WM, Auvinen A et al. Imai K et al. Determination of serum 19 Sokoll LJ, Chan DW, Mikolajczyk Use of the complex between prostate prostate-specific antigen-alpha1- SD et al. Proenzyme PSA for the early specific antigen and alpha 1-protease antichymotrypsin complex for diagnosis detection of prostate cancer in the inhibitor for screening prostate cancer. of prostate cancer in Japanese cases. 2.5–4.0 ng/ml total PSA range: J Urol 2000; 164: 1956–60 Scand J Urol Nephrol 2001; 35: 5–10 preliminary analysis. Urology 2003; 6 Brawer MK, Cheli CD, Neaman IE et al. 13 Stamey TA. Second Stanford Conference 61: 274–6 Complexed prostate specific antigen on International Standardization of 20 Parsons JK, Partin AW. Applying provides significant enhancement of Prostate-Specific Antigen Immunoassays: complexed prostate-specific antigen specificity compared with total prostate September 1 and 2, 1994. Urology 1995; to clinical practice. Urology 2004; 63: specific antigen for detecting prostate 45: 173–84 815–8 cancer. J Urol 2000; 163: 1476–80 14 Jung K, Brux B, Lein M et al. 21 Morgan TO, Jacobsen SJ, McCarthy WF, 7 Jung K, Elgeti U, Lein M et al. Ratio Determination of alpha1- Jacobson DJ, McLeod DG, Moul JW. of free or complexed prostate-specific antichymotrypsin-PSA complex in serum Age-specific reference ranges for antigen (PSA) to total PSA. Which ratio does not improve the differentiation prostate-specific antigen in black men. improves differentiation between benign between benign prostatic hyperplasia and N Engl J Med 1996; 335: 304–10 prostatic hyperplasia and prostate prostate cancer compared with total PSA cancer? Clin Chem 2000; 46: 55–62 and percent free PSA. Urology 1999; 53: Correspondence: Takashi Kobayashi, 8 Mitchell ID, Croal BL, Dickie A, Cohen 1160–7 Department of Urology, Hamamatsu Rosai NP, Ross I. A prospective study to 15 Bjork T, Piironen T, Pettersson K et al. Hospital, Shogen-cho 25, Hamamatsu, Japan, evaluate the role of complexed prostate Comparison of analysis of the different 430–8525. specific antigen and free/total prostate prostate-specific antigen forms in serum e-mail: [email protected] specific antigen ratio for the diagnosis of for detection of clinically localized prostate cancer. J Urol 2001; 165: 1549– prostate cancer. Urology 1996; 48: 882–8 Abbreviations: ACT, a1-antichymotrypsin; 53 16 Miyake H, Hara S, Nomi M, Arakawa S, ROC, receiver operating characteristic (curve); 9 Saika T, Tsushima T, Nasu Y et al. Kamidono S, Hara I. Value of prostate AUC, area under the curve.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article ANATOMICAL APPROACH TO ENDOPELVIC FASCIA TAKENAKA et al.

A novel technique for approaching the endopelvic fascia in retropubic radical prostatectomy, based on an anatomical study of ﬁxed and fresh cadavers

ATSUSHI TAKENAKA, RYOEI HARA, HIDEO SOGA*, GEN MURAKAMI† and MASATO FUJISAWA Departments of Urology, Kawasaki Medical School and *Kawachi General Hospital, and †Department of Anatomy, Sapporo Medical University School of Medicine, Japan Accepted for publication 29 November 2004

OBJECTIVE achieve continence in 23 consecutive patients endopelvic fascia to the point where who had a radical retropubic prostatectomy the sphincteric branch entered the To present the anatomical basis and details of using the new technique. rhabdosphincter was 5.5 (1.8, 3–8) mm. The a technique for an approach to the endopelvic continence rate at 1, 3, 6 and 9 months after fascia devised to preserve urinary continence. RESULTS surgery using the new technique was 44%, 83%, 96% and 100%, respectively. PATIENTS, MATERIALS AND METHODS Sectional macroscopic observation depicted the fascia of the levator ani as a definite CONCLUSIONS For cross-sectional macroscopic observation, structure adherent to but not fused with seven formalin-fixed specimens of the male the lateral pelvic fascia. The thin fascia Preserving the fascia of the levator ani pelvic contents including the pelvic wall were overlying the levator ani fascia and lateral helps to protect the levator ani muscle, serially sectioned at a 5-mm thickness. Semi- pelvic fascia represented the true endopelvic rhabdosphincter and pudendal nerve serial sections from eight other specimens fascia. Microscopically, the lower part of branches to the rhabdosphincter. In were examined histologically. Eight fresh the fascia of the levator ani was rich in retropubic radical prostatectomy, this cadavers were dissected to mimic the various smooth muscle, which interdigitated with anatomical approach to the endopelvic fascia steps in a retropubic radical prostatectomy. the framework of the rhabdosphincter. In should preserve or allow the earlier recovery After approaching the endopelvic fascia in an fresh cadavers, the levator ani muscle was of urinary continence. anatomically determined manner to reach the removed laterally still covered by its fascia, paraprostatic space, the pubic bone was without visualizing the muscle fibres. Small KEYWORDS removed and nerves near the rhabdosphincter branches from the pudendal nerve entered dissected. To assess the clinical implication of the rhabdosphincter. The mean (SD, range) endopelvic fascia, fresh cadaver, urinary this approach, we examined the time to distance from the lowest point of the incontinence

INTRODUCTION observation in formalin-fixed and fresh The mean (range) age at death was 77 male cadavers, including observations (64–90) years. The seven specimens used In urological surgery, the fascia between the on dissection by a procedure similar to for sectional macroscopic observation were pelvic wall and pelvic organs is designated the pelvic surgery, as described recently [4]. In removed from cadavers en bloc, including ‘endopelvic fascia’ (EPF). Urologists must addition, we considered how best to manage all intrapelvic organs and the pelvic wall. incise the EPF to open a route to the the EPF to protect nerves contributing to The specimens were sectioned serially, paraprostatic space. Many textbooks on urinary continence and to the either frontally or axially, at a thickness urological surgery advise that a white line of rhabdosphincter. of approximately 5 mm. The other eight condensed fascia can be identified at the specimens were processed for histological bottom of the EPF, and stress the importance study as follows: after dissecting the of incising laterally to the white line to PATIENTS, MATERIALS AND METHODS prevesical space, the pubic bone was removed avoid unnecessary haemorrhage from and the membranous urethra, the apex of the prostatovesical veins [1]. Although Myers [2,3] For the anatomical study, macroscopic prostate, the proximal portion of the corpora studied the anatomy of pelvic fascia related to sectional or histological observations were cavernosa, and the pelvic floor muscles retropubic radical prostatectomy (RP), we made in 15 intact formalin-fixed male pelves. surrounding the membranous urethra were consider that treating the EPF according to These specimens were obtained from cadavers excised en bloc. These large tissue blocks were the topographic anatomy of the fascia, nerves donated to Sapporo Medical University that cut to 12–15 cm3. The specimens were and rhabdosphincter has not been fully had been fixed by arterial injection of 10% dehydrated, embedded in paraffin (melting elucidated. We examined the configuration formalin solution and stored at room point 58∞C) and cut into 4–7 mm-thick semi- of the EPF by sectional and histological temperature for at least 1 month before use. serial frontal or axial sections. Haematoxylin

ANATOMICAL APPROACH TO ENDOPELVIC FASCIA

FIG. 1. Macroscopic findings in the area of the EPF and FLA. A: The LA, FLA and the apex of the prostate in a formalin-fixed cadaver. A frontal section along the membranous urethra shows the FLA as a well-defined structure adhering to the prostate-urethral junction. B: In an axial section from another formalin-fixed specimen, the FLA on the right side was not attached to the LPF; thin fascia connected the FLA and the LPF. We think that this thin layer is the EPF. The FLA on the left side was attached to the LPF, and there was a space between the FLA and the LA muscle. Black and white arrow, the FLA; black arrowhead, LPF; black star, junction of the FLA and the membranous urethra; white star, EPF; asterisk, space between the FLA and the LPF; #, space between the FLA and the LA; PR, prostate; UR, urethra; REC, rectum.

# LA UR LA LA

REC

and eosin staining or immunohistochemical For the clinical study, 23 patients with to be the EPF. The FLA on the left side was staining as described previously by Murakami clinically localized (T1-2N0M0) prostate attached to the LPF, and there was a space et al. [5] was used. The primary antibody used cancer had a retropubic RP using the new between the FLA and LA (Fig. 1B). Spaces in the immunohistochemical evaluation was technique for approaching the EPF. To avoid between the FLA and the LPF, or between FLA monoclonal antihuman a-smooth muscle positive margins we included in this pilot and LA, were considered artefacts created in actin (mouse IgG2a, k; Dako, Kyoto, Japan). study only patients with a PSA level of preserving the specimen. The FLA sometimes <20 ng/mL and biopsy specimens that did not adhered to the LPF, but these fascial In the eight fresh cadavers, dissections were contain Gleason grade 5 disease. The patients structures did not fuse, and could be sequential to mimic the various steps in had a mean (SD) age of 68.2 (4.8) years, PSA separated by dissection. retropubic RP leading up to exposure of the level of 11.2 (6.4) ng/mL and a mean follow- apex of the prostate. The mean age at death up of 13.5 (2.3) months. The urinary catheter In the fresh cadavers we completely removed for these specimens was 78 (71–88) years. The was removed 1–3 weeks after surgery. pre- and perivesical fat in a procedure similar cadavers had been donated to Sapporo Patients who did not use incontinence pads to pelvic surgery, and identified the EPF and Medical University within 24 h of death. No were defined as continent. Interviews were the lateral surface of the rectal wall. A white fixatives were used, and hemicorporectomy conducted at regular intervals until the condensed area represented the overlap of and femoral abscission were performed. The patient reported being completely continent. the EPF and FLA. We set out to incise the EPF cadavers were maintained at -20∞C, and according to this anatomical knowledge, and before dissection were thawed gradually to to refine surgical techniques for establishing minimize tissue damage. The dissection was RESULTS access to the paraprostatic space. We carried out using an operating microscope identified the FLA attached to the (¥2.5, Surgical Acuity, Meddleton, WI). The By sectional macroscopic observation we anterolateral side of the bladder and prostate abdominal wall, small intestine and sigmoid identified the levator ani (LA) muscle and the underlying the thin fibrous layer (Fig. 2A). colon were removed, leaving the rectum fascia of the LA (FLA) in frontal and axial When the thin layer representing the EPF was intact. After widening the prevesical space sections. Frontal sections along the incised within the attachment points of the and removing the prevesical fat, the EPF was membranous urethra in formalin-fixed FLA (Fig. 2B), the LA was removed laterally still exposed. After this anatomical approach to cadavers showed the FLA as a distinct covered by the FLA, without visualizing the the EPF, to reach the paraprostatic space, the structure adherent to the prostate-urethral muscle fibres (Fig. 2C). The incision and deep dorsal vein complex was gathered junction (Fig. 1A). In axial sections from removal of the LA was extended carefully in together and the apex of the prostate another formalin-fixed specimen, the FLA on an anteromedial direction to the apex of the exposed. The pubic bone was then removed the right side was not attached to the lateral prostate. Displacing the apex with a specially and the nerves near the rhabdosphincter pelvic fascia (LPF), and only a thin fascia devised notched retractor, we confirmed that dissected. connected them. We considered this thin layer the rhabdosphincter was not exposed

T AKENAKA ET AL.

FIG. 2. The anatomical approach to the EPF in fresh cadavers. We identified the attachment points of the FLA (black arrow) and the LA muscle fibres (dotted arrow) to the anterolateral side of bladder and prostate under the thin fibrous layer (panel A). This thin EPF was incised within the attachment points of the FLA (panel B) and the LA removed, covered laterally by the FLA without visualizing the muscle fibres (panel C). Displacing the apex with a notched retractor confirmed that the rhabdosphincter was not exposed (panel D). Removing the pubic bone showed the FLA (arrowhead) to be the plate forming the pelvic floor, bordering intrapelvic and infrapelvic areas (panel E).

ABC

D E

(Fig. 2D). Removal of the pubic bone identified branch, the pudendal nerve coursed to the junction was reached by exposing the LA the FLA as the plate forming the pelvic floor, penile hilum to become the dorsal nerve of muscle fibres. with the FLA bordering intrapelvic and the penis. infrapelvic regions (Fig. 2E). This procedure In the clinical study, all 23 men regained was completed in six of eight specimens; in Microscopically, the FLA was thick and continence, attained immediately after the other two, when we tried to remove the covered the inferomedial margin of the LA, catheter removal in three (13%), within LA laterally, the FLA was fused with the LPF bordering intrapelvic and infrapelvic regions. 1 week in eight (35%), and within 1, 3, 6 and near the apex of the prostate. In these The FLA did not appear strongly adherent to 9 months in 10 (44%), 19 (83%), 22 (96%) and specimens the prostate-urethral junction was the prostate, differing from the impression all, respectively. reached after exposing the LA muscle fibres. obtained by macroscopic observation, and appearing somewhat counter to the surgical DISCUSSION Small branches from the pudendal nerve practice of many urologists who leave the FLA reached the rhabdosphincter in all fresh on the visceral surface. The FLA overlying the Textbooks on urological surgery describing cadavers (Fig. 3); these represented the lower inner corner of the LA radiated to the retropubic RP direct urologists to incise the sphincteric branch of the pudendal nerve. This framework of the rhabdosphincter (Fig. 4A). so-called EPF to reach the paraprostatic branch was anterolateral to the Staining with anti-smooth muscle actin space. Generally, the ‘EPF’ is thought to refer rhabdosphincter. The mean (SD, range) indicated that the lower part of FLA was rich to the fascia in the transitional area between distance from the lowest point of the FLA to in smooth muscle, and that this component the pelvic wall and pelvic viscera. Many the point where the nerve branch entered the interdigitated with the rhabdosphincter descriptions not based on anatomical study rhabdosphincter was 5.5 (1.8, 3–8) mm. After (Fig. 4B). In two of the eight specimens resemble one that reads, ‘After the EPF is exposing the LA fibres beneath the FLA, the examined histologically, many vessels were incised just lateral to the white line, bare distance between the pelvic floor and the interposed between the FLA and LPF or levator muscle fibres are viewed, which then nerve entry point decreased. The defect situated under the LPF (Fig. 4C). In these are displaced bluntly and laterally from the created in the FLA rendered this nerve specimens, excessive bleeding would have lateral surfaces of prostate and rectum’ [6]. In vulnerable to injury. After giving rise to this resulted unless the prostate-urethral these accounts, the existence and

ANATOMICAL APPROACH TO ENDOPELVIC FASCIA

FIG. 3. Relationship between the FLA and the sphincteric branch from the pudendal nerve (in the right pelvis). while covered by the FLA, without visualizing A: (left) Dissection around the membranous urethra in the fresh cadaver. A small branch from the pudendal the muscle fibres. This point sometimes was nerve entered the rhabdosphincter, representing the sphincteric branch; (right) line drawing of the left anterolateral rather than lateral to the photograph. B Close-up photograph of the square in panel A, right. The distance from the lowest point of the prostate side. Conventionally, the incision FLA to the entry point into rhabdosphincter was 7 mm. PDN, penile dorsal nerve; PN, pudendal nerve; PB, could be made just lateral to this point (i.e. pubic bone; UR, urethra; PR, prostate; NVB, neurovascular bundle; arrowhead, sphincteric branch from the the arcus tendineus pelvic fascia). Thus, we pudendal nerve. advocate a new approach to the EPF based on anatomical study of both formalin-fixed A and fresh cadavers. However, the new approach cannot be applied to all cases; NVB NVB PR PR we encountered some specimens where the FLA fused with the LPF near the apex of the prostate, or where many vessels coursed between the FLA and LPF or under the LPF. In FLA FLA such cases, the approach between FLA and LA UR UR must be changed to avoid excessive blood loss. PN PB PN PB Many recent studies have discussed the PB PB neuroanatomy of the rhabdosphincter. PDN PDN Hollabaugh et al. [10] reported that both the pelvic and pudendal nerves supplied intrapelvic branches that coursed bilaterally, B PR entering the external sphincter at the 5 and 7 o’clock positions. Narayan et al. [11] FLA measured the distance from the prostate apex to the point of nearest pudendal branch entry into the sphincter as 3.2–12.7 mm, similar to the present results (3–8 mm). PB While variable, this distance sometimes was very short (Fig. 3), indicating that surgeons must be very careful manipulating in the prostatic apex and its interface with the LA PDN so as not to injure the nerve branch to the rhabdosphincter. The present new approach to the EPF should prove very useful in this implications of the FLA are not considered. EPF. Steiner [7] and Myers [2], who almost regard. When we reviewed anatomically based always used fresh cadavers for anatomical reports of the EPF the term was used in two study, recognized the existence of the FLA. The The LA is considered to be important in different senses. One meaning used by Steiner present sectional macroscopic observations continence mechanisms [12]. Murakami et al. [7] referred to the parietal fascia lateral to the in formalin-preserved cadavers sharply [5] described the rhabdosphincter as acting so-called arcus tendineus fascia pelvis, contrasted the thick FLA and the thin parietal not only as a sphincter but also as a retractor, distinguishing the EPF from the FLA. On the pelvic fascia, as being distinctly different levator, or force transmitter with the aid other hand, Myers [2] equated the EPF with structures (Fig. 5). While we support Steiner’s of the LA. The present immunostaining the FLA. We think that the intrapelvic fascial opinion, the approach to the paraprostatic finding, that smooth muscle tissue in the anatomy has not been fully elucidated, and space has not been described in detail. In lower part of the FLA interdigitated with the that the terminology is inconsistent. ordinary practice, surgeons who recognize the rhabdosphincter, supports this hypothesis. In existence of the FLA and those who do not, terms of innervation, Juenemann et al. [13] Figures in anatomical textbooks [8,9] tend to incise two fascial planes, the parietal pelvic suggested that the rhabdosphincter and LA show the FLA as a very thick membrane not fascia and the FLA, when they believe that formed a functional complex. Interestingly, attached to the LPF, while the parietal pelvic they are incising the EPF. Nelson et al. [14] described intraoperative fascia is not shown. Anatomists who work electrical stimulation of the neurovascular with formalin-fixed cadavers and have not We used the term ‘EPF’ to refer to the parietal bundle causing an increase in urethral performed surgery use the term ‘EPF’ in the and visceral pelvic fascia, similar to Steiner pressure, functionally identifying the same sense as ‘FLA’, and cannot understand [7], but we approached them by a slightly intrapelvic neural pathway that innervated references to ‘incision of the EPF’. We think different method (Fig. 5). In the fresh-cadaver the male sphincter. An additional increase in that the anatomical discrepancy between study, we incised the thin parietal and visceral urethral pressure upon pelvic wall stimulation observations from surgical and formalin-fixed pelvic fascia just medial to the attachment represented technical failure, but the result cadavers has resulted in confusion about the point of the FLA, and removed the LA laterally nonetheless emphasises the significance of

T AKENAKA ET AL.

FIG. 4. Configurations of the FLA. A: Microscopic findings (frontal section through urethra) of the FLA near the FIG. 5. Scheme of the fascial anatomy in the area apex of the prostate (haematoxylin and eosin). The FLA is thick and covers the inferomedial margin of the LA, around the prostate. Almost all urologists approach radiating to the framework of rhabdosphincter over the lower inner corner of the LA. B: High magnification the paraprostatic space on the line indicated by the of staining with anti-smooth muscle actin, corresponding to the square in panel A. The FLA was rich in solid arrow. The new anatomical approach (line with smooth muscle; this component interdigitated with the rhabdosphincter. C: Many vessels coursed between dotted arrow) might be a better alternative in many the FLA and the LPF, or deep to the LPF. Arrow, FLA; white star, vessels under LPF; black star, vessels between the cases. FLA and the LPF; Rha, rhabdosphincter. Scale bars; 10 mm in panels A and C, 2 mm in panel B. EPF LPF AC (Visceral and parietal fascia) prostate prostate LA

LA urethra prostate Rha urethra Rha

B rectum FLA

Pertinent surgical anatomy. Atlas Urol Clin North Am 1994; 2: 1–18 3 Myers RP. Practical surgical anatomy for radical prostatectomy. Urol Clin North Am 2001; 28: 473–90 4 Takenaka A, Murakami G, Soga H, Han the LA for urinary continence. Akita et al. [15] study that the new approach does not lead to SH, Arai Y, Fujisawa M. Anatomical reported various communications between more positive margins than the usual nerve- analysis of the neurovascular bundle the branches of pelvic plexus and pudendal sparing approach [22]. supplying penile cavernous tissue to nerve; these communicating branches ensure a reliable nerve graft after penetrated the LA. Thus preserving the LA is In conclusion, this anatomical study of the radical prostatectomy. J Urol 2004; very important for maintaining continence. EPF led us to a new surgical approach to the 172: 1032–5 EPF. The area under the FLA just lateral to the 5 Murakami G, Nakajima F, Sato TJ, There are conﬂicting reports on the risk prostatic apex and the sphincter should be Tsugane MH, Taguchi K, Tsukamoto T. factors for urinary incontinence after RP, e.g. considered important for urinary continence. Individual variations in aging of the male patient age, preoperative continence status, In retropubic RP, this new approach should urethral rhabdosphincter in Japanese. Clin previous TURP, anastomotic stricture, stage of facilitate preservation or early recovery of Anat 2002; 15: 241–52 disease and, of course, surgical technique and urinary continence, as preserving the FLA 6 Bartsch G, Poisel S eds. Approaches in the experience of the surgeon. Applying this leads to protection of the LA and the Urologic Surgery. New York: Thieme new technique in the present pilot study led rhabdosphincter, as well as avoiding Medical Publishers Inc., 1994: 190–204 to a good continence rate and a rapid return the pudendal nerve branch to the 7 Steiner MS. Continence-preserving of urinary control. The present continence rhabdosphincter. anatomic radical retropubic results are better than in other recent reports prostatectomy. Urology 2000; 55: 427–35 from large series [16–20], where continence CONFLICT OF INTEREST 8 Kopf-Maier P. Atlas of Human Anatomy, rates were 88.8–99.5%. In the present study, Vol. 2, 5th edn. Berlin: Karger 2001; 169– 83% of patients were continent at 3 months, None declared. 262 which compares favourable with a report by 9 Putz R, Pabst R. Atlas of Human Eastham et al. [21], where 75% of patients REFERENCES Anatomy, Vol. 2, 13th edn. Philadelphia: were continent at 4 months. Lippincott, Williams & Wilkins 2001; 132– 1 Walsh PC. Anatomic radical retropubic 261 Currently we cannot comment on whether prostatectomy. In Walsh PC, Retik AB, 10 Hollabaugh RS Jr, Dmochowski RR, the new surgical procedure causes more Vaughan ED, Wein AJ eds. Campbell’s Steiner MS. Neuroanatomy of the male positive surgical margins because we limited Urology, 8th edn. Philadelphia: WB rhabdosphincter. Urology 1997; 49: 426– patients in this pilot study to those who were Saunders, 2002; 3107–29 34 strongly predicted to have localized tumours. 2 Myers RP. Radical prostatectomy: 11 Narayan P, Konety B, Aslam K, Aboseif However, it is evident from our anatomical

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S, Blumenfeld W, Tanagho E. the male urethral sphincter. Surg Radiol 20 Selli C, De Antoni P, Moro U, Neuroanatomy of the external urethral Anat 2003; 25: 387–92 Macchiarella A, Giannarini G, Crisci A. sphincter: implications for urinary 16 Moinzadeh A, Shunaigat AN, Libertino Role of bladder neck preservation in continence preservation during radical JA. Urinary incontinence after retropubic urinary continence following radical prostate surgery. J Urol 1995; 153: 337– prostatectomy: the outcome of a surgical retropubic prostatectomy. Scand J Urol 41 technique. BJU Int 2003; 92: 355–9 Nephrol 2004; 38: 32–7 12 Mikuma N, Tamagawa M, Morita K, 17 Maffezzini M, Seveso M, Taverna G, 21 Eastham JA, Kattan MW, Rogers E et al. Tsukamoto T. Magnetic resonance Giusti G, Benetti A, Graziotti P. Risk factors for urinary incontinence after imaging of the male pelvic floor: the Evaluation of complications and results in radical prostatectomy. J Urol 1996; 156: anatomical configuration and dynamic a contemporary series of 300 consecutive 1707–13 movement in healthy men. Neurourol radical retropubic prostatectomies with 22 Sokoloff MH, Brendler CB. Indications Urodyn 1998; 17: 591–7 the anatomic approach at a single and contraindications for nerve-sparing 13 Juenemann KP, Lue TF, Schmidt RA, institution. Urology 2003; 61: 982–6 radical prostatectomy. Urol Clin North Am Tanagho EA. Clinical significance of 18 Lepor H, Kaci L, Xue X. Continence 2001; 28: 535–43 sacral and pudendal nerve anatomy. J Urol following radical retropubic 1988; 139: 74–80 prostatectomy using self-reporting Correspondence: Atsushi Takenaka, 14 Nelson CP, Montie JE, McGuire EJ, instruments. J Urol 2004; 171: 1212–5 Department of Urology, Kawasaki Medical Wedemeyer G, Wei JT. Intraoperative 19 van Randenborgh H, Paul R, Kubler H, School, 577 Matsushima, Kurashiki, nerve stimulation with measurement of Breul J, Hartung R. Improved urinary 701–0192, Japan. urethral sphincter pressure changes continence after radical retropubic e-mail: [email protected] during radical retropubic prostatectomy: prostatectomy with preparation of a long, a feasibility study. J Urol 2003; 169: partially intraprostate portion of the Abbreviations: EPF, endopelvic fascia; LA, 2225–8 membranous urethra: an analysis of 1013 levator ani; FLA, fascia of the levator ani; LPF, 15 Akita K, Sakamoto H, Sato T. Origins consecutive cases. Prostate Cancer the lateral pelvic fascia; RP, radical and courses of the nervous branches to Prostatic Dis 2004; 7: 253–7 prostatectomy.

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Original Article LYMPHOCELES AFTER RADICAL RETROPUBIC PROSTATECTOMY PEPPER et al.

The incidence and treatment of lymphoceles after radical retropubic prostatectomy

RUTH J. PEPPER, JHUMUR PATI and AMIR V. KAISARY Department of Urology, Royal Free Hospital, London, UK Accepted for publication 9 November 2004

OBJECTIVE lymphocele was suspected and then CONCLUSION conﬁrmed by imaging studies (computed To determine the incidence and treatment of tomography or ultrasonography). The rate of symptomatic lymphocele lymphoceles after retropubic radical formation was low after RP, with an overall prostatectomy (RP). incidence of 3.5%. Ultrasonography was RESULTS effective in detecting lymphoceles and PATIENTS AND METHODS ultrasonographically guided percutaneous Nine patients developed symptomatic drainage an effective treatment. Up to January 2004, 260 patients who had a lymphoceles; eight of these were detected by retropubic RP in one institution by one imaging. Four lymphoceles required KEYWORDS surgeon were assessed retrospectively, using intervention while the remainder regressed the patients’ notes or the computerized spontaneously. No complications were radical prostatectomy, lymphocele, results system to determine whether a reported in the group that was treated. ultrasonography, percutaneous aspiration

INTRODUCTION RP and determine the best method of limb swelling leading to investigation and diagnosis and treatment. the diagnosis of a deep vein thrombosis, A lymphocele, also known as a lymphocyst, is abdominal distension and constipation, a collection of lymphatic fluid occurring as a and urinary frequency. These patients were consequence of surgical dissection and PATIENTS AND METHODS evaluated further with abdominal and pelvic inadequate closure of afferent lymphatic US (Fig. 1a) and CT (Fig. 1b). In the ninth vessels. It is an uncommon although well In this retrospective study, 260 patients patient US failed to detect a lymphocele or documented complication after renal had retropubic RP for localized prostatic any other pathology, and the condition transplantation or pelvic surgery. A large carcinoma by one surgeon, up to January was presumed. This patient presented with study of 1243 patients [1] treated by radical 2004. The operative approach was through a abdominal distension and lower limb oedema. prostatectomy (RP) showed that 75 had a lower midline incision, followed by bilateral Imaging failed to show a lymphocele and lymphocele afterward, an incidence of 6%; internal iliac pelvic nodal clearance along the the symptoms gradually resolved with no 2.3% of these were minor lymphoceles and iliac vessels, up to the level of the obturator intervention or further investigation. In four were drained under ultrasonographic nerve inferiorly and including the lymph node patients there was spontaneous resolution guidance, with only eight patients (0.6%) of Cloquet laterally. All patients received peri- of the symptoms and they were treated requiring CT-guided drainage or operative antibiotics and had a pelvic drain expectantly with regular US surveillance marsupializiation. In the remaining 3.1% the placed after RP. as outpatients until the resolution was lymphoceles were considered a minor complete. In these patients the main complication, which resolved spontaneously The patients’ notes or the computerized symptom was pelvic fullness. The remaining and required no intervention. results system were examined to determine four patients with proven lymphoceles Ultrasonography (US) and occasionally CT are whether a lymphocele was suspected and required percutaneous or fluoroscopically used to diagnose lymphoceles, as well as then confirmed by imaging studies (CT or US). guided drainage, in the radiology suite by a cytological and biochemical analysis of the uroradiologist with the patient under local aspirate, which can be used to aid in their anaesthesia. Each patient was given a course diagnosis. The incidence of clinically detected RESULTS of prophylactic antibiotics during and for 72 h lymphoceles in laparoscopic pelvic lymph after the procedure. node dissection has been reported to be as Nine patients developed symptomatic low as 1%, and lower than the 4.7–14.8% lymphoceles, which were apparent at Clinically significant lymphoceles were after open pelvic lymph node dissection [2]. 12–120 days after RP. The main presenting detected in eight of the nine symptomatic symptoms were pelvic fullness and lower patients, using US or CT. One of the eight The aim of the present study was to determine abdominal pain in four patients, and one lymphoceles detected was a multilocular the incidence of lymphoceles after retropubic patient each with lower limb oedema, lower collection and none of them was infected. In

L YMPHOCELES AFTER RADICAL RETROPUBIC PROSTATECTOMY

FIG. 1. A, An ultrasonogram and B, a CT image of a dissection, but only a few became clinically In cases of transplant surgery, when lymphocele. evident and required treatment [4]. After collections can occur laterally and either pelvic node dissection the incidence of inferior or posterior to the graft, the A lymphoceles in one study was 54%, detected percutaneous approach may not be possible. by CT, with lower rates after laparoscopic (8%) Techniques such as laparoscopic fenestration than after open pelvic lymph node dissection [18] or open surgical marsupialization with (27%). Despite an incidence of 27%, only or without omentopexy [19,20] may be three patients (2.3%) had clinically significant more effective. Laparoscopic marsupialization lymphoceles [5]. This shows that not only is may be considered in the renal transplant the rate of lymphocele formation lower after patient with a symptomatic lymphocele laparoscopic surgery, but that the overall and no infection [9]. Larger collections incidence of clinically significant lymphoceles may require a draining catheter [21] but was low. Additionally, retroperitoneal [6] and this technique may need to be repeated groin [7] lymphoceles may arise after because of recurrence in 80–90% of patients, inserting vascular grafts [8]. increasing the risk of bleeding and infection B [9]. Percutaneous aspiration or drainage and microbiological testing of the fluid has been Numerous sclerosants have been used, e.g. suggested before procedures such as internal tetracycline, doxycycline, bleomycin, ethanol, drainage, to exclude a urinoma and super- povidone iodine and sodium amidotrizoate. infection in the management of renal These sclerosing agents produce undesirable transplant patients and lymphoceles [9]. inflammatory reactions [22], unlike simple Treatments include controlled percutaneous percutaneous catheter drainage. In one series drainage [10], with or without sclerotherapy, of patients after renal transplant, the percutaneous catheter drainage [11], incidence of lymphoceles was 26%; laparoscopic surgery [12,13] or open surgical percutaneous drainage had a recurrence rate drainage [14]. of 33%, compared to the instillation of a the four patients requiring intervention, one sclerosing agent (ethanol) after percutaneous attempt at percutaneous US-guided drainage The symptoms of such a collection depend on drainage, which had a recurrence rate of 25%. was successful in three. The multilocular the site, size and the presence of infection. A There may be a role for sclerotherapy in collection required two separate punctures visible or palpable pelvic mass may be present, treating lymphoceles, especially in recurrent to allow complete drainage. The procedures resulting in abdominal/pelvic pain. Symptoms lymphoceles before surgery is to be resulted in complete cure with no recurrence; or signs may be a result of venous/ureteric contemplated [23]. the four spontaneously resolving lymphoceles compression resulting in unilateral leg did not recur either. The procedures were oedema and leg pain, hydronephrosis with The role of heparin in the formation of associated with no complications apart deterioration in renal function, and deep vein lymphoceles remains contentious. An early from mild discomfort. All the patients thrombosis [15]. Fever and chills should raise paper [24] suggested a high risk when low- with clinically detectable lymphoceles the suspicion of an infected collection. dose heparin prophylaxis was given, but had received low molecular weight heparin The risk of infection is higher in other reports have not supported this [25]. after RP; most of the other 251 patients had immunosuppressed patients after kidney and Lymphoceles are reportedly increased with not received prophylactic heparin routinely pancreatic transplantation, although the use the use of heparin in both RP [26] and renal after RP. of steroids in these patients minimizes the transplantation [27]. formation of adhesions and loculation. The intraoperative application of fibrin glue DISCUSSION Treatment options depend on factors such does not reduce the rate of lymphoceles as size, position, infection risk, loculations after lymphadenectomy in patients with Lymphoceles occur as a result of tissue and the recurrence of the collections. gynaecological malignancies [28] or after trauma or surgery, subsequent to the leakage Pelvic lymphoceles after radical or renal transplantation [29]. The technique of of lymph from afferent lymphatic channels. transplant surgery can be treated by single omentoplasty and omentopexy after pelvic The incidence of collections can be minimized or recurrent percutaneous aspiration of lymphadenectomy during surgery for by meticulous surgical technique and lymphatic fluid [16], percutaneous drainage gynaecological malignancies has had attention to sealing the lymph vessels during [11], sclerotherapy or open surgical methods. promising results in one study [30], with node dissection. There was a high incidence Surgical drainage reportedly gives 50–70% the authors concluding that this resulted (27%) of subclinical lymphoceles after staging success and >90% success was reported in a lower incidence of lymphoedema, lymphadenectomy for prostate carcinoma, after peritoneal marsupialization [17]. lymphoceles and lymphocysts associated with most of which regressed spontaneously, with Disadvantages of this last technique severe complications. 44% needing intervention [3]. Other data include the requirement for a general report a 30% rate of subclinical lymphoceles anaesthetic, longer hospitalization, and The advantage of percutaneous controlled after laparoscopic pelvic lymph node surgical trauma. aspiration of lymphoceles is that it may be

PEPPER ET AL.

done under local anaesthesia in the radiology Retroperitoneal lymphocele: a rarely 19 Perrin LC, Goh J, Crandon AJ. The department, rather than the operating reported complication of abdominal treatment of recurrent pelvic lymphocysts theatre. Complications such as bleeding, aortic surgery. Ann Radiol (Paris) 1994; with marsupialisation and functioning infection and accidental transection of a 37: 270–3 omental flap. Aust NZ J Obstet Gynaecol transplanted ureter [31,32] have been 7 Tyndall SH, Shephard AD, Wilczewsky 1995; 35: 195–7 reported with laparoscopic and open surgical JM, Reddy DJ, Elliot JP, Ernst CB. Groin 20 Sibert L, Descargues G, Scotte M et al. drainage. Percutaneous drainage by a skilled lymphatic complications after arterial Laparoscopic drainage of a lymphocele interventional radiologist is associated with reconstruction. J Vasc Surg 1994; 19: after radical prostatectomy. Ann Urol minimal morbidity, with patients requiring a 858–63 (Paris) 1994; 28: 202–6 shorter hospital stay. 8 Bray AE, Harrison CL, Coleman PD. 21 Lucas BA, Gill IS, Munch LC. Common femoral vein compression after Intraperitoneal drainage of recurrent In conclusion, lymphocele formation after femoro-popliteal bypass surgery. Eur J lymphoceles using an internalised retropubic RP should be considered when Vasc Surg 1994; 8: 747–9 Tenckoff catheter. J Urol 1994; 151: 970– lower abdominal symptoms are reported. US 9 Duepree HJ, Fornara P, Lewejohann JC, 2 is simple and effective in confirming the Hoyer J, Bruch HP, Schiedeck THK. 22 Sawhney R, D’Agostino HB, Zinck position and size of the fluid collection. Not Laparoscopic treatment of lymphoceles in S et al. Treatment of post-operative all lymphoceles require intervention and some patients after renal transplantation. Clin lymphoceles with percutaneous drainage may resolve spontaneously. Where Transplant 2001; 15: 375–9 and alcohol sclerotherapy. JVIR 1996; 7: intervention is required, US-guided 10 Zanetta G, Trio D, Lissoni A et al. Early 241–5 percutaneous drainage is safe, easy and and short term complications after US 23 Atray NK, Moore F, Zaman F et al. Post- minimally invasive. More studies are required guided puncture of gynaecologic lesions: transplant lymphocele: a single centre to assess the role of low molecular weight evaluation after 1000 consecutive cases. experience. Clin Transplant 2004; 18 heparin in the cause of lymphoceles. Radiology 1993; 189: 161–4 (Suppl. 12): 46–9 11 Kim JK, Jeong YY, Kim YH et al. Post- 24 Tomic R, Granfors T, Sjodin JG, Ohberg CONFLICT OF INTEREST operative pelvic lymphocele: treatment L. Lymph leakage after staging pelvic with simple percutaneous catheter lymphadenectomy for prostatic None declared. drainage. Radiology 1999; 212: 390–4 carcinoma with and without heparin 12 Fallick ML, Long JP. Laparoscopic prophylaxis. Scand J Urol Nephrol 1994; REFERENCES marsupialisation of lymphocele after 28: 273–5 laparoscopic lymph node dissection. 25 Seiber PR, Rommel FM, Augusta VE 1 Augustin H, Hammerer P, Graefen M J Endourol 1996; 10: 533–4 et al. Is Heparin contra-indicated in et al. Intraoperative and perioperative 13 Thurlow JP, Gelpi J, Schwaitzberg SD, pelvic lymphadenectomy and radical morbidity of contemporary radical Rohrer RJ. Laparoscopic fenestration and prostatectomy. J Urol 1997; 158: retropubic prostatectomy in a consecutive internal drainage of lymphoceles after 869–71 series of 1243 patients: results of a single renal transplantation. Surg Laparosc 26 Koch MO. Low molecular weight heparin centre between 1999 and 2002. Eur Urol Endosc 1996; 6: 290–5 and radical prostatectomy: a prospective 2003; 43: 113–8 14 Gruessner RW, Fasola C, Benedetti analysis of safety and side effects. 2 Sogani PC, Watson RC, Whitmore WF E et al. Laparoscopic drainage of Prostate Cancer Prostatic Dis 1997; 1: Jr. Lymphoceles after pelvic lymphoceles after kidney transplantation. 101–4 lymphadenectomy for urologic cancer. Indications and limitations. Surgery 1995; 27 Lundin C, Bersztel A, Wahlberg J, Urology 1981; 17: 39–43 117: 288–95 Wadstrom J. Low molecular weight 3 Spring DB, Schroeder D, Babu S, 15 Burgos FJ, Teruel JL, Mayayo T et al. heparin prophylaxis increases the Agee R, Gooding GAW. Ultrasonic Diagnosis and management of incidence of lymphocele after kidney evaluation of lymphocele formation lymphoceles after renal transplantation. transplantation. Ups J Med Sci 2002; 107: after staging lymphadenectomy for Br J Urol 1998; 61: 289 9–15 prostate carcinoma. Radiology 1981; 16 Gilliland JD, Spies JB, Brown SB et al. 28 Scholz HS, Petru E, Benedicic C, 141: 479–83 Lymphoceles: percutaneous treatment Haas J, Tamussino K, Winter R. Fibrin 4 Freid RM, Siegel D, Smith AD, Weiss with povidone-iodine sclerosis. Radiology application for preventing lymphocysts GH. Lymphoceles after laparoscopic 1989; 171: 227 after retroperitoneal lymphadenectomy in pelvic node dissection. Urology 1998; 51: 17 Meyers AM, Levine E, Myburgh JA patients with gynaecologic malignancies. 131–4 et al. Diagnosis and management of Gynecologic Oncol 2002; 84: 43–6 5 Solberg A, Angelsen A, Bergan U, lymphoceles after renal transplantation. 29 Kokesch-Hauser S, Beer M, Staehler G. Haugen OA, Viset T, Klepp O. Frequency Urology 1977; 10: 497–502 Effect of intra-operative fibrin gluing on of lymphoceles after open and 18 Gill IS, Hodge EE, Munch LC, lymph flow and lymphocele formation laparoscopic pelvic lymph node dissection Goldfarb A, Novik AC, Lucas BA. after kidney transplantation. Urologe A in patients with prostate cancer. Scand J Transperitoneal marsupialisation 1993; 32: 334–8 Urol Nephrol 2003; 37: 218–21 of lymphoceles: a comparison of 30 Fujiwara K, Kigawa J, Hasegawa K 6 Paule AM, LeDreff P, Noment M, laparoscopic and open techniques. et al. Effect of simple omentoplasty Braesco J, LeGuyader J, Bellet M. J Urol 1995; 153: 706–11 and omentopexy in the prevention

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of complications after pelvic drainage of lymphocele. J Urol 1994; 151: Correspondence: Amir Kaisary, Royal Free lymphadenectomy. Int J Gynecol Cancer 162–5 Hospital, Pond Street, London NW3 2QG, UK. 2003; 13: 61–6 32 Lange V, Schardey HM, Meyer G, Illner e-mail: [email protected] 31 Shokeir AA, Eraky I, El-Kappany H, WD, Petersen P, Land W. Laparoscopic Ghoneim MA. Accidental division of the derooﬁng of post-transplant Abbreviations: US, ultrasonography; RP, transplanted ureter during laparoscopic lymphoceles. Transpl Int 1994; 7: 140–3 radical prostatectomy.

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Original Article TESTOSTERONE AND BONE DENSITY AFTER STOPPING LONG-TERM LHRH WESTON et al.

Testosterone recovery and changes in bone mineral density after stopping long-term luteinizing hormone- releasing hormone analogue therapy in osteoporotic patients with prostate cancer

ROBIN WESTON, ASAD HUSSAIN, EMMANUEL GEORGE and NIGEL J. PARR Arrowe Park Hospital, Wirral NHS Trust, Liverpool, UK Accepted for publication 1 November 2004

OBJECTIVE antiandrogen monotherapy, and prostate CONCLUSIONS speciﬁc-antigen (PSA) and total testosterone To investigate the rate of testosterone monitored at 3-monthly intervals. The Osteoporotic patients, after stopping LHRH recovery and changes in bone mineral density forearm densitometry was repeated at analogues, continue to have suppressed levels in patients found to be osteoporotic while 1 year. of testosterone which have a detrimental receiving luteinizing hormone-releasing effect on bone mineral density. We therefore hormone (LHRH) analogues after changing to RESULTS would not advocate conversion to antiandrogen monotherapy in an attempt to antiandrogen monotherapy to improve bone reduce further demineralization. All patients had some testosterone recovery; density, and suggest alternative therapeutic the mean (range) duration to initial detectable intervention e.g. bisphosphonate therapy, for PATIENTS AND METHODS testosterone was 12.8 (6–22) months. Six these patients. patients had a normal testosterone level after Fifteen patients receiving LHRH analogue a mean of 17.5 (14–30) months. In the year KEYWORDS therapy for ≥1 year were identiﬁed as after stopping LHRH analogue therapy the osteoporotic by distal forearm dual X-ray mean bone mineral density (t-score) prostate carcinoma, osteoporosis, densitometry. They were then converted to decreased by 7.2%. testosterone, hormone therapy

INTRODUCTION comparable survival outcomes and potential the mean for a healthy population group aged quality-of-life benefits [6,7]. In the present 20–40 years (t-score £ -2.5), with or without Depot LHRH analogues are currently the most study we investigated the time taken for pre-existing fragility fractures. Osteopenia is popular method of hormone manipulation for testosterone levels to recover in osteoporotic defined by a t-score of -1.0 to -2.4 and a patients with carcinoma of the prostate. They patients established on long-term LHRH normal BMD t-score as >-1.0. are effective in delaying the progression of therapy, after changing to antiandrogen the disease and hence patients are often monotherapy, and assessed the changes in Eight patients were found to be osteoporotic on this treatment for many years [1]. BMD. while already receiving LHRH analogues, and However, LHRH analogues, because of their a further seven were osteopenic at the initial testosterone ablative effects, disturb bone scan before treatment, and subsequently metabolism, resulting in osteoporosis, a PATIENTS AND METHODS went on to develop osteoporosis while on widely recognized complication of long-term LHRH analogues. Six patients developed testosterone ablation [2,3]. Osteoporosis is The study comprised 15 osteoporotic osteoporosis within a year; their mean characterized by low bone mineral density patients enrolled between November 2000 (SD) t-score on initial DEXA scanning was (BMD) and is asymptomatic, only clinically and July 2002. The mean (range) follow-up -2.07 (0.15), decreasing to -2.72 (0.13) after a manifesting itself when a low-trauma was 18 (12–30) months. The BMD of the year, while one further patient progressed to ‘osteoporotic fracture’ occurs. Several studies subordinate forearm was measured by dual- osteoporosis after 2 years. All patients had show that the incidence of osteoporotic energy X-ray absorptiometry (DEXA) using a received 3-monthly depot goserelin 10.8 mg fractures in patients receiving LHRH densitometer; the system used has a unique for ≥1 year, replaced by bicalutamide 150 mg analogues is far higher than the incidence of protocol for evaluating BMD at the ultra- once daily as an alternative monotherapy pathological fractures [4,5]. An alternative distal radius and ulna. The BMD result is after osteoporosis was diagnosed, the first method of hormone manipulation which expressed as the SD about the mean for a dose being 3 months after the last depot maintains testosterone levels is antiandrogen healthy age-matched population (the t- injection. They also received calcium and therapy. This is increasingly popular as score). Osteoporosis was defined using the vitamin D supplement (Ca2+ 12.6 mmol and monotherapy in prostate cancer, as it offers WHO criteria as a BMD of £-2.5 SD (below) cholecalciferol 400 units once daily). Total

TESTOSTERONE AND BONE DENSITY AFTER STOPPING LONG-TERM LHRH

FIG. 1. Testosterone recovery after stopping LHRH analogue therapy in 15 men with osteoporosis. The black 14 months. Two of these patients were horizontal line is the normal level (>9 nmol/L). converted back to goserelin injections because of a persistently rising PSA level. The 20 PSA level in these two patients has continued to rise, despite achieving castrate levels of 18 testosterone after reinstating LHRH analogue. 16 In the year after discontinuing LHRH 14 analogue therapy the mean (SD) decrease in t-score was 7.2% (0.11) during this period of 12 hypogonadism, from -3 (0.73) to -3.2 (0.70) (P 0.02). 10 =

estosterone, nmol/L DISCUSSION T 6 The BMD is testosterone-dependent and 4 both the administration of LHRH analogues 2 [8,9] and orchidectomy [10] have been associated with severe osteoporosis. The exact 0 mechanism by which testosterone maintains BMD is not fully understood, but local 061218 24 30 aromatization of testosterone to oestradiol Months is necessary for normal bone homeostasis [11]. There is also evidence that prostate cancer itself is a significant risk factor testosterone and PSA levels were measured mean t-score was -1.6, with only six being for osteoporosis, and hence fractures, by at baseline and at ª3-month intervals osteoporotic. However, there was no causing disturbances in bone turnover thereafter. A further forearm DEXA scan was statistical difference in the testosterone levels and mineralization even before androgen- taken a year after stopping LHRH analogue between the osteoporotic control patients deprivation therapy [12–14]. therapy. and the remainder (P = 0.86). Bone densitometry scanning amongst men To determine the normal testosterone levels All study patients had undetectable being treated with LHRH analogues for in patients with prostate cancer before testosterone levels at the time of prostate cancer will inevitably identify hormonal treatment, 30 consecutive patients monotherapy conversion (<1.5 nmol/L). They patients who are already osteoporotic. As presenting to our unit had their testosterone all had some degree of testosterone recovery there is an increased rate of fragility fracture levels measured and forearm densitometry (Fig. 1), the mean (range) time to initial resulting in significant morbidity and assessed (control group). The laboratory detectable testosterone level (≥1.5 nmol/L) mortality [15], some form of therapeutic reference range for a normal testosterone being 12.8 (6–22) months. Six patients had intervention is therefore indicated. Currently level is 9–40 nmol/L. The two-tailed Student’s normal testosterone levels after a mean of no therapy has been convincingly confirmed t-test was used for statistical comparison, 17.5 (14–30) months. The remaining patients to be effective in preventing osteoporotic with a statistically significant result assumed are yet to reach normal testosterone levels. fractures in men. However, as it is known at P £ 0.05. that LHRH therapy is responsible for BMD Ten patients received goserelin therapy for loss by testosterone suppression, we RESULTS 1–2 years and five for ≥2 years; the mean investigated whether changing from duration to initial detectable testosterone was goserelin to bicalutamide would be The mean (range) age of the 15 osteoporotic 12.6 and 13.0 months, respectively, with no beneficial. Bicalutamide is a pure nonsteroidal patients was 72 (55–86) years, the median statistical difference between the groups antiandrogen which inhibits the action of Gleason grade at diagnosis 6 (2–10), median (P = 0.70). dihydrotestosterone and testosterone at tumour stage T3 (T1–T4), mean PSA 57 target sites, by competitively binding to (1.7–312) ng/mL and the mean duration on The mean (range) PSA at baseline (before the cytosolic androgen receptor [16]; goserelin therapy 27 (12–96) months. At conversion) was 0.65 (undetectable-3.3) however, because of its effect on the the time of converting to bicalutamide ng/mL; 11 patients had a baseline PSA of hypothalamic-pituitary axis it causes an monotherapy the mean (SD) t-score was £0.5 ng/mL and after a mean of 17.5 months increase in circulating testosterone and -3.0 (0.73). only one increased from 0.5, to 3.2 ng/mL oestrogen levels. We therefore postulated (after 15 months). The remaining four that if testosterone levels could sufficiently The mean age of the control group was patients had an initial mean (range) PSA recover after the change in hormone 73 (56–85) years, with a mean (SD) of 1.9 (0.7–3.3) ng/mL, which increased manipulation, we might confirm a positive testosterone level of 11.8 (3.5) nmol/L. The to 4.8 (0.1–9.8) ng/mL after a mean of effect on BMD.

WESTON ET AL.

There are no published studies examining consistent with the low or castrate administered every 13 weeks to patients testosterone recovery in osteoporotic testosterone levels. Therefore, with castrate with advanced prostate cancer. BJU Int patients after stopping LHRH analogues levels of testosterone remaining for a mean of 1999; 83: 801–6 and subsequently starting antiandrogen 12.8 months, the present study showed that 2 Daniell HW, Dunn SR, Ferguson DW therapy. The largest study [17] examining discontinuing LHRH analogue therapy is not et al. Progressive osteoporosis during testosterone recovery after androgen ablation sufficient to protect osteoporotic patients androgen deprivation therapy for examined 267 patients, all of whom received from further demineralization. prostate cancer. J Urol 2000; 163: 181–6 radiotherapy, and most (67%) received 3 Stoch SA, Parker RA, Chen L et al. Bone stilboestrol and cyproterone, with only nine Although becoming more popular, the use of loss in men with prostate cancer treated having >2 years of androgen ablation. The antiandrogen monotherapy in advanced with gonadotropin-releasing hormone authors showed that over half the men had prostate cancer is still controversial. agonists. J Clin Endocrinol Metab 2001; normal testosterone levels after a year, and Tachyphylaxis did not appear to be a problem 86: 2787–91 83% after 3 years. Nejat et al. [18] reported in the present study, with PSA levels 4 Townsend MF, Sanders WH, Northway on 68 men after withdrawing androgen remaining low despite testosterone recovery. RO et al. Bone fractures associated with deprivation therapy, 60% of whom had The two patients who had had a persistent luteinizing hormone-releasing hormone received external beam radiotherapy. They rise in PSA levels to >0.5 ng/mL have failed to agonists used in the treatment of prostate found that the median time to testosterone show a PSA response despite being rendered carcinoma. Cancer 1997; 79: 545–50 recovery was 7 months, after a median pharmacologically castrate by reinstating 5 Hatano T, Oishi Y, Furuta A et al. duration of androgen deprivation of LHRH analogues. We suggest that this Incidence of bone fracture in patients 9 months. In contrast to the present study, probably reflects the natural history of the receiving luteinizing hormone-releasing they reported a statistically significant delay prostate cancer in these patients, as opposed hormone agonists for prostate cancer. in testosterone recovery in patients receiving to the effect of changing their hormone BJU Int 2000; 86: 449–52 >2 years of LHRH analogue compared with manipulation. 6 Tyrrell CJ, Kaisary AV, Iversen P et al. treatment for <2 years. Radiation scatter A randomised comparison of ‘Casodex’ affecting the testes may be a confounding There is no doubt from increasing reports that 150mg monotherapy versus castration in factor in both these studies. Hall et al. [19] LHRH analogues cause a decrease in BMD and the treatment of metastatic and locally investigated 14 patients after a mean therefore increase the risk of osteoporotic advanced prostate cancer. Eur Urol 1998; duration of 38.6 months on LHRH analogues, fracture. Men are twice as likely as women to 33: 447–56 with castrate levels of testosterone being die within a year of a hip fracture and are 7 Iversen P, Tyrrell CJ, Kaisary AV et al. reported for a median of 6 months; however, more likely to become dependent on nursing Casodex 150mg monotherapy compared the follow-up was limited to a year and homes after such fractures [15]. Urologists with castration in patients with previously therefore normalization of testosterone was should be more aware of the risk of untreated nonmetastatic prostate cancer. not assessed. osteoporosis amongst their patients with results from two multicenter randomised prostate cancer receiving hormone trials at a median follow-up of 4 years. The present results show that patients manipulation. Urology 1998; 51: 389–96 who develop osteoporosis while being treated 8 Stoch SA, Parker RA, Chen L et al. Bone with LHRH analogues will continue to have The present study highlights the continued loss in men with prostate cancer treated hypogonadism for a mean of 17.5 months testosterone suppression after stopping long- with gonadotrophin-releasing hormone after conversion to an antiandrogen. The term LHRH analogues and the detrimental agonists. J Clin Endocrinol Metab 2001; control group showed that some patients effect on BMD. Conversion to antiandrogen 86: 2787–91 may have mild hypogonadism before initial therapy seems to offer no significant short- 9 Goldray D, Weisman Y, Jaccard N et al. hormone therapy, and therefore we would not term benefit to these patients, and we Decreased bone density in elderly men expect all the study group to achieve normal therefore suggest alternative therapeutic treated with the gonadotrophin-releasing testosterone levels. However, Amin et al. [20], intervention, e.g. bisphosphonate therapy; hormone agonist decapeptyl (D-Trp6- using data from the Framingham study, further studies are required to investigate GnRH). J Clin Endocrinol Metab 1993; 76: indicated that low levels, as opposed to this. 288–90 castrate levels, of testosterone did not 10 Harry DW. Osteoporosis after correlate with a decrease in BMD, although orchiectomy for prostate cancer. J Urol oestradiol levels have a strong and positive CONFLICT OF INTEREST 1997; 157: 439–44 association with BMD in men. This raises the 11 Smith EP, Boyd J, Frank GR et al. point that normal levels of testosterone may None declared. Oestrogen resistance caused by a not be necessary for maintaining BMD, as has mutation in the oestrogen receptor gene been shown with physiological functions such in man. N Engl J Med 1994; 331: 1056–61 as potency, but the availability of some REFERENCES 12 Percival RC, Urwin GH, Harris S et al. testosterone for aromatization to oestradiol is Biochemical and histological evidence essential for normal bone homeostasis. 1 Sarosdy MF, Schellhammer PF, Soloway that carcinoma of the prostate is MS et al. Endocrine effects, efficacy associated with increased bone In the year after stopping LHRH analogues the and tolerability of a 10.8-mg depot resorption. Eur J Surg Oncol 1987; 13: 41– decrease in bone mineral density was formulation of goserelin acetate 9

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13 Charhon SA, Shapuy MC, Delvin EE 16 Verhelst J, Denis L, Van Vliet P et al. luteinising hormone-releasing hormone et al. Histomorphometric analysis of Endocrine proﬁles during administration agonist treatment in patients with sclerotic bone metastasis from prostatic of the new non-steroidal anti-androgen prostate cancer. Urology 1999; 53: 898– carcinoma with special reference to Casodex in prostate cancer. Clin 903 osteomalacia. Cancer 1983; 51: 918–24 Endocrinol 1994; 41: 525–30 20 Amin S, Zhang Y, Sawin CT et al. 14 Hussain SA, Weston R, Stephenson RN, 17 Pickles T, Agranovich A, Berthelet E Association of hypogonadism and George E, Parr NJ. Immediate DEXA et al. Testosterone recovery following estradiol levels with bone mineral density scanning reveals a high incidence of prolonged adjuvant androgen ablation for in elderley men from the Framingham osteoporosis in advanced prostate cancer prostate cancer. Cancer 2002; 94: 362–7 Study. Ann Intern Med 2000; 133: 951– prior to hormonal manipulation. BJU Int 18 Nejat RJ, Rashid HH, Bagiella E et al. 63 2003; 92: 690–4 A prospective analysis of time to 15 Ray NF, Chan JK, Thamer M et al. normalization of serum testosterone after Correspondence: Robin Weston, Wirral NHS Medical expenditures for the treatment of withdrawal of androgen deprivation Trust, Urology, Liverpool, UK. osteoporotic fractures in the United therapy. J Urol 2000; 164: 1891–4 e-mail: [email protected] States in 1995: Report from the National 19 Hall CM, Fritzsch RJ, Sagalowsky AI Osteoporosis Foundation. J Bone Miner et al. Prospective determination of the Abbreviations: BMD, bone mineral density; Res 1997; 12: 24–35 hormonal response after cessation of DEXA, dual energy X-ray absorptiometry.

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Original Article PROSTATE CANCER ‘COUPLE’ SOLOWAY et al.

Sexual, psychological and dyadic qualities of the prostate cancer ‘couple’

CYNTHIA T. SOLOWAY, MARK S. SOLOWAY, SANDY S. KIM and BRUCE R. KAVA Department of Urology, University of Miami School of Medicine, Miami, Florida, USA Accepted for publication 29 November 2004

OBJECTIVES depressed mood, psychological distress and CONCLUSIONS dyadic adjustment. To examine the levels of sexual, psychological Information from this study could be useful in and dyadic functioning of the prostate RESULTS constructing interventions that allow the cancer ‘couple’ (as studies have shown that physician and the prostate cancer ‘couple’ to spouses/partners play an integral role in The partners’ mean scores on sexual function reflect on issues of sexual function and the patient’s adjustment to prostate cancer questions were 55.75, significantly higher psychological distress that might once treatment), to encourage the creation of than those of the patients (51.7, P = 0.018), have been considered taboo. The results innovative psychosexual interventions to be showing that partners perceived their sexual characterize the disparities between patients used in the outpatient setting, and to offer performance at a better level. Partners’ mean with prostate cancer and their partners on insights into a novel area of prostate cancer scores on the depression and distress self-reported questionnaires, and underscore research. measures were also significantly higher. On how important it is to hear the voice of the those items that monitored the accuracy of ‘couple’. the patients’ perceptions of their sexual PATIENTS AND METHODS function, partners rated the patients KEYWORDS significantly lower in ability to gain erections In all, 103 men newly diagnosed with prostate (patient/partner means 2.67/4.52; P < 0.001) prostate cancer, sexual function, depression, cancer, and their partners, were assessed and to perform sexually (patient/partner psychological distress, marital quality in an academic outpatient setting using means 1.38/4.68; P < 0.001) than they rated instruments measuring sexual function, themselves.

INTRODUCTION cancer treatment, significantly affects the affected the couple’s coping skills [5,9]. marital relationship [4]. Changes in role Building on these findings, we hypothesized Major challenges confront men with prostate during the treatment and recovery periods that prostate cancer is a couple’s disease and, cancer and their partners. Because most men may lead to emotional distancing, making consequently, at different points during with prostate cancer are asymptomatic, it is sexual interactions difficult as the patient and treatment it might be the ‘couple’ that should not surprising that couples are not prepared his partner attempt to protect each other’s be counselled as the ‘patient’. for the diagnosis of prostate cancer and the dignity [5]. Often, the only discussion between difficult treatment decisions they face. the patient and his partner related to sexual This study was conducted to define ‘the function comes when couples are presented couple’ with newly diagnosed prostate cancer. Quality-of-life concerns and patient values with treatment options. If there is a Variables thought to be important were the are important in determining treatment loss of sexual function after treatment, levels of sexual, psychological and dyadic choice [1]. Patients might choose a treatment communication related to sexual function is functioning, and sociodemographic factors. with a lower long-term survival rate to likely to stop [6]. By examining differences within individual increase the possibility of remaining sexually couples we hoped to encourage the creation potent [2]. For the partner, survival is Two pilot studies from Memorial-Sloan of innovative psychosexual interventions for paramount [3]. Although most partners wish Kettering Cancer Center, examining the outpatient setting, as well as to offer to be an active participant in the patient’s psychological distress in men with prostate insights into a novel area of prostate cancer treatment decisions, they are much less cancer and their partners, suggested that the research. concerned about the patient’s sexual partner plays an integral role in the patient’s morbidity [3,4]. This challenges a traditional adjustment to treatment [7,8]. In the few notion that sexual intercourse is equally other studies where both the patient and PATIENTS AND METHODS important to the patient and his partner. partner were considered, sexual activity before diagnosis, and social and psychological Data from 103 newly diagnosed, untreated Nonetheless, erectile dysfunction, the most resources, were predictors of sexual men with prostate cancer and their partners common long-term side effect of prostate adjustment and as antecedent conditions that were analysed in a study approved by the

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Depression Inventory (BDI) [13] examined Sociodemographic factors Partner Patient TABLE 1 attitudes and symptoms frequently shown by Mean (median, range) 58 (60, 34–78) 62 (62,43–80) The demographic data depressed patients. The Profile of Mood States age, years (POMS) [14] assessed overall distress and six Education level: mood states (tension-anxiety, depression- Mean duration at college 3 year, Bachelor dejection, anger-hostility, vigour-activity, degree fatigue-inertia, and confusion-bewilderment). Frequency of 2 years 38 64 ≥ Visual analogue scales of distress (VAS) [15] at college, % were two horizontal VAS with equally spaced Racial/ethnic balance, % unlabelled intervals (0–10) characterizing the Black 4 10 level of distress at the diagnostic evaluation White Non-Hispanic 54 48 and before treatment. The Dyadic Adjustment White Hispanic 37 38 Scale (DAS) [16] evaluated dyadic satisfaction, Asian 1 1 dyadic cohesion, dyadic consensus, Employed in last 6 months, % and the expression of affection. The Yes 47 66 Sociodemographic Questionnaire (SQ) No 53 34 provided demographic and medical Health problems, % information. No health problems 59 54 High blood pressure 25 34 Descriptive statistical analysis, Pearson Diabetes 3 7 product-moment correlation, one-way ANOVA, Heart disease 3 3 independent t-tests, paired samples t-tests Other cancer 9 1 and multiple linear regression analysis were Satisfaction with care, % used to assess the results. ‘Somewhat’ to ‘very’ satisfied 71 73 ‘Somewhat’ to ‘very’ 17 13 RESULTS dissatisfied Chances of being diagnosed with cancer, % The sociodemographic characteristics are Not likely 37 51 shown in Table 1; 85% of the study Somewhat unlikely 27 27 participants were 45–70 years old, with the ‘Highly’ to ‘extremely’ likely 9 6 mean ages of the partners and patients being Stress during evaluation, % similar. Of the couples, 95% were married and ‘Moderate’ to ‘very’ 58 41 83% were in relationships of >10 years. The Stress at diagnosis, % study population was highly educated; nearly ‘Moderate’ to ‘very’ 66 44 43% of the participants had completed at PSA, ng/mL, at diagnosis, % least a bachelor’s degree. The participants 10 – 80 < were also ethnically diverse (Table 1) and more 20 – 95 < than half were employed. Gleason score at diagnosis, % 6–59 £ Most of the men presented at diagnosis with 7–22 what was thought to be organ-confined 8 or 9 – 6 prostate cancer, most having a PSA level of £10 ng/mL and more than half with a Gleason score of £6; 85% of the patients had been Institutional Review Board at the University outpatient office. Thirty-five couples declined diagnosed within the last 3 months. During of Miami. Homosexual men were excluded to participate. the evaluation, half of the patients felt it was from the study because too few partnered ‘not likely’ they would be given a diagnosis of homosexual men were seen in the urology The following instruments were selected: the prostate cancer; only 37% of their partners outpatient clinic for effective analysis. Brief Index of Sexual Function for Women were that optimistic. Because the patients Following methods of convenience (BISF-W) [10] and The Brief Sexual Function were relatively young it was not surprising sampling, consecutive untreated referrals Questionnaire for Men (BSFQ) [11] measured that 54% had no comorbid conditions. (patients, married or in committed sexual satisfaction, desire, and activity. An relationships, and their partners) were appendix to the BSFQ, questions validating Pearson product-moment correlation of the identified in the academic outpatient setting the accuracy of the man’s responses, was sexual function measures indicated that the and familiarized with the variables of the added to the BISF-W. Ad hoc questions from SAQ total score was linearly related to the study by the urologist. The patient and his the Sexual Adjustment Questionnaire (SAQ), selected core sexual function questions from partner, after reading and agreeing to the an instrument designed to assess sexual the BISF-W and BSFQ (P < 0.001). ANOVA terms of the informed consent, independently function in alcoholics and their spouses, were indicated there were no significant mean completed the questionnaires in the added to both inventories [12]. The Beck differences of sexual function within groups

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TABLE 2 Partner and patient sexual function means

Questionnaire variables Scores Female dimensions (BISF-W) [18] Healthy with partners Menopause surgically Present study D1: Thoughts and desires 5.31 2.5 3.67 D2: Arousal 6.21 3.85 3.61 D3: Frequency of sex activity 3.9 1.83 3.9 D4: Receptivity/initiation 8.85 6.39 9.96 D5: Pleasure/orgasm 4.91 2.26 2.74 D6: Relationship satisfaction 8.9 7.07 5.24 D7: Problems affecting sex function* 4.47 5.55 5.36 Composite score (D1 + D2 + D3 + D4 + D5 + D6-D7) 33.6 18.35 24.1 Male dimensions (BSFQ) [11] Controls Depressed Impotent Present study Sexual activity/performance 36.8 17.2 24.1 36.58 Satisfaction 13.7 6.6 9.4 7.25 Interest 9.2 7.2 9.1 5.89 Physiological competence† 3.3 4.4 11.6 6.23 ‘Paired’ sexual function scores Patient mean Partner mean P Total SAQ 51.70 55.75 0.018 Total BSFQ and BISF-W 40.57 49.61 <0.001

*Lower mean score suggests fewer problems affecting sexual function. In all other variables higher mean score suggests higher functioning. †Lower mean score suggests higher physiological competence.

of the study sample for ethnicity (P = 0.095), For sexual function (Table 2), compared On the SAQ, the paired t-test results indicated educational level (P = 0.440), patient’s PSA at with the mean scores of normal controls and that the partners were significantly more diagnosis (P = 0.124), and patient’s Gleason of depressed and impotent men examined positive about the communication and sexual score at diagnosis (P = 0.306). with the BSFQ, the men in the current components in their relationship than were study appeared to present at diagnosis with the patients (patient/partner means 51.70/ Student’s t-tests were used to confirm that several sexual function issues [11]. In the 55.75, P = 0.02). Although the BISF-W was there were no significant mean differences of areas of sexual satisfaction, interest in sexual modelled after the BSFQ, the actual key variables within the two largest ethnic activity and physiological competence, the questionnaires were not identical. Twenty sample populations (non-Hispanic whites and men’s mean scores were similar to depressed questions from each measure were re-coded Hispanics). There were no significant mean and/or impotent populations rather than to allow for comparability. Paired-sample t- differences for depression, sexual function normal controls (Table 2). For example, 65% tests showed that the mean partner score was and dyadic relationship, but there were were dissatisfied with their sex life, 55% significantly higher than that of the patients (P = 0.039) for psychological distress (POMS expressed decreased frequency of sexual drive (patient/partner means 40.57/49.61, score), with Hispanics showing a higher mean and sexual thoughts and 60% reported P < 0.001), showing that partners perceived score. erections that were insufficient for their sexual performance at a better level. penetration. Results also established that the partner was COUPLES AT DIAGNOSIS significantly more satisfied in the relationship When comparing scores from the BISF-W [18] than the patient. The patient had significantly The data were initially analysed using administered to healthy women (mean higher mean scores on the frequency of independent t-tests to determine if there age 40.4 years) with partners and with sexual thoughts (patient/partner means 2.96/ were any significant differences in the surgically menopausal women (mean 1.96, P < 0.001) and the level of pleasure felt individual men (patient) and women (partner) age 47.1 years), the present women from sexual experiences (patient/partner populations. As the term ‘patient’ was functioned similarly to the surgically mean 3.88/1.85, P < 0.001). On those items redefined for this study to include the menopausal group, especially in the areas of that monitored the accuracy of the patients’ prostate cancer ‘couple’, paired-sample arousal, pleasure/orgasm and relationship perceptions of their sexual function, the t-tests were then used on all the data, satisfaction (Table 2). In only two of the seven partners rated the patients significantly lower consistent with similar studies [8,17], to BISF-W subtests (frequency and receptivity/ in ability to gain erections, with patient/ ascertain whether the patient and his initiation of sexual activity) did the present partner means of 2.67/4.52 (higher number partner scored significantly different from women have equivalent mean scores to lower score; P < 0.001) and to perform each other. healthy women with partners. sexually, with patient/partner means of

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the SAQ questions, as well as the results from TABLE 3 Means and P values of affective and dyadic adjustment scores the multiple linear regression analysis, were helpful in validating that the instruments Mean scores chosen for the study created an integrated Affective and dyadic adjustment scales Patient Partner P and focused tool. BDI (lower mean score suggests less depression) Total 5.63 8.13 0.006 DISCUSSION POMS factors (lower mean score suggests less psychological distress for all variables except vigour/activity) Since the mid-1990s there has been Tension-anxiety 9.41 11.69 0.006 extensive research into health-related Depression-dejection 6.05 9.03 0.02 quality of life (HRQoL) aspects of prostate Anger-hostility 5.74 7.10 0.043 cancer, concentrating on the patient’s level Vigour-activity 18.91 17.37 NS of functioning and emotional status [5,19] Fatigue-inertia 4.39 6.17 0.001 No HRQoL studies have examined sexual Confusion-bewilderment 6.60 7.76 0.007 function, depression, psychological distress Total 51.52 59.04 0.024 and dyadic relationship levels in the patient DAS factors (higher mean score suggests healthier dyadic adjustment) and his partner. The present study provides Dyadic consensus 53.64 53.99 NS evidence that the prostate cancer ‘couple’ Affective expression 11.64 11.70 NS at diagnosis has complex and disparate Dyadic satisfaction 27.36 27.30 NS needs, and shows a need for psychosexual Dyadic cohesion 16.29 16.44 NS interventions that augment current Total 108.30 110.38 NS treatments for sexual and psychological VAS factors (lower mean score suggests less stress) problems arising from a prostate cancer Stress during evaluation 4.92 6.06 0.004 diagnosis. Stress before treatment 4.93 6.24 <0.001 THE ROLE FOR THE PARTNER NS, no significance difference. Researchers have discovered that partners are often the communication conduit between the patient and his physician, in addition to 1.38/4.68 (higher number lower score; independently. The VAS results confirmed that serving as key advocates during diagnosis and P < 0.001). These results further characterize partners were significantly more distressed at treatment [9]. However, studies have reported the disparities in self-reported levels of sexual evaluation and diagnosis than the patients. that the partner often feels ignored by the functioning and emphasize how important it There were no significant differences in the patient’s physician [9]. Sneeuw et al. [17] is to hear the voice of the ‘couple’. means of the patient/partner responses on advocated that spouses serve as proxy ‘raters’ the DAS or its four subtests. when assessing HRQoL of the patient. Although the mean BDI scores for patients Therefore, the physician might wish to include and partners (Table 3) were significantly To assess the strength of the instruments the partner in the consultation process, with different, with the mean depressed mood in measuring study variables, multiple informational and emotional support offered level for partners significantly greater, these regression analysis was conducted to to both [17,20]. There might also be poor mean values were within the normal range. evaluate if the total BDI, POMS and DAS agreement between the professional and Nevertheless, the frequency of depression in score (and/or their subtest scores), as well patient assessment of distress, with the study population (ª30%) was (patient/ as any sociodemographic variable, predicted physicians underestimating severity [20]. partner): mild-moderate, 26.2%/19.2%; sexual function. The analysis showed that Using questionnaires before treatment, as in moderate-severe, 2%/10.2%; and severe, the predictors of sexual activity were the present study, seems to be informative to partner only, 2.2% [13]. An independent t-test dyadic cohesion (DAS subtest), ethnicity, the physician and therapeutic for couples, as assessing the patients and partners resulted employment status and the patient’s it stimulates discussion about sexual and in similar findings. thoughts about his chance of being emotional issues relevant to the couple’s diagnosed with cancer. The linear concerns [20]. The mean POMS total mood disturbance score combination of these factors in the patients of the partner was also significantly higher and partners was significantly related to THE IMPACT OF THE PARTNER’S than the patient’s. Of the six mood states sexual activity (P < 0.001). The sample PSYCHOLOGICAL DISTRESS ON OUTCOME measured, the means, all within the normal correlation coefficient was 0.542, indicating range, of the tension-anxiety, depression- that ª30% of the variance of sexual function In the 1994 Memorial-Sloan Kettering Cancer dejection, anger-hostility, fatigue-inertia and could be accounted for by these factors. Center study, researchers examined the effect confusion-bewilderment subscales were of disease stage and treatment regimen on significantly greater in the partner than in the Correlations assessed between depression- HRQoL in patients with prostate cancer and patient. These findings were similar to the dejection (POMS subtest) and the BDI, and in their partners [8]. The authors concluded, scores computed for men and women between comparable BISF-W/BSFQ items and as in the present study, that partners had

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significantly higher levels of psychological surgery [21,22]. Patients undergoing external relationship in silence, both the patient and distress, and needed to be assessed regularly beam radiation therapy might, because of age partner often feel isolated [9]. For couples, to identify how that distress might affect and stage of disease, have poorer sexual this isolation can lead to distress, and distress the patient’s adaptation to his prostate function outcomes [4]. Therefore up to half of might place patients with prostate cancer at cancer. Patient and partner depression were all patients treated for prostate cancer might risk of poor adjustment to their disease. measured in a later study [7], and 31% of have erectile dysfunction 12 months after Recognizing from the present study that the evaluable patients and their partners were treatment. Moreover, partners reported partners are already distressed over the referred for psychological assessment. The that patients had lower levels of sexual diagnosis and the treatment choices, the present study confirmed that, at diagnosis, performance and poorer quality erections additional distress caused by sexual isolation 30% of both patients and partners might be than study patients themselves reported. could be even more detrimental to patient appropriate for referral for further evaluation Thus, if partners were asked to assess the outcome. As perhaps only half of all patients and treatment, and that partners of patients patient’s erectile function after treatment, it who report they are potent at diagnosis will with prostate cancer have significantly higher might be even less than half of all patients have an acceptable level of potency after depression scores than the patients. The treated that have erections adequate for treatment, it is critical to develop new question remains as to whether patients and sexual activity. The partner’s decreased level psychosexual educational interventions as partners are being evaluated and/or referred of sexual function must also be included in alternatives for pharmacological or by their physician for their depression, a the equation. Given the emphasis that many technological options. Even before any diagnosis that might ultimately affect patients place on sexual function, physicians decision is made about treatment, discussion adjustment to treatment, and the outcome. might find it helpful to address the of these issues could help to address challenging problems facing 50% of men differences about issues of sexual activity, The POMS total mood disturbance score with erectile dysfunction that might not be psychological distress and intimacy and, and the subtests of depression-dejection, resolved by current medical therapies. ultimately, enhance sexual satisfaction after tension-anxiety, fatigue-inertia, confusion/ treatment. bewilderment and anger/hostility were also While technological assistance for erectile significant, suggesting that the partners are dysfunction (e.g. injections, prostheses) might Most of the couples studied were in long- more psychologically distressed and, in fact, help some patients adjust to what they term relationships. Moreover, the scores on might be distracted (higher confusion/ believe is a loss of virility, partners might find the DAS describe a sample of couples that bewilderment score) by their distressed mood. these methods unappealing [23]. To confound showed dyadic cohesion, consensus, affection In addition, the Hispanic patient and his matters, aids to promote erections might and satisfaction. In a study examining partner were significantly more distressed make patients feel vulnerable and awkward sexuality and marital life, Trudel [24] than the white non-Hispanic couples. and, ultimately, produce barriers to seeking concluded that there was a statistically Together with the fact that the partner’s mean any kind of help for sexual problems [4]. It has significant relationship between marital score on each VAS was significantly higher been reported that physicians avoid functioning and sexual behaviour. As dyadic than the patient’s, we concluded that partners discussions on the impact of sexual problems cohesion was a predictor of sexual function in are more likely to be psychologically because of lack of knowledge or comfort with the present study, there is obvious potential distressed than patients, and this should be issues of sexual intimacy [1,9,23]. This leaves for prostate cancer ‘couples’ to adapt to the carefully considered, as the partner’s couples to ‘grieve’ in silence over the loss of sexual function outcomes of treatment. That psychological distress might predict a greater an integral part of their marriage [1,9]. Thus, adjustment is possible if couples continue to HRQoL problem index for men with prostate some investigators, including the present communicate during the diagnosis, treatment cancer [1]. authors, suggest that counselling should be and the recovery process on critical sexual expanded from primarily helping patients to issues, and if partners can be encouraged to WHAT ARE THE REAL SEXUAL choose an appropriate prostate cancer be active in the decision-making process FUNCTION ISSUES? treatment, to facilitating the couples’ regarding treatment and its sexual successful adjustment to treatment outcomes consequences. The return of sexual function after treatment [1]. for prostate cancer depends on patient age, Because of the nature of the present the clinical and pathological stage of his Partners are extremely reticent about population, the study design had at least one disease, the treatment method and, in the addressing sexual issues for fear of further limitation. A convenience-sampling model surgical patient, whether the neurovascular increasing patient anxiety about the diagnosis was used to recruit patients seeking bundles have been preserved [21]. In the of prostate cancer [5]. Tacitly they wish for treatment at an academic outpatient clinic, present study, 69 of 103 patients elected to patients to have erections, understanding but the sample might not be representative of have radical surgery; 46 (66%) of those that erections are how men define their the entire population of patients with patients reported normal erectile function to masculinity [6]. Patients, on the other hand, prostate cancer and their partners. the urologist at diagnosis. Interestingly, in the are demoralised by their changing role and Nevertheless, the information from this study same study population, 75 men (78%) the potential for impaired performance, and could be very useful in constructing a admitted having erections that were not have reported that they assume, based on receptive environment (i.e. sexual, sufficient for penetration, when questioned their partner’s silence, that the loss of sexual psychological and dyadic assessment; more specifically. At best, 66% of all patients, relations has little effect on the partner [1,9]. psychosexual educational interventions) irrespective of age, are potent after radical Left to adjust to the loss of their sexual where the newly diagnosed patient with

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prostate cancer and his partner can, with their Peabody E, Scher HI, Holland JC. Rapid life in men with metastatic prostate physician, begin to reflect on the WHO screening for psychologic distress in men cancer. J Urol 2001; 165: 478–82 definition of sexual heath, the ‘integration of with prostate carcinoma: a pilot study. 18 Mazer NA, Leiblum SR, Rosen RC. The somatic, emotional, intellectual and social Cancer 1998; 82: 1904–8 Brief Index of Sexual Functioning for aspects’ of being sexual [3], in ways that 8 Kornblith AB, Herr HW, Ofman US, Women (BISF-W): a new scoring might once have been considered taboo. Scher HI, Holland JC. Quality of life of algorithm and comparison of normative patients with prostate cancer and their and surgically menopausal populations. ACKNOWLEDGEMENTS spouses. The value of a database in clinical Menopause 2000; 7: 350–63 care. Cancer 1994; 73: 2791–802 19 Litwin MS, Hays RD, Fink A et al. This study was supported by the Spector 9 Harden J, Schafenacker A, Northouse L Quality-of-life outcomes in men treated Family Foundation donation awarded to Mark et al. Couples’ experiences with prostate for localized prostate cancer. JAMA 1995; S. Soloway, MD, to use at his discretion to cancer: focus group research. Oncol Nurs 273: 129–35 fund prostate cancer research. Forum 2002; 29: 701–9 20 Cliff AM, MacDonagh RF. Psychosocial 10 Taylor JF, Rosen RC, Leiblum SR. Self- morbidity in prostate cancer: II. A CONFLICT OF INTEREST report assessment of female sexual comparison of patients and partners. BJU function: psychometric evaluation of the Int 2000; 86: 834–9 None declared. Source of funding: private Brief Index of Sexual Functioning for 21 Quinlan DM, Epstein JI, Carter BS, donation from Spector Family Foundation. Women. Arch Sex Behav 1994; 23: 627– Walsh PC. Sexual function following 43 radical prostatectomy: influence of REFERENCES 11 Reynolds CF 3rd, Frank E, Thase ME preservation of neurovascular bundles. et al. Assessment of sexual function in J Urol 1991; 145: 998–1002 1 Bokhour BG, Clark JA, Inui TS, Silliman depressed, impotent and healthy men: 22 Catalona WJ, Carvalhal GF, Mager DE, RA, Talcott JA. Sexuality after treatment factor analysis of a Brief Sexual Function Smith DS. Potency, continence and for early prostate cancer: exploring the Questionnaire for Men. Psychiatry Res complication rates in 1,870 consecutive meanings of ‘erectile dysfunction’. J Gen 1988; 24: 231–50 radical retropubic prostatectomies. J Urol Intern Med 2001; 16: 649–55 12 O’Farrell TJ, Kleinke CL, Cutter HS. A 1999; 162: 433–8 2 Incrocci L, Madalinska JB, Essink-Bot Sexual Adjustment Questionnaire to use 23 Monturo CA, Rogers PD, Coleman M, ML, Van Putten WLJ, Koper PC, in therapy and research with alcoholics Robinson JP, Pickett M. Beyond sexual Schroder FH. Sexual functioning in and their spouses. J Subst Abuse Treat assessment: lessons learned from couples patients with localized prostate cancer 1997; 14: 259–68 post radical prostatectomy. J Am Acad awaiting treatment. J Sex Marital Ther 13 Beck AT, Steer RA, Garbin MC. Nurse Pract 2001; 13: 511–6 2001; 27: 353–63 Psychometric properties of the Beck 24 Trudel G. Sexuality and marital life: 3 Bertero C. Altered sexual patterns after Depression Inventory: Twenty-four years results of a survey. J Sex Marital Ther treatment of prostate cancer. Cancer of evaluation. Clin Psych Rev 1988; 8: 77– 2002; 28: 229–49 Pract 2001; 9: 245–51 100 4 Neese LE, Schover LR, Klein EA, Zippe 14 McNair DM, Lorr M, Droppelman LF. Correspondence: Mark S. Soloway, PO Box C, Kupelian PA. Finding help for sexual Profile of Mood States (MH-08954). San 016960 (M-814), Miami, Florida 33101, USA. problems after prostate cancer treatment: Diego, CA: Education and Industrial e-mail: [email protected] a phone survey of men’s and women’s Testing Service, 1971 perspectives. Psychooncology 2003; 12: 15 Goodkin K, Gullion C. Antidepressants Abbreviations: BISF-W, The Brief Index of 463–73 for relief of chronic pain: Do they work? Sexual Function for Women; BSFQ, The Brief 5 Ofman US. Sexual quality of life in men Ann Behav Med 1989; 11: 83–101 Sexual Function Questionnaire for Men; SAQ, with prostate cancer. Cancer 1995; 75 16 Spanier GB. Measuring dyadic The Sexual Adjustment Questionnaire; BDI, (Suppl. 7): 1949–53 adjustment: new scales for assessing the The Beck Depression Inventory; POMS, Profile 6 Boehmer U, Clark JA. Communication quality of marriage and similar dyads. of Mood States; VAS, Visual Analogue Scales about prostate cancer between men J Marriage Fam 1976; 38: 15–28 of Distress; DAS, The Dyadic Adjustment and their wives. J Fam Pract 2001; 50: 17 Sneeuw KC, Albertsen PC, Aaronson Scale; SQ, The Sociodemographic 226–31 NK. Comparison of patient and spouse Questionnaire; HRQoL, health-related quality 7 Roth AJ, Kornblith AB, Batel-Copel L, assessments of health related quality of of life

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article STAGING and RADICAL CYSTECTOMY FOR BLADDER CARCINOMA FICARRA et al.

Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma

VINCENZO FICARRA, ORIETTA DALPIAZ, NAJATI ALRABI, GIACOMO NOVARA, ANTONIO GALFANO and WALTER ARTIBANI Department of Urology, University of Verona, Italy Accepted for publication 29 October 2004

OBJECTIVE RESULTS locally advanced cases only. Pathological lymph node involvement was diagnosed in 45 To analyse the rate of concordance The clinical stage of the primary tumour was patients (28.8%); this was foreseen with between the clinical and pathological carcinoma in situ in three patients (1.9%), cT1 pelvic computed tomography in 19 (12%) Tumour-Nodes-Metastasis staging in 67 (42.9%), cT2 in 70 (44.9%), cT3 in five only (P < 0.001). All patients designated cN+ systems in a homogeneous series of (3.2%) and cT4 in nine (5.8%). Clinical lymph were also pN+. patients who had undergone radical node involvement was detected in 19 patients cystectomy for locally advanced or (12.2%). The differences between clinical and CONCLUSION recurrent multifocal superficial bladder pathological stages were statistically carcinoma. significant (P 0.001), the concordance was < These data confirm the high risk of clinical moderate ( 0.27, P 0.001). Of the 70 k = < understaging of both local extension of the patients with cT1, 40 (57%) were £ primary tumour and lymph node involvement. PATIENTS AND METHODS reconfirmed as having pathological stage £T1; of the 70 with cT2, 16 (23%) had pT2 The clinical data of 156 patients who had carcinoma. Of the 140 patients with clinically KEYWORDS undergone radical cystectomy and bilateral organ-confined (£T2) neoplasms, 70 (50%) iliaco-obturator lymphadenectomy for had been understaged after radical bladder cancer, TCC, squamous cell bladder cancer in our department were cystectomy. The clinical and pathological carcinoma, survival, radical cystectomy, analysed retrospectively. systems were statistically overlapping for staging, TNM

INTRODUCTION imaging (ultrasonography, CT and MRI). cystectomy specimens underscore the Moreover, the same imaging aims to detect inaccuracy of clinical staging in patients with The definition of the local extension of the clinical loco-regional lymph node cT1. Bimanual examination under general primary tumour and the eventual detection of involvement and distant metastasis, as do anaesthesia and CT have a low sensitivity for loco-regional lymph node or distant chest X-rays or bone scans. defining the local extension of tumours. metastases are fundamental steps both in Bimanual palpation is subjective and depends treatment planning and assessing the Despite the relevant clinical role of staging in on both the experience of the surgeon and the outcome for patients with cancer. The need to selecting the most appropriate therapy for physical constitution of the patient. CT can compare overall and cancer-specific survival patients with bladder cancer, reports highlight misdiagnose 30–50% of locally advanced data, both in terms of stratifying patient risk that 30–50% of patients undergoing radical bladder cancers [6–10]. Moreover, the and treatment efficacy, makes mandatory the cystectomy had been understaged, both for currently available imaging techniques use of a worldwide staging system [1]. The local extension of the primary tumour and cannot identify loco-regional lymph node TNM staging system is the most widely used lymph node involvement [3–5]. The most micrometastases. to report local, lymph node and distant relevant clinical issues are a more appropriate extension of neoplasms. The latest edition of staging of cT1 cancers and the preoperative Thus the purpose of the present study was to the TNM system for bladder cancer was identification of those patients with locally analyse the rate of concordance between defined by Union International Contre le advanced and/or loco-regional lymph node- clinical and pathological staging systems in a Cancer and American Joint Committee on involving tumours (cT3-4 and/or cN+). The homogeneous series of patients who had Cancer in 2002 [2]. accuracy of clinical staging of cT1 tumours undergone radical cystectomy for locally can be markedly improved if bladder wall advanced or recurrent multifocal superficial As far as local extension of the primary smooth muscle is present in the initial TUR bladder carcinoma. tumour is concerned, bladder cancer staging specimen. A second staging TUR is strongly is based on histological analysis of the recommended in all cases with no smooth PATIENTS AND METHODS transurethral resection (TUR) specimen, muscle in the specimens [4]. However, the bimanual examination under general presence of residual cancer at the second TUR We retrospectively analysed the clinical data anaesthesia before and after TUR, and on and the pathological findings of radical of 156 patients who had undergone radical

STAGING AND RADICAL CYSTECTOMY FOR BLADDER CARCINOMA

adjacent to and distant from the tumour, Clinical characteristic Mean (SD) [range] or n (%) TABLE 1 along with the ureters and regional lymph Age 65.6 (9.01) [36–91] The main clinical and nodes. In men, tissue was obtained from the Male/female, % 90.4/9.6 pathological characteristics seminal vesicles and prostate, and in women Bladder cancer history of the 156 patients from ovaries, uterus and vagina when ﬁrst diagnosis 62 (39.7) appropriate [12]. progression of superﬁcial cancer 94 (60.3) Upper urinary tract neoplasm Clinical and pathological stages were reported absent 147 (94.2) according to the 2002 TNM system [2], but present 9 (5.8) combining CIS and Ta with T1 (

FICARRA ET AL.

Table 2 shows the correlations between Pathological TABLE 2 clinical and pathological stages of the primary Stage pT1 pT2 pT3 pT4 Overall The correlation between tumour. The concordance between clinical £ clinical and pathological and pathological staging systems was All, n (%) Clinical staging of the primary moderate (P < 0.001). Only 40 of the 70 £T1 40 (57) 11 (16) 13 (19) 6 (9) 70 (100) tumour for all tumours and patients with £cT1 (57%) were reconﬁrmed as cT2 2 (3) 16 (23) 42 (60) 10 (14) 70 (100) for TCC having £pT1 bladder cancer. In this subgroup the percentage of upstaging correlated with cT3 1 4 2 7 the bladder cancer history; in particular there cT4 9 9 was upstaging in two-thirds of those with a Overall 42 (27) 28 (18) 59 (38) 27 (17) 156 (100) ﬁrst diagnosis of cT1 and in 30% of those TCC where the diagnosis of cT1 was a progression

na, not available. DISCUSSION

This study confirmed the moderate The present results were similar to those specimens obtained from the margins correlation between the clinical and reported previously (Table 3) [15–23]. Paulson separately after macroscopically complete pathological TNM staging system in bladder et al. [16] found an understaging rate of 35% resection [24]. Herr [4], in a series of 150 cancer. The exact definition of clinical T1 in a cohort of patients treated with radical patients, reported that 19.8% of £cT1 stage bladder cancers is relevant for the therapeutic cystectomy for cT1 stage cancers. Freeman et cancers were upstaged to cT2 after repeat strategy. T1 tumours could be adequately al. [19], analysing data from 182 patients for TUR. Moreover, stratifying by clinical stage, treated conservatively with TUR and clinical stage £T1 bladder cancer, reported 32% of cTa-Tis and 27.6% of T1 cases were intravesical immunotherapy. This strategy is understaging rates of 19%, 40% and 34% in understaged at the second TUR. The overall inappropriate if the tumours are understaged, stage cTa, cT1 and £cT1, respectively. In two understaging rates were 14% and 49% in the for which the standard treatment could recent series [21,23] the authors underlined cases with and with no smooth muscle in the currently be radical cystectomy and/or that TUR understaged the primary tumour in initial TUR specimen, respectively. Generally, a systemic chemotherapy. 52% and 46% of cases, respectively. second TUR could modify the therapeutic strategy in a proportion of patients, i.e. In our experience, 43% of patients staged cT1 More reports support the need to repeat a 24–33% [3,4]. Similarly, Schips et al. [24] were upstaged at pathological examination of second staging TUR at 2–6 weeks after the detected residual cancer on repeat TUR in the radical cystectomy specimen. The results first [3]. The possible indications for a repeat 40 of 110 (36%) patients analysed, and Grimm were even worse for patients with cT2 disease, TUR could be clinical T1 tumours, any G3 et al. [5] reported higher 3- and 5-year who were correctly staged in only 23%. On lesions, all samples with no smooth muscle in recurrence-free survival rates in patients who the contrary, there was a substantial the surgical specimen, and all those in which had had a second TUR than in those who had correlation in cT3–4 tumours. cancer tissue was detected in the TUR one TUR only. To date, to the best of our

STAGING AND RADICAL CYSTECTOMY FOR BLADDER CARCINOMA

knowledge, the only available data comparing Classification of Malignant Tumours, 6th classification of urothelial (transitional pathological stage and clinical stage after a edn. New York: Wiley-Liss, 2002 cell) neoplasms of the urinary bladder. second TUR were reported by Dalbagni et al. 3 Brauers A, Buettner R, Jakse G. Second Bladder Consensus Conference [25]; they analysed 15 patients with clinical resection and prognosis of primary high Committee. Am J Surg Pathol 1998; 22: stage £T1 bladder carcinoma after a second risk superficial bladder cancer: is 1435–48 TUR and who had had immediate radical cystectomy often too early? J Urol 2004; 14 Munoz S, Bangdiwala S. Interpretation cystectomy. Only two of 15 patients had 165: 808–10 of Kappa and B statistics measures of pathological stage ≥T2. However, other 4 Herr HW. The value of a second agreement. J Appl Statistics 1997; 24: authors indicate the morbidity and costs transurethral resection in evaluating 105–11 related to readmission and second patients with bladder tumors. J Urol 1999; 15 Pagano F, Bassi P, Galetti TP et al. anaesthesia [26], while others denied the 162: 74–6 Results of contemporary radical usefulness of such a procedure unless smooth 5 Grimm MO, Steinhoff C, Simon X, cystectomy for invasive bladder cancer: muscle was absent in the initial TUR specimen Spiegelhalder P, Ackermann R, Vogeli a clinicopathological study with an [27]. A second TUR was not routinely used in TA. Effect of routine repeat transurethral emphasis on the inadequacy of the tumor, the present patients, not being part of the resection for superficial bladder cancer: nodes and metastases classification. J Urol current clinical practice at our department a long-term observational study. J Urol 1991; 145: 45–50 during the years analysed for this report. 2003; 170: 433–7 16 Paulson D. Critical review of radical 6 Jakse G, Algaba F, Fossa S, Stenzl cystectomy and indicators of prognosis. Imaging techniques provide insufficient A, Sternberg C. The 2004 European Semin Urol 1999; 11: 205–13 information to the clinical staging, mostly Association of Urology guidelines on 17 Soloway MS, Lopez AE, Patel J, limited to assessing loco-regional lymph node muscle-invasive and metastatic bladder Lu Y. Results of radical cystectomy for involvement. Paik et al. [8], analysing 82 cancer. http://www.uroweb.org/ transitional cell carcinoma of the bladder patients who had abdominal and pelvic CT, index.php?structure_id=140/ and the effect of chemotherapy. Cancer reported an overall accuracy of up to 55%, EAU_guidelines_online. Accessed July 1994; 73: 1926–31 with understaging and overstaging rates of 2004 18 Amling CL, Thrasher JB, Frazier HA, 39% and 6%, respectively. Similar data were 7 Herr HW. Routine CT scan in cystectomy Dodge RK, Robertson JE, Paulson DF. reported by Kim et al. [10] in 36 patients. The patients: does it change management? Radical cystectomy for stages Ta, Tis and detection of lymph node involvement was an Urology 1996; 47: 324–5 T1 transitional cell carcinoma of the important limitation of CT. In our experience, 8 Paik ML, Scolieri MJ, Brown SL, Spirnak bladder. J Urol 1994; 151: 31–5 CT identified only a third of patients with JP, Resnick MI. Limitations of 19 Freeman JA, Esrig D, Stein JP et al. pathological lymph-node involvement. The computerized tomography in staging Radical cystectomy for high risk patients present data and the analysis of earlier invasive bladder cancer before radical with superficial bladder cancer in the era reports underlines the need for more reliable cystectomy. J Urol 2000; 163: 1693–6 of orthotopic urinary reconstruction. staging techniques. Promising but insufficient 9 Barentsz JO, Engelbrecht MR, Witjes Cancer 1995; 76: 833–9 data are currently available for the use of JA, de la Rosette JJ, van der Graaf MV. 20 Ghoneim MA, el-Mekresh MM, el-Baz MRI in the clinical staging of bladder cancer. MR imaging of the male pelvis. Eur Radiol MA, el-Attar IA, Ashamallah A. Radical Tavares et al. [28] and Jager et al. [29] reported 1999; 9: 1722–36 cystectomy for carcinoma of the bladder: higher sensitivity rates in staging local 10 Kim B, Semelka RC, Ascher SM, Chalpin critical evaluation of the results in 1,026 extension of the primary tumour in two small DB, Carroll PR, Hricak H. Bladder tumor cases. J Urol 1997; 158: 393–9 cohorts of patients with locally advanced staging. comparison of contrast- 21 Cheng L, Neumann RM, Weaver AL et al. bladder cancer, while the overall accuracy in enhanced CT, T1- and T2-weighted MR Grading and staging of bladder carcinoma lymph node assessment was disappointing, imaging, dynamic gadolinium-enhanced in transurethral resection specimens. with false-negative rates as high as 40%. The imaging, and late gadolinium-enhanced Correlation with 105 matched cystectomy results of other imaging techniques, e.g. imaging. Radiology 1994; 193: 239–45 specimens. Am J Clin Pathol 2000; 113: positron emission tomography, are still 11 Skinner DG, Lieskovsky G. Management 275–9 preliminary [30] and not very encouraging. of invasive high-grade bladder cancer. In 22 Dutta SC, Smith JA Jr, Shappell SB, Skinner DG, Lieskovsky G eds. Diagnosis Coffey CS, Chang SS, Cookson MS. CONFLICT OF INTEREST and Management of Genitourinary Clinical under staging of high risk Cancer. Vol. 1. Philadelphia, PA: WB nonmuscle invasive urothelial carcinoma None declared. Saunders, 1988: 295–312 treated with radical cystectomy. J Urol 12 Stein JT, Lieskovsky G, Cote R et al. 2001; 166: 490–3 REFERENCES Radical cystectomy in the treatment of 23 Chang BS, Kim HL, Yang XJ, Steinberg invasive bladder cancer: long-term results GD. Correlation between biopsy and 1 Gospodorowicz MK, Miller D, Groome in 1054 patients. J Clin Oncol 2001; 19: radical cystectomy in assessing grade and PA, Greene FL, Logan PA, Sobin LH. The 666–75 depth of invasion in bladder urothelial process for continuous improvement of 13 Epstein JI, Amin MB, Reuter VR, carcinoma. Urology 2001; 57: 1063–6 the TNM classification. Cancer 2004; 100: Mostofi FK. The World Health 24 Schips L, Augustin H, Zigeuner RE et al. 1–5 Organization/International Society of Is repeated transurethral resection 2 Sobin DH, Witteking CH eds. TNM Urological Pathology consensus justified in patients with newly diagnosed

superﬁcial bladder cancer? Urology 2002; Huguet-Perez J, Salvador-Bayarri J. Re: gradient-echo sequence. Am J Roentgenol 59: 220–3 The value of a second transurethral 1996; 167: 1503–7 25 Dalbagni G, Herr HW, Reuter VE. Impact resection in evaluating patients with 30 Hain SF, Maisey MN. Positron emission of a second transurethral resection on the bladder tumors. J Urol 2000; 163: 1258 tomography for urological tumours. BJU staging of T1 bladder cancer. Urology 28 Tavares NJ, Demas BE, Hricak H. Int 2003; 92: 159–64 2002; 60: 822–4 MR imaging of bladder neoplasms: 26 Miladi M, Peyromaure M, Zerbib M, correlation with pathologic staging. Urol Correspondence: Vincenzo Ficarra, Saïghi D, Debré B. The value of a second Radiol 1990; 12: 27–33 Department of Urology, University of Verona, transurethral resection in evaluating 29 Jager GJ, Barentsz JO, Oosterhof GO, Piazzale Ludovico Scuro, 37100 – Verona, Italy. patients with bladder tumours Eur Urol Witjes JA, Ruijs SJ. Pelvic adenopathy in e-mail: vincenzo.ﬁ[email protected] 2003; 43: 241–5 prostatic and urinary bladder carcinoma: 27 Millan-Rodriguez F, Palou J, Chechile- MR imaging with a three-dimensional T1- Abbreviations: TUR, transurethral resection; Toniolo G, Montlleo-Gonzalez M, weighted magnetization-prepared rapid CIS, carcinoma in situ.

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Original Article PATHOLOGY OF TCC OF THE BLADDER and UPPER URINARY TRACT STEWART et al.

A comparison of the pathology of transitional cell carcinoma of the bladder and upper urinary tract

GRANT D. STEWART, SIMON V. BARIOL, KEN M. GRIGOR*, DAVID A. TOLLEY and S. ALAN McNEILL Departments of Urology and *Pathology, Western General Hospital, Edinburgh, UK. Accepted for publication 8 December 2004

OBJECTIVE obtained from the hospital database and CONCLUSIONS case-note review. To clarify the histopathological patterns of Upper urinary tract TCC is a higher grade and upper and lower urinary tract transitional cell RESULTS stage disease than bladder cancer, a finding carcinomas (TCCs), as previous reports that emphasizes the need for aggressive suggest that upper urinary tract TCCs have a In all, 164 patients with upper urinary tract treatment of upper urinary tract TCC. If greater tendency towards high-grade disease TCC and 2197 with bladder TCC were endourological management of upper urinary than bladder TCCs, of which most are low- identified. There was a correlation between tract TCC is considered, histopathological grade and low-stage tumours. grade and stage of both upper urinary tract determination of tumour grade before and bladder TCCs. 35% of the upper tract TCCs treatment is essential. PATIENTS AND METHODS were classified as grade 2 and 44% as grade 3, while for bladder TCCs, 31% of lesions were All patients presenting with TCC of bladder or classified as grade 2 and 35% as grade 3 KEYWORDS upper urinary tract between February 1991 (P = 0.003). Of the upper urinary tract lesions and December 2001 at one institution were 33% were stage pT2–T4, compared with only carcinoma, transitional cell, bladder, kidney, identified. Further patient information was 20% of bladder TCCs (P = 0.001). ureter, TCC

INTRODUCTION TCC, as information obtained from these reviewed by one uropathologist (K.M.G.); data biopsies correlated well with that of the final from patients’ initial pathology were included It has been previously stated that most TCCs pathological specimen. in the analysis. Most of the bladder TCCs in are low-grade (G1 and G2) and low-stage this study were resected endoscopically, and tumours (pTa and pT1), even when the upper Although endourological management is we are confident that these patients have not tract is affected [1], but several published indicated for patients with a single kidney, been understaged because of inadequate studies have shown a varying distribution of synchronous bilateral disease, chronic renal muscle in the specimen. The experienced grade and stage of upper urinary tract TCC. failure or those unfit for major surgery [14], pathologist who reviewed all the specimens Most studies have shown a preponderance of there is a trend towards endourological gave a staging of pTx if there was any doubt high-grade (G3) and stage (pT2–4) disease management of patients with a normal of the stage from the specimen. Further data when the upper urinary tract is affected [2–6]. contralateral kidney. However, this were obtained from the hospital database and Mazeman [2], in a review of 893 patients with recommendation is confined to the patient notes, which included patient upper urinary tract TCC, found that 55.3% of management of small, low-grade lesions demographics, anatomical location of the tumours were high-grade. Hall et al. [4], in a [14–16]. tumour and method of resection. Data on cohort of 252 patients with upper urinary disease recurrence, disease-specific survival tract TCC, found that 42.5% had high-grade We sought to evaluate the stage and grade of and overall survival were not collected, as it disease and 43.8% had high-stage tumours. upper and lower urinary tract TCC using a was not the aim of the study to evaluate these By contrast, Anderström et al. [7] found that large series over a 10-year period, to assess factors. Independent statistical advice was 75% of patients with upper urinary tract TCC differences in the pathology of the disease obtained. The Pearson chi-square test was had low-stage and -grade tumours. affecting the different parts of the urinary used for analysis unless otherwise stated, and tract. P < 0.05 taken to indicate significance. There is an established correlation between the grade and stage for TCC affecting the PATIENTS AND METHODS RESULTS upper and lower urinary tract [6,8–12]. Furthermore, advanced grade and stage is All patients with TCC of the bladder or upper In all, 164 patients with an upper urinary associated with a poorer prognosis, which urinary tract presenting to the Department of tract TCC and 2197 with bladder TCC influences management decisions [1]. Keeley Urology at the authors’ institution between were reviewed, and Table 1 shows the et al. [13] showed that accurate grading and February 1991 and December 2001 were demographic details; 102 patients with staging is possible from specimens obtained identified from a prospectively collected upper urinary tract TCC (62%) had an by ureteroscopic biopsy of upper urinary tract pathology database. Histological material was open nephroureterectomy, 45 (27%) had a

STEWART ET AL.

laparoscopic nephroureterectomy, five (3%) Bladder Upper urinary TABLE 1 had ureteroscopic resection of TCC and Variable TCC tract TCC P Comparison of TCCs of the 12 (7%) had other procedures (anterior Demographic characteristics bladder and upper urinary exenteration, distal ureterectomy or Number 2197 164 NA tract percutaneous treatment). Most patients with Sex, n (%) 0.02 bladder TCC had a transurethral resection, 214 Male 1519 (69) 100 (61) (10%) with muscle-invasive disease had a Female 678 (31) 64 (39) cystectomy, and the rest were treated with Mean (SD): radiotherapy. Follow-up data were not age, years 77.3 (12) 76.9 (11) 0.359† evaluated. months from surgery 95.3 (40) 81.0 (42) <0.001† Of the patients with upper urinary tract TCCs, Grade of tumour, n (%) 0.003 92 (56%) were found to have CIS 45 (2) 1 (0.6) had a bladder TCC either before or after the G1 704 (32) 32 (20) diagnosis of the upper urinary tract lesion, 14 G2 683 (31) 58 (35) (8.5%) had synchronous bladder TCC, and 70 G3 762 (35) 72 (44) (43%) had metachronous bladder TCCs (data Gx 3 (0.1) 1 (0.6) missing for the remaining eight patients). Tumours in the calyces or renal pelvis were Stage of tumour, n (%) 0.001 found in 97 patients (59%), and 13 (8%), nine Tis 45 (2) 1 (0.6) (6%) and 40 patients (24%) had TCC of the Ta 1228 (60) 79 (50) upper, mid and lower ureter, respectively. In 11 T1 370 (18) 25 (16) patients (7%) with ureteric tumours the site T2–T4 411 (20) 52 (33) was not specified. Six patients (4%) had multifocal tumours, and are included in two Relationship between grade and stage*, n (%) of the above groups. Low-grade: superficial 1155 (56) 74 (47) *Low-grade G1, G2; high- Table 1 shows the distribution of the grade = deeply invasive 202 (10) 15 (10) grade carcinoma in situ, and stage of TCCs. There were significant = High-grade: G3; superficial Tis, Ta, T1; differences between the groups in tumour = superficial 117 (6) 6 (4) deeply invasive T2, T3, T4. stage and grade; 35% of upper urinary tract = deeply invasive 579 (28) 62 (40) †Mann-Whitney U test. TCC lesions were graded as G2 (moderately differentiated, low-grade) and 44% as G3 (poorly differentiated, high-grade), compared with only 31% and 35%, respectively, for DISCUSSION The main aim of the present study was to patients with bladder TCC (P = 0.003). Of establish any differences in the pathology of upper urinary tract lesions, 33% were stage The anatomical location of upper urinary tract TCC of the bladder and upper urinary tracts. pT2–T4 lesions compared with only 20% of TCCs in the present study conforms with that Upper urinary tract TCC was significantly bladder TCCs (P = 0.001). The incidence of described by Mazeman [2], who also reported more aggressive and deeply invasive than TCC high-grade deeply invasive disease was that there were almost twice as many affecting the bladder. Although this has been significantly higher in the upper urinary tract pelvicalyceal as ureteric tumours (60% and alluded to previously, particularly in studies of than in the bladder (Table 1). Correspondingly, 40%, respectively, in the present study). Of the patients with synchronous upper urinary tract the proportion of low-grade (G1 and G2) present patients with upper urinary tract TCC, and bladder TCC [5,17], this difference has superficial (pTa/pT1) TCC was significantly 43% had metachronous bladder cancer, a not, until now, been well established. The higher in the bladder than in the upper proportion similar to that reported previously more aggressive nature of upper urinary tract urinary tract (P = 0.021). [14]. The pattern of pathology of the bladder cancer might be a consequence of the higher- tumours is consistent with standard teaching grade lesions found, or might represent There was an association between stage and that ª70% of tumours are superficial [1]. It is anatomical differences between the bladder grade in all cases (Pearson correlation well established that 70% of superficial and ureter or renal pelvis and earlier coefficient, r = 0.7). Of all patients, 1229 lesions present as stage pTa, 20% as pT1 and transmural spread. (56%) had low-grade and pTa/pT1 disease, 10% as pTis, which was also reflected in the and 641 tumours (29%) were high-grade and present findings. There was a strong In the present study, 44% of upper urinary deeply invasive. Only 217 patients (10%) with correlation between grade and stage of TCC tract TCCs were grade G3; upper urinary tract low-grade disease had deeply invasive for both upper urinary tract and bladder TCCs; TCC should therefore be regarded as an tumours, and 123 (6%) had high-grade most low-grade tumours were noninvasive or aggressive, high-grade cancer unless proven superficial tumours (P < 0.001). This superficially invasive, and high-grade otherwise. These findings are important relationship was the same when grade and tumours were predominantly deeply invasive for managing upper urinary tract TCC, stage of upper urinary tract and bladder TCC (muscle or renal parenchyma), which is in particularly as nephron-sparing procedures were analysed separately. good agreement with published data [6,8–12]. are redefining the management of these

PATHOLOGY OF TCC OF THE BLADDER AND UPPER URINARY TRACT

lesions. Endourological techniques, which REFERENCES 12 Murphy DM, Zincke H, Furlow WL. were until recently used for clearly defined Management of high grade transitional situations (note above) are now more widely 1 Messing EM. Urothelial tumours of the cell carcinoma of the upper urinary tract. applied to patients with normal contralateral urinary tract. In Walsh PC, Retik AB, J Urol 1981; 125: 25–9 kidneys. However, indications for Vaughan ED, Wein AJ eds, Campbell’s 13 Keeley FX, Kulp DA, Bibbo M, McCue endourological management should be Urology, 8th edn, Vol. 4 Chapt 76. PA, Bagley DH. Diagnostic accuracy of related to tumour rather than patient factors, Philadelphia: WB Saunders, 2002: 2732– ureteroscopic biopsy in upper tract i.e. small (<2.0 cm) solitary low-grade 84 transitional cell carcinoma. J Urol 1997; superficial lesions. Under these circumstances 2 Mazeman E. Tumours of the upper 157: 33–7 endourological management is safe and urinary tract calyces, renal pelvis and 14 Gettman MT, Segura JW. effective [14]. As upper urinary tract TCC ureter. Eur Urol 1976; 2: 120–6 Endourological management of upper appears to be potentially more aggressive 3 McNeill SA, Chrisofos M, Tolley DA. The tract transitional cell carcinoma. BJU Int than bladder tumours, a rigorous surveillance long-term outcome after laparoscopic 2003; 92: 881–5 programme should be followed after initial nephroureterectomy: a comparison with 15 Elliot DS, Blute ML, Patterson DE, conservative treatment. Patients must also be open nephroureterectomy. BJU Int 2000; Bergstralh EJ, Segura JW. Long-term aware of the risk of recurrence and possible 86: 619–23 follow-up of endoscopically treated upper future requirement for nephroureterectomy 4 Hall MC, Womack S, Sagalowsky AI, urinary tract transitional cell carcinoma. [14]. Patients with multifocal disease, larger Carmody T, Erickstad MD, Roehrborn Urology 1996; 47: 819–25 tumours, high-stage (pT2–T4) or grade 3 TCC CG. Prognostic factors, recurrence, and 16 Elliot DS, Segura JW, Lightner DJ, should be offered nephroureterectomy [18], survival in transitional cell carcinoma of Patterson DE, Blute ML. Is but the outcome after radical the upper urinary tract: a 30-year nephroureterectomy necessary in all nephroureterectomy in patients with locally experience in 252 patients. Urology 1998; cases of upper tract transitional cell advanced disease (stage pT3–T4, N1–N2) is 52: 594–601 carcinoma? Long-term results of poor, with a 5-year survival rate of 23% [19]. 5 Auld CD, Grigor KM, Fowler JW. conservative endourological management In these patients, consideration might be Histopathological review of transitional of upper tract transitional cell carcinoma given to adjuvant therapies such as local or cell carcinoma of the upper urinary tract. in individuals with a normal contralateral systemic chemotherapy. However, these Br J Urol 1984; 56: 485–9 kidney. Urology 2001; 58: 174–8 treatments have not been evaluated in 6 Huben RP, Mounzer AM, Murphy GP. 17 Kang CH, Yu TJ, Hsieh HH et al. The prospective randomized trials, as this would Tumor grade and stage as prognostic development of bladder tumours and be difficult given the low prevalence of upper variables in upper tract urothelial tumors. contralateral upper urinary tract tumors urinary tract TCC [20]. Cancer 1988; 62: 2016–20 after primary transitional cell carcinoma 7 Anderström C, Johansson SL, of the urinary tract. Cancer 2003; 98: The present study clearly shows that upper Pettersson S, Wahlqvist L. Carcinoma of 1620–6 urinary tract TCC is a more aggressive tumour the ureter: a clinicopathological study of 18 Jarrett TW, Sweetser PM, Weiss GH, than that of the bladder. The clinical 49 cases. J Urol 1989; 142: 280–3 Smith AD. Percutaneous management of significance of this finding is important. If 8 Jewett HJ, Strong GH. Infiltrating transitional cell carcinoma of the renal tumours of the upper urinary tract are carcinoma of the bladder: relation of collecting system: 9-year experience. automatically assumed to be of low grade and depth of penetration of the bladder wall J Urol 1995; 154: 1629–35 stage, as some reviews have suggested, and to incidence of local extension and 19 Batata MA, Whitmore WF, Hilaris BS, are fulgurated without previous biopsy, a metastases. J Urol 1946; 55: 366–72 Grabstald H. Primary carcinoma of the patient with high-grade disease could 9 Charbit L, Gendreau M-C, Mee S, ureter: a prognostic study. Cancer 1975; potentially be denied curative surgery, in Cukier J. Tumors of the upper urinary 35: 1626–32 the form of a nephroureterectomy. tract: 10 years of experience. J Urol 1991; 20 Oosterlinck W, Solsona E, van der Ureteroscopic biopsies should be mandatory 146: 1243–6 Meijden AP et al. EAU Guidelines on if endourological management is to be 10 Nielsen K, Ostri P. Primary tumors of the diagnosis and treatment of upper urinary used, as it cannot be assumed that TCC of renal pelvis: evaluation of clinical and tract transitional cell carcinoma. Eur Urol the upper urinary tracts is of low grade and pathological features in a consecutive 2004; 46: 147–54 stage. series of 10 years. J Urol 1988; 140: 19–21 11 Murphy DM, Zincke H, Furlow WL. Correspondence: Mr S. Alan McNeill, CONFLICT OF INTEREST Primary grade 1 transitional cell Department of Urology, Western General carcinoma of the renal pelvis and ureter. Hospital, Edinburgh, EH4 2XU, UK. None declared. J Urol 1980; 123: 629–31 e-mail: [email protected]

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Original Article ACCURACY OF ASSESSING LIFE-EXPECTANCY WILSON et al.

The assessment of patient life-expectancy: how accurate are urologists and oncologists?

JAMES R.M. WILSON, MICHAEL G. CLARKE, PAUL EWINGS, JOHN D. GRAHAM† and RUARAIDH MacDONAGH Department of Urology, Taunton & Somerset Hospital, Taunton, and *Department of Oncology, Beatson Oncology Centre, Western Inﬁrmary, Glasgow, UK Accepted for publication 19 November 2004

OBJECTIVE probability by an overall mean of 10.8% (95% assessing patient life-expectancy is an confidence interval, 10.1–11.5%). The 18 important finding and has significant To assess the degree of accuracy, precision individual doctors ranged from a mean implications for managing patients. Many and consistency with which consultant underestimation of 33.2% to a mean patients may be denied treatment after a urologists, oncologists and junior doctors overestimation of 3.9%. Variation around pessimistic assessment of life-expectancy and predict a patient’s 10-year life-expectancy. these means was considerable for each (less commonly) some may inappropriately be doctor, the standard deviations being offered treatment after an optimistic SUBJECTS AND METHODS 14.5–20.9%. Inter-doctor reliability was 0.58, assessment. The particular inaccuracy in while overall intra-doctor reliability was 0.74, junior doctors compared with their senior Eighteen doctors of varying seniority but for individual doctors was 0.31–0.94. colleagues also highlights the need for independently examined 70 patient case Junior doctors were less accurate in their training. The development of a tool to assist in scenarios containing detailed medical predictions than the senior doctors. Five both training and clinical practice has the histories; 13 of these cases were duplicate doctors tended to overestimate where life- potential to improve doctors’ decision- scenarios. Bland-Altman analyses were used expectancy was poor and underestimate making and patient care. to compare doctors’ estimates of the where it was good. probability of each hypothetical patient KEYWORDS surviving 10 years with that calculated using CONCLUSIONS actuarial methods. Intra- and interdoctor life expectancy, comorbidity, actuarial, reliability were also assessed. Doctors were poor at predicting 10-year prostate cancer survival, tending to underestimate when RESULTS compared with actuarial estimates. There was also substantial variability both within and Compared with actuarial estimates, doctors between doctors. The inaccuracy, imprecision underestimated the 10-year survival and inconsistency amongst the doctors in

INTRODUCTION and comorbidity into an estimate of life- This is easy to use and has been previously expectancy. There is some evidence of an incorporated in the context of prostate cancer Treatment decisions for individual patients age bias, such that older patients are to predict survival [12,13], although it could are based on several factors; in addition to the being offered curative treatments less be criticised for being developed in a relatively immediately relevant clinical variables, frequently [3], and it has been suggested that low-risk population. Of the other available existing comorbidities and patient choice this might arise from the clinicians’ inability generic measures, the Kaplan-Feinstein Index must also be considered [1]. The issue of life- to accurately assess patient life-expectancy with its recent modification to produce expectancy can make the difference between [4]. the Adult Co-morbidity Evaluation-27, has patients receiving treatment and being denied generated most interest [14,15] and has been it; e.g. current guidelines suggest that To assess life-expectancy, incorporating a used in creating a combined head and neck patients with localized prostate cancer should patient’s age and comorbidity is necessary; comorbidity and pathological score [16]. in general be offered curative treatment only there are several measures for assessing if their estimated life-expectancy is >10 years comorbidity [5–8], but these are often too An alternative system involves the use of [2]. However, multidisciplinary team meetings disease-specific to incorporate into wider actuarial data; the actuarial system, first frequently only have clinical data available, clinical practice [9]. An example of a more proposed by Rodgers and Hunt in 1919, and information on comorbidity, if presented generic measure is the Charlson score, the has been used by insurance companies for at all, is often incomplete. Moreover, even most widely used validated index [10,11]. This many years to estimate the perceived risks when such information is available, it is consists of 19 conditions, each allocated a associated with policyholders [17]. Data are unclear how well clinicians are able to weighting that equates to the relative risk of continually updated in line with available translate factors such as family history, age death, with an additional adjustment for age. evidence and enable life-expectancy to be

ACCURACY OF ASSESSING LIFE-EXPECTANCY

FIG. 1. The total percentage of cases either over- (red) or underestimated (green) by the individual clinicians. The Charlson index [10] was then applied to the comorbidity-attuned age to derive a 100 percentage chance of surviving 10 years. This 80 approach circumvents the criticism that the 60 Charlson index is only valid in a low-risk 40 population, as the actuarial method has 20 already been used to attune the age according 0 to the comorbidities. In Charlson’s initial -20 model the age score equated to 1 point per -40 decade over 50 years, but this was adapted to -60 allow an increase of 0.1 per single year of age. Percentage of cases, % -80 -100 The doctors’ predictions of 10-year survival Consultant Consultant Registrars SHOs PRHOs were then compared with those calculated Urologists Oncologists using actuarial figures, using ANOVA and Bland-Altman analyses. Differences between each prediction and the corresponding calculated on the basis of age, sex, smoking hypertension and hypercholesterolaemia’ actuarial figure were calculated, and the status, weight, blood pressure and other (Appendix). No details of any presenting mean (SD) of these differences derived for comorbid factors. Such information has condition were included. each doctor separately. Any propensity been used to assess the accuracy of two for a trend in these differences (e.g. consultant urologists in selecting for radical Then 18 doctors, including four consultant underestimation when life expectancy is high prostatectomy those patients with at least urologists, two consultant oncologists, four and overestimation when life-expectancy is a 10-year life expectancy [18]. The notes of urology specialist registrars, four surgical low) was examined using nonparametric 261 patients, on whom they had previously senior house officers (SHOs) and four surgical correlation coefficients. The 13 repeated cases performed radical prostatectomies for pre-registration house officers (PRHOs) were used to assess intra-doctor reliability, prostate cancer, were reviewed by the were instructed to assign a probability of and an overall inter-doctor reliability American General Life and Accident Insurance surviving 10 years (sometimes referred to coefficient also calculated. Company with subsequent calculation of the as 10-year life-expectancy) for each of the remaining life-expectancy for each patient on 70 case scenarios. To represent the clinical the basis of their comorbid factors, using and multidisciplinary team setting more actuarial data. About 20% of the patients who accurately, the nature of the study and RESULTS had undergone surgery had had a calculated the use of patient scenarios were fully life-expectancy of <10 years, suggesting explained to all the participating clinicians. The 18 doctors assigned a percentage some inaccuracy amongst clinicians in using In addition, no time restraints were given chance of 10-year survival for each of the comorbidity data to predict remaining life- and completion of the scenarios was 70 case scenarios. The patients were aged expectancy. supervised. 55–82 years and the median (range) actuarial percentage chance of 10-year survival Thus the aims of the present study were to In collaboration with a professional actuary, was 70 (5–94)%. Compared with actuarial assess the degree of accuracy, precision and actuarial tables were used to derive mortality predictions, the doctors tended to consistency with which consultant urologists, ratios based on the comorbid factors for each underestimate the probability of 10-year oncologists and junior doctors predicted a case, using the actuarial ‘numerical rating survival, with considerable variability within patient’s 10-year life-expectancy, based on system’, in which factors influencing and between doctors; this was particularly comorbid factors. mortality are represented by either a debit or marked among the more junior doctors credit score. The mortality of a ‘standard life’ (Fig. 1); 15 doctors predominantly (i.e. healthy patient with no comorbidity) is underestimated, with 10 underestimating SUBJECTS AND METHODS taken as 100%. Each comorbid factor has an over three-quarters of the cases. associated additional mortality rating factor, In all, 57 case scenarios were constructed expressed as a percentage of the standard life, The Bland-Altman plots and analyses to represent a realistic selection of patients e.g. sinus tachycardia with no organic cause; confirmed the impression of underestimation, seen in a general urology clinic. To assess 96–100 beats per minutes (bpm) = no e.g. Fig. 2a shows such a plot for an SHO with consistency in estimating life-expectancy, addition, 101–110 bpm = + 25%, 111– an extreme tendency to underestimate. 13 cases were repeated but distributed 120 bpm = + 50% and >120 bpm = + 100%). However, while many of the clinicians were randomly, and consequently 70 case scenarios A sum total of these rating factors was relatively consistent in their underestimation in all were presented to the clinicians. calculated using a rating schedule, such that a (or, rarely, overestimation), the Bland-Altman Each case included the patient’s age and comorbidity-attuned age was derived, e.g. a plots for some clinicians suggested a more medical history, e.g. ‘a 66-year-old-man 65-year-old man with additional ratings of complicated picture, with a propensity to with poorly controlled insulin-dependent 100% has a comorbidity attuned age of overestimate when the life-expectancy is low diabetes mellitus, diabetic retinopathy, 69 years [17]. and underestimate when it is high (Fig. 2b).

WILSON ET AL.

Results of the Bland-Altman analyses for each A FIG. 2. clinician are shown in Table 1. The common Bland-Altman plots for A, SHO D, propensity to underestimate is evident from 60 and B, Registrar D. the (mostly negative) mean differences 40 between the clinician’s estimate and the Overestimates actuarial figure for life-expectancy; the mean 20 (range, 95% CI from a random-effects ANOVA) 0 was -10.8 (-33.2 to 3.9, -11.5 to -10.1). By 0102030405060708090 contrast, the SDs of the differences show -20 relatively smaller variation (at 14.5–21.1), but -40 the values are relatively large, i.e. all clinicians show considerable variation whatever their -60 Underestimates overall mean reflects in the way of under- or chance of 10-year life expectancy -80 overestimation. The mean differences Average between the doctors’ estimates and the Difference between predicted and calculated actuarial figures (Table 1) highlights in B particular the inaccuracy in the predictions by SHOs and PRHOs compared with consultant 60 Overestimates urologists, oncologists and registrars. 40

Spearman’s correlation coefficients in Table 1 20 indicate a correlation between the differences 0 (clinician’s estimate minus actuarial figure) 010203040506070800 90 100 and the level of life-expectancy (average of -20 the two values); this confirms the impression 40 from Bland-Altman plots that some clinicians - are not consistent in their under- or -60 Underestimates overestimation. For example, registrar D had a chance of 10-year life expectancy -80 significant negative correlation confirming Average the impression from Fig. 2b of overestimation Difference between predicted and calculated when life-expectancy was low, and underestimation when it was high. Five clinicians had such a negative correlation, while one had a significant positive Spearman’s Test-retest TABLE 1 correlation, suggesting increasing Clinician Mean (SD) correlation (P)* reliability† The accuracy of each overestimation with life-expectancy. Consultant clinician’s predictions A -15.76 (16.82) 0.21 (0.08) 0.77 Results of test-retest (i.e. ‘intra-doctor’) B -5.09 (20.91) 0.18 (0.14) 0.51 reliability based on the 13 repeated cases C 2.76 (17.09) -0.02 (0.86) 0.84 showed a mixed picture, with considerable D -4.7 (16.85) -0.32 (0.007) 0.62 variation between clinicians (Table 1). Oncologist Reliability coefficients were 0.31–0.94, with A 3.89 (14.52) -0.21 (0.08) 0.81 an overall intra-doctor reliability of 0.74. The B -12.53 (15.83) 0.14 (0.25) 0.93 inter-doctor reliability from these same 13 Registrar repeated cases was 0.58, similar to the 0.56 A -5.12 (20.32) 0.16 (0.19) 0.58 obtained for the 57 unique cases (i.e. ignoring B -11.73 (21.11) 0.31 (0.01) 0.31 the 13 repeats). C -5.23 (17.76) -0.22 (0.07) 0.77 *Based on Bland-Altman D -1.89 (15.83) -0.38 (0.001) 0.92 analyses: mean (SD) of As a final illustration of the (in)accuracy of the SHO differences between doctors’ assessments, consider a situation A -14.29 (16.70) 0.08 (0.54) 0.94 clinician’s estimate and where guidelines suggest that treatment B -18.26 (20.73) 0.23 (0.06) 0.65 actuarial life-expectancy should be proffered if the estimated C -22.26 (20.54) 0.13 (0.28) 0.79 for 70 patient scenarios; the probability of 10-year survival is >50%. Using D -33.16 (18.16) -0.08 (0.51) 0.70 correlation is between these the actuarial estimates as a ‘gold standard’ it PRHO differences and the means is possible to calculate the sensitivity and A -19.23 (16.39) -0.33 (0.005) 0.60 of the two values; specificity of the doctors’ implied decisions. Of B 0.89 (20.02) 0 (1) 0.48 †Calculated from the two the 70 case scenarios, actuarial estimates C -11.7 (16.68) -0.26 (0.03) 0.47 sets of readings taken on 13 would suggest treatment for 53 of them under D -20.8 (16.79) -0.33 (0.006) 0.83 of the patients. this situation. For these 53 cases, the 18

ACCURACY OF ASSESSING LIFE-EXPECTANCY

doctors would on average recommend of patients in this study denied curative data, updated in line with current evidence- treatment for 66%, ‘denying’ treatment treatment based on a pessimistic assessment based literature, has the potential to provide for 34%. Conversely, for the 17 cases of life-expectancy, and 24% undergoing an accurate source of information. The that actuarial estimates would suggest inappropriate treatment based on an authors are currently engaged in developing a withholding treatment, the doctors would on optimistic view of life-expectancy. computer-based tool that could lead to average concur in 76%, hence ‘inappropriately’ improving the consistency and accuracy recommending treatment in 24%. If the The variability among doctors in the extent to amongst clinicians of all seniority levels and threshold for recommending treatment is which they either underestimated or specialities in their assessment of patient life- increased to 70% survival probability (where overestimated 10-year survival also has expectancy. The results of this study suggest actuarial estimates would lead to treatment clinical implications. Presentation of that the scope for such improvement is for half of the 70 cases), the sensitivity and treatment options to an individual patient considerable. specificity for the doctors’ assessments would might well vary according to doctors’ become 44% and 93%, respectively. assessments of life-expectancy. Moreover, the ACKNOWLEDGEMENTS inconsistency in many of the individual doctors when assessing the 13 repeat cases Funding: AstraZeneca provided funding for DISCUSSION suggests that treatment decisions may also the input of a professional actuary and IT vary daily, even when patients are seen by the specialist (for the ongoing development of a Even with detailed data on comorbidity, the same consultant. Although many treatment software tool). The authors acted completely clinicians in this study were generally decisions are now discussed in the independently in the conduct of the study, inaccurate, imprecise and inconsistent in their multidisciplinary team setting and this might over which AstraZeneca had no control. predictions of patient 10-year survival, with reduce variability, the decision will still be an overall tendency towards underestimation. influenced by the overall tendency of the Competing interests: the authors are Junior doctors were generally less accurate in majority of clinicians present; this study currently engaged in the development of a their predictions than their senior colleagues. suggests that that tendency might generally software tool that will use actuarial data and In addition, several doctors appeared to be one of pessimism about life-expectancy. techniques to assess life-expectancy based on overestimate where 10-year survival was poor the parameters for an individual patient. and underestimate where it was good. The general tendency to underestimate There is no intention that there would be any implies that some patients with good life- commercial gain from such a tool. Relatively few doctors were assessed but expectancy may be denied appropriate more (and more varied) case scenarios were treatment, but also that the reverse (patients CONFLICT OF INTEREST used than in previous studies. In addition, with a poor life-expectancy inappropriately although the use of case scenarios does not being offered radical treatment) should be None declared. represent the true clinic setting, such ‘paper less common. However, the situation is representations’ of real patients are potentially worse for the small group of REFERENCES frequently used in multidisciplinary meetings clinicians who underestimate when life- to enable treatment plans to be formulated, expectancy is good and overestimate when it 1 Wilson J, Graham J, MacDonagh R. and indeed high correlations between the is poor, as this could result in both denial of Patient life-expectancy: a vital element in assessments made by clinicians based on both treatment for patients with a good life- planning treatment? BJU Int 2004; 93: real and ‘paper’ patients were identified expectancy and inappropriate treatment if it 461–3 previously [19]. It is inevitable that clinicians is poor. 2 Royal College of Radiologists’ Clinical are more knowledgeable about outcomes in Oncology Information Network British conditions directly relevant to their speciality; The particularly poor accuracy of the junior Association of Urological Surgeons. thus cardiologists (for example) may have doctors (SHOs and PRHOs) raises the issue of Guidelines on the management of been better at assessing life-expectancy than training. Educating clinicians to more prostate cancer. BJU Int 1999; 84: 987– the clinicians in this study, because of the accurately assess life-expectancy should in 1014 generic nature of the comorbidities presented. principle be relatively straightforward, but 3 Alibhai SMH, Krahn MD, Cohen MM However, whenever treatment decisions this study highlights that experience alone is et al. Is there age bias in the treatment of relating to a presenting condition are not enough, and suggests that applying localized prostate cancer? Cancer 2004; influenced by assessing life-expectancy, these comorbidity data is complex and difficult to 100: 72–81 generic comorbidities are essential in such an learn and retain. Although senior doctors 4 Krahn MD, Bremner KE, Asaria J et al. assessment and need to be understood by a were better in their predictions, they still had The ten-year rule revisited. accuracy of broad range of clinicians. a substantial degree of variability and clinicians’ estimates of life expectancy in inaccuracy, suggesting that training and patients with localised prostate cancer. The findings have important implications for education should be targeted at doctors of all Urology 2002; 60: 258–63 managing conditions where perceived life- levels. 5 Linn BS, Linn MW, Gurel L. Cumulative expectancy influences treatment options and illness rating scale. J Am Geriatr Soc 1968; patient choice. The implication is one of Additional aids to assess life-expectancy 16: 622–6 potentially inappropriate management of could be useful both in the clinical and 6 Greenfield S, Aronow HU, Elashoff RM, some patients, with perhaps as many as 34% educational settings. The use of actuarial Watanabe D. Flaws in mortality data. the

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hazards of ignoring comorbid disease. Heijnen ML, Crommelin MA, Coebergh 17 Brackenridge RDC, Elder JW. Medical JAMA 1988; 260: 2253–5 JW. Comorbidity in patients with prostate selection of life risks. Macmillan 7 Goldman L, Caldera DL, Nussbaum SR cancer and its relevance to treatment Reference 1998 et al. Multifactorial index of cardiac risk in choice. BJU Int 1999; 84: 652–6 18 Koch MO, Miller DA, Butler R et al. noncardiac surgical procedures N Engl J 13 Barry MJ, Albertsen PC, Bagshaw MA Are we selecting the right patients for Med 1977; 297: 845–50 et al. Outcomes for men with clinically treatment of localized prostate cancer? 8 Copeland GP, Jones D, Walters M. non-metastatic prostate carcinoma Results of an actuarial analysis. Urology POSSUM. a scoring system for surgical managed with radical prostatectomy, 1998; 51: 197–202 audit. Br J Surg 1991; 78: 355–60 external beam radiotherapy, or expectant 19 Kirwan JR. Clinical judgement in 9 Singh R, O’Brien TS. Comorbidity management: a retrospective analysis. rheumatoid arthritis. I. Rheumatologists’ assessment in localized prostate cancer. A Cancer 2001; 91: 2302–14 opinions and the development of paper review of currently available techniques. 14 Kaplan MH, Feinstein AR. The patients. Ann Rheum Dis 1983; 42: 644– Eur Urol 2004; 46: 28–41 importance of classifying initial 7 10 Charlson ME, Pompei P, Ales KL, comorbidity in evaluating the outcome of MacKenzie CR. A new method of diabetes mellitus. J Chron Dis 1974; 27: Correspondence: James R.M. Wilson, classifying prognostic comorbidity in 387–404 Department of Urology, Taunton & Somerset longitudinal studies: Development and 15 http://www.oto.wustl.edu/clinepi/Forms/ Hospital, Musgrove Park, Taunton, TA1 5DA, validation. J Chron Dis 1987; 40: 373–83 com_form.doc UK. 11 Charlson M, Szatrowski TP, Peterson 16 Picirillo JF, Lacy PD, Basu A, Spitznagel e-mail: [email protected] J, Gold J. Validation of a combined EL. Development of a new head and neck comorbidity index. J Clin Epidemiol 1994; cancer-specific comorbidity index. Arch Abbreviations: SHO, senior house officer; 47: 1245–51 Otolaryngol Head Neck Surg 2002; 128: PRHO, pre-registration house officer. 12 Post PN, Kil PJ, Hendrikx AJ, Janssen- 1172–9

APPENDIX

Age 57 Case 42

PMH Insulin Dependent diabetic, blood sugar found to be 12, drinks more than 30 units per week, father died myocardial infarct at 56. Has mild calf pain walking up steep hills.

What do you believe is the percentage chance of this patient being alive at TEN years?

Age 74 Case 43

PMH Angina with Atrial Fibrillation, mild dyspnoea on exertion, slight cardiomegaly on chest x-ray, blood pressure found to be 165/90.

What do you believe is the percentage chance of this patient being alive at TEN years?

Age 67 Case 44

PMH Mild asthma

What do you believe is the percentage chance of this patient being alive at TEN years?

Age 69 Case 45

PMH Lower Urinary Tract Symptoms, femoral-popliteal bypass for peripheral vascular disease 2 years ago, currently asymptomatic, blood pressure 165/85 and smokes 5 cigarettes per day.

What do you believe is the percentage chance of this patient being alive at TEN years?

Age 74 Case 46

PMH Lower Urinary Tract Symptoms, blood pressure found to be 170/90, also has mild gout.

What do you believe is the percentage chance of this patient being alive at TEN years?

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article UNDERSTANDING INVOLUNTARY DETRUSOR ACTIVITY BRADSHAW et al.

There is a wide spectrum of topics Towards a better understanding of covered in this section. The ever- present problem of nocturia is involuntary detrusor activity further explored by authors from HELEN D. BRADSHAW, STEPHEN C. RADLEY*, DEREK J. ROSARIO† and Sweden, with interesting CHRISTOPHER R. CHAPPLE† conclusions. In addition, several Departments of Urology Research, *Obstetrics and Gynaecology, and †Urology, Sheffield papers describe various issues Teaching Hospitals, UK relating to the surgical correction Accepted for publication 6 December 2004 of stress urinary incontinence. Finally, authors from Switzerland OBJECTIVES (3%) as having such IDA. The correlation describe their use of sacral between symptom severity (measured by the magnetic stimulation in non- To compare the measured variables of BFLUTS-Q) and urodynamics was higher when inflammatory chronic pelvic pain involuntary detrusor activity (IDA) during these criteria were applied (r = 0.52 vs 0.38, syndrome. ambulatory cystometry (AC) in women with P £ 0.01). and with no overactive bladder symptoms, and to evaluate the correlation between these CONCLUSION variables and symptom severity. There are quantifiable differences between PATIENTS AND METHODS IDA found during AC in symptomatic and asymptomatic women. The measured In all, 61 symptomatic and 39 asymptomatic variables of IDA may be useful to determine women completed the Bristol Female Lower its clinical relevance, which may be indicated Urinary Tract Symptoms Questionnaire by contractions associated with leakage or (BFLUTS-Q) and underwent AC. Measured contractions of >30 s occurring at bladder variables of IDA (amplitude, duration, bladder volumes of <300 mL. volume and symptoms) were compared in the two cohorts. KEYWORDS

RESULTS detrusor overactivity, overactive bladder, ambulatory urodynamics IDA was detected in 47 of 61 symptomatic women (77%) and in 17 of 36 (47%) controls (P £ 0.01). The maximum IDA (defined as the INTRODUCTION highest amplitude contraction in any fill-void cycle) occurred at significantly lower volumes The poor correlation between LUTS and (328 vs 450 mL, P £ 0.05), was of higher conventional urodynamic findings has been amplitude (26 vs 12 cmH2O, P = 0.14) and well documented [1]. Despite individual longer duration (83 vs 14 s, P £ 0.05) in laboratory cystometric (LC) measurements symptomatic women than in controls. There not being clinically useful in quantifying was coincident incontinence in 22 (36%) detrusor overactivity, and the tests’ apparent symptomatic women and no controls lack of sensitivity [2], the method is still (P £ 0.01). Discriminatory levels for clinically commonly held to be a reliable and objective relevant IDA were established, and when measure of detrusor function [3–5]. applied retrospectively, classified 35 of 61 Ambulatory cystometry (AC) uses principles symptomatic women (55%) and one control derived from established urodynamic practice

BRADSHAW ET AL.

but has the theoretical advantages of natural markers on the ambulatory box. Subjects The association between symptoms reported bladder filling, a longer period of observation graded the severity of urgency as mild (+), in the BFLUTS-Q and urodynamic variables and a relatively normal environment. The moderate (++) or severe (+++). To identify was evaluated using Spearman’s correlation higher detection of involuntary detrusor detrusor activity associated with voiding, the coefficient. activity (IDA) in symptomatic individuals may subject pressed a specific event marker on the reflect more physiological lower urinary tract ambulatory box before each void. Connection function during AC [6–8]. However, the to the flow meter was also automatically RESULTS detection of IDA in a large proportion of recorded. The investigator independently apparently healthy asymptomatic individuals documented the time of voids, interventions In all, 61 AC datasets from symptomatic during AC casts doubt on the clinical and events. Provocative testing with repeated women were included in the analysis. Of the relevance of this finding [9,10]. coughs and cold-water hand-washing was original cohort of 104 symptomatic women, carried out during the third hour of 41 were excluded because they had The present study was designed to test the monitoring. During each ambulatory study urodynamic stress incontinence detected hypothesis that IDA detected during AC in the signal quality was assessed with regular during conventional LC and a further two had symptomatic individuals is quantitatively cough tests and real-time monitoring of uninterpretable AC data. In all, 39 healthy distinct from IDA observed in healthy, pressure. volunteers were eligible and underwent AC; asymptomatic volunteers. We also wished to the AC traces in three were uninterpretable determine which variables might be usefully At the end of each investigation, recorded and were excluded from the analysis. The employed to establish the characteristics of data were downloaded onto a personal mean (SEM) age of the symptomatic and clinically relevant IDA (CRIDA). computer and analysed in conjunction with asymptomatic groups was 56 (1.9) and the event diary, independent of the subject. 34 (1.6) years, respectively. Sections containing artefacts that might PATIENTS, SUBJECTS AND METHODS mimic or mask true changes in detrusor The maximum cystometric capacity, fill rate, pressure were excluded. All IDA detected number of fill-void cycles and total duration In all, 104 women referred for investigation of during the filling phase was analysed along of monitoring in symptomatic women and urgency, frequency and/or urge incontinence with the estimated bladder volume at that controls are shown in Table 1. In controls IDA were recruited from gynaecology and urology point and any recorded symptoms. was detected in 17 of 36 studies (47%), outpatient clinics and underwent AC and LC. whereas in symptomatic women there Women found to have urodynamic stress The following variables were documented: the was IDA in 47 of 61 studies (77%; P £ 0.01, incontinence during LC were excluded amplitude and duration of IDA detected chi-square). This activity coincided with from further analysis. A control group of during filling; the maximum bladder capacity the recording of severe urgency in seven 39 healthy volunteers was recruited by local for each fill-void cycle; coincident symptoms controls and 40 symptomatic women advertisement. Controls were excluded if they and urinary leakage; the bladder volume at (P £ 0.01, chi-square). No controls had reported bothersome urgency, frequency or which IDA occurred. The first involuntary any urinary incontinence, whereas 22 any urge incontinence on the Bristol Female contraction was defined as that seen at the symptomatic women had leakage coincident Lower Urinary Tract Symptoms Questionnaire lowest bladder volume, in any fill-void cycle. with IDA (P £ 0.01). (BFLUTS-Q) which all women completed The maximum contraction was defined as before undergoing AC, according to a that with the highest amplitude, in any fill- Table 1 also shows the characteristics of the standard protocol [7,11]. Women with void cycles. first and maximum episodes of IDA detected AC studies of inadequate quality for in each cohort. The first episode of IDA was at interpretation were excluded from further Voided volumes were measured and the significantly higher median bladder volumes analysis. Methods, definitions and units residual urine volume estimated by (P £ 0.01) and of lower amplitude and shorter conform to the standards recommended by ultrasonography at the beginning and end of duration in controls than in symptomatic the ICS unless otherwise stated. each investigation. Pre-weighed pads were women. Similarly, the maximum IDA was at used to quantify urinary leakage during the significantly higher bladder volumes and of AC was carried out using micro-tip pressure test. The mean fill rate was calculated for each significantly shorter median duration (both transducers mounted on silicone-coated 7 F fill/void cycle as (voided volume + leaked P £ 0.01) in controls than in symptomatic catheters (Gaeltec Ltd, Isle of Skye, UK) which volume + residualend – residualinitial)/time. This women. were inserted urethrally and rectally to value was then used to determine the bladder measure intravesical and intra-abdominal volume at specific times during the study. Linear regression showed that the pressure, respectively. The transducers were symptomatic status of the subject was an calibrated before each investigation and For the statistical analysis, IDA in the two important factor in the variability of certain zeroed to atmospheric pressure before groups was compared using tests for AC variables, i.e. the volume at which IDA first insertion. Pressure was sampled at 8 Hz nonparametric data (Mann–Whitney U). occurred and the amplitude and duration of using a solid-state recorder (UPS-2020, Linear regression was used to explore the the maximum activity (Table 2). Age was not a Medical Measurements Systems, MMS®, factors responsible for the variability between significant factor in the variability of any of the Netherlands). Symptoms of urgency and the cohorts, and the chi-squared test to the urodynamic variables other than the urinary leakage were recorded by the subject compare differences between proportions of amplitude of maximum IDA, which was using a contemporaneous diary and event healthy volunteers and symptomatic subjects. negatively correlated with increasing age.

UNDERSTANDING INVOLUNTARY DETRUSOR ACTIVITY

than symptomatic women had a maximum TABLE 1 The total duration, ﬁll rate, maximum bladder capacity, and ﬁrst and maximum detrusor contraction of £30 s in duration (71% of contractions during AC in controls and patients controls and 23% of symptomatic women).

Variable Controls Symptomatic P* Number 36 61 DISCUSSION Median (IQ): total duration, min 177 (127–234) 180 (124–234) 0.64 In the present study, the detection of IDA Median (range): during AC in 47% of asymptomatic women is N fill/void cycles 1 (1–3) 2 (1–3) 0.01 comparable with rates reported in other series Median (IQ) [9,10,12]. Such observations have previously max. bladder capacity, mL 600 (400–688) 425 (335–580) 0.05 cast doubt on the reliability of AC for fill rate, mL/min 3.8 (1.3–8.3) 4.7 (1.7–12.7) 0.40 evaluating detrusor function. However, we Detrusor contractions found statistically significant differences N1747 between the variables of IDA in symptomatic First detrusor contraction and asymptomatic women. Median (IQ) volume, mL 400 (339–592) 205 (145–334) 0.001 To eliminate artefactual changes in detrusor amplitude, cmH O10 (7–17) 13 (6–25) 0.12 2 pressure which could have been erroneously duration, s 13 (9–37) 40 (15–85) 0.03 interpreted as IDA, the interpretation of AC Maximum detrusor contraction: during the present study adhered to a strict volume, mL 450 (357–625) 328 (190–450) 0.009 protocol (as recommended by the ICS [13]). amplitude, cmH O 12 (8–25) 26 (8–48) 0.14 2 Consequently, 5% of studies were rejected, a duration, s 14 (9–70) 83 (40–140) 0.002 rate similar to that in other centres with experience of AC [12]. *Mann–Whitney U-test; IQ, interquartile range. Although the incidence of overactive bladder symptoms is known to increase with age [14], detrusor contractility actually decreases and TABLE 2 Linear regression analysis evaluating the effect of type (control or symptomatic woman) and the amplitude of IDA might also be expected age on ambulatory cystometry parameters to decline [15]. This was supported by the multivariate analysis, which showed that the Type (control or symptomatic) Age amplitude of maximum IDA was negatively Coefficients P Coefficients P correlated with increasing age. First detrusor contraction Volume 0.419 0.005 0.075 0.68 When comparing symptomatic with Amplitude -0.262 0.106 0.052 0.744 asymptomatic women there were statistically Duration -0.221 0.163 0.12 0.444 significant differences in the duration of Maximum detrusor contraction maximum IDA and the bladder volume at Volume 0.216 0.168 -0.155 0.320 which IDA occurred, and these variables Amplitude -0.499 <0.001 -0.416 0.003 appeared to be independent of age. It is Duration -0.409 0.008 -0.032 0.975 therefore apparent that discriminatory levels may be identified which, when combined, may be used to give an indication of the clinical The symptom of urgency in the BFLUTS-Q symptomatic women and controls. At any relevance of IDA, and that such an approach before AC was reported as ‘never’ by 25 given bladder volume <800 mL, IDA was may offer an easily applicable and practical controls. The remaining 11 (30%) reported detected in a relatively smaller proportion system for the descriptive interpretation of occasional urgency that was ‘not a problem’. of controls than symptomatic women. For ambulatory urodynamic studies. In six of these 11, IDA was detected during example, at bladder volumes of £300 mL, the AC. All symptomatic women reported first IDA had occurred in 72% of symptomatic For each variable the point of maximum troublesome overactive bladder symptoms women and 17% of controls. difference between the cohorts can be (urgency, frequency or/and urge identified on the cumulative frequency curves incontinence). The symptom of urgency was Figure 1B,C shows the cumulative frequency (Fig. 1). This point may be used empirically to reported in the BFLUTS-Q ‘occasionally’ by 13 for amplitude and duration of the maximum indicate discriminatory levels that distinguish symptomatic women, ‘sometimes’ by 19, IDA; a larger proportion of controls than IDA in controls from that in symptomatic ‘most of the time’ by 19 and ‘always’ by ten. symptomatic women had a maximum rise women. There were significant differences

in detrusor pressure of £20 cmH2O in between the groups in the volume at which Figure 1A shows the cumulative frequency amplitude (70% and 30%, respectively). IDA occurred and the duration of IDA, of IDA with increasing bladder volume in Similarly, a larger proportion of controls therefore the following discriminatory levels

BRADSHAW ET AL.

were identified as being most useful in A FIG. 1. distinguishing the two cohorts; first IDA 100 Cumulative frequency charts for: occurring at a bladder volume £ 300 mL; 90 A, volume; B, amplitude of duration of maximal IDA 30 s. maximum contraction; and C, > 80 duration of maximum 70 Applying these criteria to define CRIDA contraction, in symptomatic retrospectively in the two cohorts, CRIDA was 60 women (red closed squares) and detected in 32 (55%) of symptomatic and one % 50 controls (green open circles). (3%) of the asymptomatic women, whereas 40 before applying these criteria the respective 30 IDA detection rates were 77% and 47%. The 20 loss of urine when a subject is attempting to inhibit bladder emptying is clearly suggestive 10 of a clinical problem, but may also have an 0 impact on measurable detrusor variables; 0 100 200 300 400 500 600 700 800 900 when IDA is associated with leakage, its Volume, mL amplitude and duration may be reduced [3]. Miller et al. [16] reported an inverse B correlation between the frequency of urge 100 incontinence and the amplitude of 90 uninhibited contractions during LC, that they 80 ascribed to the effect of urethral sphincteric 70 deficiency. When urethral sphincter function 60 is adequate, high-amplitude IDA can develop, but when inadequate, only low-amplitude IDA % 50 can be recorded. To limit the confounding 40 effect of sphincteric insufficiency, women 30 with urodynamic stress incontinence during 20 LC were excluded from the present study. 10 Therefore, in addition to the discriminatory 0 levels described, it seems appropriate to classify any IDA associated with urinary 5152535455565758595 incontinence as CRIDA. In the original cohort Pressure, cmH2O of 61 symptomatic women, 32 had CRIDA C based on duration and bladder volume alone, 100 and three additional patients who did not 90 fulfil these criteria had associated leakage. 80 Reclassifying these three as CRIDA resulted in 70 60 35 of the original cohort of 61 symptomatic

% 50 women (55%) and one control having CRIDA. 40 CRIDA defined in this way was strongly 30 associated with troublesome overactive 20 bladder symptoms reported in the BFLUTS-Q 10 0 before the investigation (P £ 0.01) and improved the correlation between symptoms 5 20 35 50 65 80 95 110 125 140 155 175 190 205 220 235 and the urodynamic diagnosis (any IDA, Time, s r = 0.38; CRIDA, r = 0.52, both P < 0.001). Aside from its complexity, the frequency and detected during AC in asymptomatic and This study shows that IDA during AC is total duration of detrusor activity are difficult symptomatic women. Activity occurring at quantifiable and that its quantification to measure reliably if a study is not of optimal high bladder volumes and of short duration is improves the correlation with symptoms. It quality in its entirety. Practical methods for common in asymptomatic individuals and supports the theory of van Waalwijk van interpreting ambulatory urodynamic traces may thus represent a variation of normal. In Doorn et al. [17] underlying the detrusor must circumvent the fact that discrete practice, it appears that IDA may indeed be a activity index, a scoring system which is sections of an investigation may be normal occurrence at one end of a spectrum based on logistic regression and uses several suboptimal, whilst striving to maintain ranging from normal to pathological in terms variables, including fluid intake, voided objectivity and simplicity. of its measured variables and associated volume, and the frequency and duration of symptoms. Its more severe and clinically activity. The detrusor activity index is yet to In conclusion, there are significant and relevant form (CRIDA) may be identified by a find general application in clinical practice. quantifiable differences in the variables of IDA duration of >30 s and bladder volume of

UNDERSTANDING INVOLUNTARY DETRUSOR ACTIVITY

<300 mL or associated leakage. We think that 4 Jarvis GJ, Hall S, Stamp S, Millar testing of the lower urinary tract in these findings will help to overcome the DR, Johnson A. An assessment of female volunteers. J Urol 1992; 147: earlier controversy relating to the specificity urodynamic examination in incontinent 1319–25 of AC, and the use of discriminatory levels as women. BJOG 1980; 87: 893–6 13 van Waalwijk van Doorn ES, Anders described here may be of considerable 5 Flisser AJ, Blaivas JG. Role of cystometry K, Khullar V et al. Standardisation of practical value in this context. However, in evaluating patients with overactive ambulatory urodynamic monitoring. perhaps more importantly, the present study bladder. Urology 2002; 60 (Suppl. 1): 33– Report of the Standardisation Sub- gives greater insight into normal and 42 Committee of the International abnormal detrusor function during natural 6 van Waalwijk van Doorn ES, Remmers Continence Society for Ambulatory filling, and should be considered when A, Janknegt RA. Extramural ambulatory Urodynamic Studies. Neurourol Urodyn evaluating cystometric findings in general. urodynamic monitoring during natural 2000; 19: 113–25 During medium fill LC, it is recognized that filling and normal daily activities: 14 Milsom I, Abrams P, Cardozo L, Roberts nonphysiological filling and the abbreviated evaluation of 100 patients. J Urol 1991; RG, Thuroff J, Wein AJ. How widespread nature of the test may affect the assessment 146: 124–31 are the symptoms of an overactive of detrusor function [6–8,16]. In addition, the 7 Radley SC et al. Conventional and bladder and how are they managed? A relatively rapid changes in bladder volume will ambulatory urodynamic findings in population-based prevalence study. BJU further influence the measured variables of women with symptoms suggestive of Int 2001; 87: 760–6 IDA, perhaps explaining the test’s inability bladder overactivity. J Urol 2001; 166: 15 Resnick NM, Yalla SV. Detrusor to usefully quantify the overactive detrusor 2253–8 hyperactivity with impaired contractile and to discriminate between the relevant 8 Webb RJ, Griffiths CJ, Zachariah KK, function. An unrecognized but common and irrelevant, as appears to be possible Neal DE. Filling and voiding pressures cause of incontinence in elderly patients. using AC. measured by ambulatory monitoring and JAMA 1987; 257: 3076–81 conventional studies during natural and 16 Miller KL, DuBeau CE, Bergmann M, CONFLICT OF INTEREST artificial bladder filling. J Urol 1991; 146: Griffiths DJ, Resnick NM. Quest for a 815–8 detrusor overactivity index. J Urol 2002; None declared. 9 Heslington K, Hilton P. Ambulatory 167: 578–84 monitoring and conventional cystometry 17 van Waalwijk van Doorn ES, Ambergen REFERENCES in asymptomatic female volunteers. BJOG AW, Janknegt RA. Detrusor activity 1996; 103: 434–41 index: quantification of detrusor 1 Bates C, Whiteside C, Turner-Warwick 10 Robertson AS, Griffiths CJ, Ramsden overactivity by ambulatory monitoring. R. Synchronous urine pressure flow PD, Neal DE. Bladder function in healthy J Urol 1997; 157: 596–9 cystourethrography with special volunteers: ambulatory monitoring and reference to stress and urge incontinence. conventional urodynamic studies. Br J Correspondence: Helen D. Bradshaw, Br J Urol 1970; 42: 714–23 Urol 1994; 73: 242–9 Department of Urology Research, J Floor, 2 Wagg A, Bayliss M, Ingham NJ, Arnold 11 Jackson S, Donovan J, Brookes S, Royal Hallamshire Hospital, Sheffield, S10 2JF, K, Malone-Lee J. Urodynamic variables Eckford S, Swithinbank L, Abrams P. UK. cannot be used to classify the severity of The Bristol female lower urinary tract e-mail: h.d.bradshaw@sheffield.ac.uk detrusor instability. Br J Urol 1998; 82: symptoms questionnaire: development 499–502 and psychometric testing. Br J Urol 1996; Abbreviations: LC, AC, laboratory, ambulatory 3 Maes D, Wyndaele JJ. Correlation 77: 805–12 cystometry; (CR)IDA, (clinically relevant) between history and urodynamics in 12 van Waalwijk van Doorn ES, Remmers involuntary detrusor activity; BFLUTS-Q, neurologically normal incontinent A, Janknegt RA. Conventional and Bristol Female Lower Urinary Tract Symptoms women. Eur Urol 1988; 14: 377–80 extramural ambulatory urodynamic Questionnaire.

Blackwell Science , LtdOxford , UKBJUBJU International1464-41 0XBJU InternationalApril 2005 956

Original Article PHARMACOKINETICS OF ORAL DESMOPRESSIN IN ELDERLY PATIENTS WITH NOCTURIA HVISTENDAHL et al.

The pharmacokinetics of 400 mg of oral desmopressin in elderly patients with nocturia, and the correlation between the absorption of desmopressin and clinical effect

GITTE M. HVISTENDAHL, ANDERS RIIS*, JENS P. NØRGAARD* and JENS C. DJURHUUS Department of Clinical Experimental Research, Aarhus University Hospital, Aarhus, and *Ferring International Centre, Copenhagen, Denmark Accepted for publication 26 November 2004

OBJECTIVE for a pharmacokinetic analysis of voids and nocturnal diuresis were half that desmopressin. The pharmacodynamics after with placebo. The time to the first nocturnal To investigate the pharmacokinetic profile of an equivalent oral dose before bedtime were void was almost doubled compared with oral desmopressin in elderly patients with assessed by measuring changes in the number placebo. nocturia, and to analyse any possible of nocturnal voids, time to first nocturnal void correlation between the absorption and and nocturnal diuresis, from placebo to active CONCLUSIONS clinical effect. treatment. There seems to be a relationship between PATIENTS AND METHODS RESULTS gender, plasma level of desmopressin and the incidence of adverse events. Plasma In all, 32 patients were screened to determine There was a linear relationship between desmopressin at 2 h after dosing cannot be the baseline number of nocturnal voids and plasma desmopressin at 2 h after dosing and used to predict the pharmacodynamic the nocturia index; of these, 24 fulfilled the the area under the plasma concentration response, although desmopressin lowers the inclusion criteria and were enrolled for a curve from 0 to infinity (Pearson’s 0.923, r nocturnal diuresis and the number of pharmacokinetic evaluation of oral P 0.001). Women had a significantly higher < nocturnal voids. desmopressin 400 mg. A double-blind, plasma desmopressin concentration than randomized, placebo-controlled, crossover- men (P = 0.0012) and more adverse events. effect evaluation period was then used to test There was no correlation between plasma KEYWORDS the association between the absorption of desmopressin at 2 h after dosing and the desmopressin and pharmacodynamic effect. within-patient response in any of the effect desmopressin, elderly, nocturia, Serial plasma samples were collected for 8 h variables. Generally, the number of nocturnal pharmacology

INTRODUCTION (V2-receptor agonist) of vasopressin. Contrary effect of antidiuresis on nocturnal polyuria to vasopressin, desmopressin has very poor [6–10] and the pharmacokinetics of

Vasopressin is produced in the anterior affinity for V1 receptors and therefore no desmopressin have been studied in healthy hypothalamus and is involved in regulating pressor effect [1]. This specific antidiuretic adult volunteers [7,7,11–16], in adult patients body water homeostasis (antidiuresis). effect makes desmopressin useful for with central diabetes insipidus [17] and in Various physiological stimuli of the osmotic managing several disorders involving the children with nocturnal enuresis [18]. All receptors in the lamina terminalis induce the regulation of the urine production, e.g. these studies were in subjects aged <60 years, release of vasopressin. The most important nocturia, nocturnal enuresis and diabetes so the information on the bioavailability and stimuli are increased plasma osmolality and insipidus. pharmacokinetics of desmopressin in the hypotension. Vasopressin receptors have been highly relevant group of elderly people is identified in, e.g. the kidney, liver, brain, Nocturia, defined as voiding that disturbs sparse. pituitary gland, aortic smooth muscle and on sleep, has many causes [2]; there is a gradual platelets. These receptors are divided into increase in the prevalence of nocturia with A few years ago a pharmacokinetic study

three subtypes, V1, V2 and V3. The V2 receptors age in both men and women [3–5]. Before was conducted using of 200 mg of oral in the basolateral membrane of the collecting starting treatment for nocturia with an desmopressin in a group of healthy duct cells are the basis for regulating urine antidiuretic drug it is important to distinguish volunteers aged 55–70 years (unpublished). output and hence body water balance. between nocturnal polyuria (>35% of daily Unfortunately the oral dose used resulted urine volume in people with no 24-h polyuria) in signiﬁcantly lower plasma levels than Desmopressin (1-desamino-8-D-argenine and nocturnal frequency of other causes. reported in other studies, albeit that the vasopressin) is a synthetic analogue There are several studies investigating the clinical effect was evident, and consequently

PHARMACOKINETICS OF ORAL DESMOPRESSIN IN ELDERLY PATIENTS WITH NOCTURIA

FIG. 1. The study design.

Screening Inclusion Randomization Evaluation- Termination Start PK Evaluation- Period2 Experimental Day Period 1

placebo placebo

dDAVP dDAVP

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

the pharmacokinetic results for oral informed consent approved by the local Ethics consecutive days, followed by a 7–14-day desmopressin were limited and inconclusive. Committee before entering the trial. wash-out period before entering the second The efficacy studies of desmopressin in period of 3 days; the daytime was spent as nocturia have shown that doses of 400 mg are After giving informed consent the patients’ outpatients. Desmopressin or placebo was sometimes needed to obtain the full effect health was confirmed by a complete physical given during 3 nights each in a randomized [10], although other studies claim that the examination, including dipstick testing a urine crossover design. On the test nights drug pharmacodynamic response does not increase sample, uroflowmetry and ultrasonography intake was at a standardized bedtime at when the dose is increased from 200 to after voiding to exclude residual urine. The 23.00 hours. Only one blood sample to 400 mg [19]. patients then entered a 1-week screening determine plasma desmopressin was taken at period, during which they were asked to 2 h after drug administration. The time and Thus the aim of the present study was to register the time and volume of each day- and volume of each nocturnal void, and the time investigate the pharmacokinetic profile of night-time void, and the time and volume of and volume of the morning void, was 400 mg of oral desmopressin in elderly men fluid intake for at least three 24-h cycles. For registered. The time of rising in the morning and women complaining of nocturia, and to the remaining nights of the week, the time was standardized to 07.00 hours. analyse any possible correlation between the and volume of each nocturnal void, including absorption of desmopressin and the the first morning void, were recorded. From Safety was assessed during the study, as pharmacodynamic effect. the registered data the number of nocturnal measurements of serum sodium, weight, voids and the nocturia index were calculated. blood pressure and pulse, taken before drug After the screening period, patients who administration and 8 h afterward. The patient fulfilled the inclusion criteria were included in was withdrawn from the trial if the serum PATIENTS AND METHODS the trial. sodium declined to <125 mmol/L or there was symptomatic hyponatraemia with water Thirty-two patients reporting a large The trial was in two parts, i.e. part A, a retention (e.g. weight increase, oedema), nocturnal diuresis were screened; of these, pharmacokinetic evaluation of one oral dose cerebral symptoms or convulsions. Other 24 (15 men and nine women) fulfilled the of desmopressin 400 mg, and part B, a intolerable adverse events, as judged by the inclusion criteria and were included in randomized, placebo-controlled, crossover- patient or by the doctor (e.g. persisting the study. The inclusion criteria were age effect evaluation period (Fig. 1). The patients nausea, headache or tiredness, feeling sick), or ≥65 years, nocturia more than twice per received information to drink no more than significant protocol violations (e.g. high night and a nocturia index of >1 (defined enough to satisfy their thirst from 1 h before diuresis >40 mL/kg) led to withdrawal. as the mean nocturnal urine volume during to 8 h after taking the drug. The intake of the screening period divided by the largest coffee, tea or caffeinated beverages and other All blood samples for desmopressin analysis voided volume). The exclusion criteria were diuretic liquids were standardized as much as were stored immediately on ice and then any clinical significant renal, hepatic, possible during the study days. centrifuged at 1550 g within 45 min of gastrointestinal, pulmonary, cardiovascular, collection. The plasma fraction was obtained endocrinological or neurological disorder, any On the day of the pharmacokinetic evaluation and stored in labelled tubes at -70∞C pending significant symptoms from the urinary tract the patients arrived at the laboratory in the desmopressin analysis at the Department of apart from nocturia, medical treatment with morning. The first blood sample (0 h) was Bioanalytical Chemistry, Ferring AB, Denmark, drugs known or suspected to interact with taken just before drug administration and using a validated radioimmunoassay method. desmopressin, and diuresis during the then at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 h The lower limit of quantification for human screening period of >40 mL/kg body weight. afterward. A standardized lunch was served at plasma was 2.50 pg desmopressin/mL plasma. The study was conducted according to the 3 h and an afternoon snack at 7 h. To evaluate The mean intra- and interassay coefficients of Declaration of Helsinki and ICH Good Clinical the effects the patients arrived at 18.00 hours variation of spiked human EDTA-plasma at 5, Practice. Each patient signed a statement of and were hospitalized for 14 h on 3 10 and 100 pg/mL was 10.1%, 7.0% and

HVISTENDAHL ET AL.

5.33%, and 18.1%, 10.6% and 8.65%, TABLE 1 Serum sodium values for the nine women during placebo/desmopressin treatment. The values in respectively. italics represent those women with no clinically relevant changes in serum sodium below normal range (136–146 mmol/L). Serum sodium was measured before the first dose and 8 h afterward. If the patient The common pharmacokinetic characteristics had a weight gain of >2% from baseline the serum sodium was checked before giving the next dose of desmopressin were calculated using noncompartmental analysis. The area under Placebo Desmopressin the plasma desmopressin concentration vs Patient Dose I Dose II Dose III Dose I Dose II Dose III time curve (AUC ) was calculated using t no a/b a/b a/b a/b a/b a/b the linear trapezoidal method and AUCt 1 137/140 –/138 –/137 138/136 –/131 127/ex extrapolated to infinity (AUCinf) according to the following equation: 2 143/142 –/142 –/141 146/142 –/141 –/142 3 142/142 –/142 –/142 142/140 –/135 –/132 4 139/141 –/141 –/141 140/140 –/140 –/140 AUCinf = AUCt + Clast/lz 5141/141 –/142 –/141 140/138 –/140 –/139 6 139/139 –/141 –/139 138/138 –/132 131/ex where Clast denotes the last measurement for 7 137/139 –/140 –/139 138/137 –/132 129/ex the patient in question and lz the estimated slope from a log-linear regression on the last 8 138/141 –/141 –/140 140/138 –/135 –/132 measurements from the patient in question. 9 ex/ex ex/ex ex/ex 141/139 134/130 127/ex The terminal half-life was calculated as ex, excluded; a, 18.00 hours; b, 07.00 hours. t1/2 = ln(2)/lz. The concentrations used for estimating lz, and consequently t1/2, were chosen after inspecting the ln-transformed plasma drug concentration plotted against time; the values in the tail of the curve where 45 FIG. 2. The desmopressin plasma the transformed concentrations seem to 40 follow a linear elimination rate were used. A concentrations with time for all 35 descriptive statistical analysis, e.g. geometric 24 patients, with the mean (SD) mean and corresponding percentage 30 superimposed. coefficient of variation, median and range, 25 and harmonic mean with corresponding interquartile range, was generated for the 20 pharmacokinetic variables. 15 Desmopressin, pg/mL 10 The correlation between one plasma desmopressin value 2–3 h after intake and 5 AUCinf was assessed graphically and using 0 Pearson’s correlation coefficients with 012345678 corresponding 95% CI. A logistic regression Time after study drug, h analysis was used to describe correlations between the response (reduction in number of nocturnal voids) and absorption (2–3 h after excluded because of protocol violations; in whereas none of the men had similar dosing), baseline mean voided nocturnal the pharmacodynamic part (A), 24 were reductions during active treatment (Table 1). volume or baseline nocturnal diuresis. A included and analysed. The mean (SD) age of response was defined as a ≥45% reduction in the included patients was 71.7 (6.5) years and Figure 2 shows the plasma desmopressin the number of nocturnal voids from placebo the body weight 75.1 (11.3) kg. Eleven drug- concentration vs time curve for all patients treatment. Pearson’s and Spearman’s related adverse events were reported during (with the mean values) and Fig. 3 the data for correlation coefficients were calculated to desmopressin treatment and one with women and men, respectively. There was a detect any pairwise correlation between placebo. Four patients, all women, were mean peak concentration within 1–2 h after absorption and the desmopressin-placebo withdrawn from part B because of adverse administration; the plasma concentration difference in time to first void and the events related to low serum sodium values. then gradually decreased during the following desmopressin-placebo reduction in nocturnal There were no serious adverse events during 6–7 h. The plasma concentrations were then diuresis. Descriptive statistics, e.g. median and the study. The most common adverse events still above the lower level of the assay for range, were calculated for the effect variables, reported were hyponatraemia (below normal 16 of the 24 patients. The women had with the level of significance set at P < 0.05. range), headache and weight increase (>2% significantly higher AUCinf values than the of the initial body weight). All but one adverse men. The results of the descriptive statistical RESULTS event after desmopressin treatment were in analysis of the pharmacokinetic variables are

the women. Six of the nine women had a listed in Table 2 for all patients and for AUCinf Finally 23 patients were included in the gradual decrease in serum sodium after the for men and women in Table 3. Pearson’s analysis of pharmacokinetics, as one was second and third dose of desmopressin, correlation coefﬁcient (95% CI) between

PHARMACOKINETICS OF ORAL DESMOPRESSIN IN ELDERLY PATIENTS WITH NOCTURIA

FIG. 3. A DISCUSSION Individual desmopressin proﬁles 45 in women (A) and men (B). One of the aims of the present study was to 40 investigate the pharmacokinetic proﬁle of one 35 dose of oral desmopressin in elderly men and 30 women. The relatively high dose was chosen based on a previous pharmacokinetic study in 25 elderly men (unpublished data), where low 20 plasma levels of desmopressin only gave 15 limited information on the pharmacokinetics

Desmopressin, pg/mL in this age group. The elderly were chosen as 10 they represent a large group with a medical 5 problem that may be resolved by treatment 0 with desmopressin. Studies on LUTS show that 72% of elderly people have nocturia and B find it very bothersome [5,20]. Furthermore, 45 the elderly may have different patterns of 40 absorption and elimination of drugs. Based on 35 the data from this study, the AUCinf strongly depends on the plasma desmopressin 30 concentration at 2 h after dosing. 25 Theoretically it is possible that the 20 pharmacokinetic characteristics may differ with different doses, which makes it difficult 15 to apply this model to other age groups or Desmopressin, pg/mL 10 other doses of desmopressin. Surprisingly, the 5 desmopressin plasma levels in the women 0 were higher than in the men; when adjusting 02468the AUCinf for body weight the difference Time after drug intake, h persisted. This is clinically important and illustrates that extra care is required when elderly women are treated with desmopressin. The plasma level of desmopressin was still TABLE 2 Mean plasma desmopressin pharmacokinetic variables after one oral dose of 400 mg for all patients and for men and women over the lower limit of quantification 8 h after drug intake in 16 of the 23 patients, indicating Geometric mean % Coefficient Harmonic mean Median that in these elderly patients desmopressin Variable (95% CI) of variation (95% Hodges-Lehman CI) (interquartile range) may have had a long duration of action at this specific dosage. For treating nocturia, a AUC 63.1 (49.6–80.2) 60.2 – 55.4 (47.7–84.8) t duration of 6–8 h is sufficient. A longer AUC 79.1 (61.9–101.2) 61.9 – 70.7 (62.3–106.5) inf duration is unwarranted because of the risk of C 16.0 (12.7–20.2) 58.2 – 14.2 (11.6–22.6) max water retention and related adverse events. t1 ––3.1 (2.9–3.6) 3.3 (2.7–3.8) /2 Even though the mean serum sodium level for t ––– 1.5 (1.0–2.0) max the whole group was rather stable during the 3 days of desmopressin treatment, most of the women had a decrease in sodium level plasma desmopressin at 2 h after dosing and desmopressin - placebo difference in below the normal range. This may have been AUCinf was 0.923 (0.824–0.967) (P < 0.001). nocturnal diuresis and absorption, with incidental, but it suggests that these women The relationship between AUCinf and rSpearman of -0.01 (P = 0.531) and 0.06 were dosed above the therapeutic range and desmopressin concentration at 2 h is shown (P = 0.612), respectively. supports the suspicion of an overly long in Fig. 4 (AUCinf 6.36 ¥ desmopressin + 1.73). duration of action. In a recent desmopressin The mean number of nocturnal voids was less dose-titration study in men, serum sodium Of all 23 patients, 13 (57%) were responders on desmopressin than placebo, the mean time levels below the normal range were reported (nine men and three women). The response from drug intake to first micturition in 22% of the patients and 4% had serum could not be significantly predicted by the significantly higher (P = 0.0261), and the sodium levels of <130 mmol/L [10]. plasma desmopressin level 2–3 h after dosing mean nocturnal diuresis significantly lower Furthermore, patients at the highest risk of or baseline mean voided nocturnal volume. (P < 0.001; Table 4). The baseline median developing hyponatraemia were those aged There was no correlation between the nocturnal voided volume decreased during ≥65 years. Similar adverse events were desmopressin - placebo difference in desmopressin treatment by 60 (-213 to reported in other studies of desmopressin time to first void and absorption, or as 55) mL. treatment in elderly patients [6].

HVISTENDAHL ET AL.

FIG. 4. The relationship between desmopressin TABLE 3 Mean plasma desmopressin pharmacokinetic variables after one oral dose of 400 mg for men plasma concentrations at +2 h and AUCinf, with 95% and women CI for the 24 individual predicted values.

Geometric mean (95% CI) Female/male ratio 325 Variable Women Men (90% CI) P 300 275 AUCinf, pg/mL*h 120.7 (84.5–172.4) 63.2 (48.7–82.0) 1.91 (1.32–2.75) 0.0219 250 225 AUCinf/body weight 1.8 (1.2–2.5) 0.8 (0.6–1.0) 2.20 (1.53–3.15) 0.0012 200 175

, pg/mL*h 150 inf 125 100 AUC 75 50 TABLE 4 The median (range) of the effect variables for all patients and by gender 25 0 051015 20 25 30 35 40 45 Difference Desmopressin, pg/mL (desmopressin – placebo) All Women Men Mean number of nocturnal voids -1 (-3 to 0) -1 (-3 to 0) -1 (-2 to 0) REFERENCES time to first micturition, h 1.9 (-0.6 to 6.4) 1.2 (-0.6 to 6.4) 2.1 (-0.2 to 5.5) nocturnal diuresis, mL/min -0.8 (-2.4 to -0.1) -0.9 (-2.4 to -0.3) -0.7 (-1.0 to -0.1) 1 Vilhardt H. Basic pharmacology of nocturia index -1.0 (-2.3 to -0.1) -1.3 (-2.3 to -0.3) -0.9 (-1.7 to -0.1) Desmopressin: a review. Drug Invest 1990; 2 (Suppl. 5): 2–8 2 Weiss JP, Blaivas JG. Nocturia. J Urol 2000; 163: 5–12 The pharmacodynamic study was intended to primarily increase the duration of action and 3 Britton JP, Dowell AC, Whelan P. determine whether the response (as the not the response. Prevalence of urinary symptoms in men difference in the number of nocturnal voids) aged over 60. Br J Urol 1990; 66: 175–6 was predicted by absorption 2 h after drug In conclusion, the present results indicate 4 Malmsten UG, Milsom I, Molander U, intake. There was a clear reduction in the clearly that the AUCinf strongly depends on Norlen LJ. Urinary incontinence and number of nocturnal voids, significantly the plasma level at 2 h after dosing with lower urinary tract symptoms: an reduced nocturnal diuresis and significantly 400 mg of oral desmopressin, suggesting that epidemiological study of men aged 45–99 increased time to first void during in future studies it might be possible to years. J Urol 1997; 158: 1733–7 desmopressin treatment, matching results characterize the absorption/elimination of the 5 Barker JC, Mitteness LS. Nocturia in from other studies [7], but there was no clear drug using only a few blood samples. There the elderly. Gerontologist 1988; 28: association between absorption and response seems to be a relationship between gender, 99–104 in any of the variables analysed. Interestingly, plasma desmopressin and the incidence of 6 Cannon A, Carter PG, McConnell AA, the men had a longer median time to first adverse events. Therefore, care should be Abrams P. Desmopressin in the treatment void than women after desmopressin taken when treating elderly women with of nocturnal polyuria in the male. BJU Int (Table 4). However, the groups were small desmopressin. Desmopressin about halved the 1999; 84: 20–4 and the range in each group very large, number of nocturnal voids and nocturnal 7 Asplund R, Sundberg B, Bengtsson P. which may explain the difference. Differences diuresis. The time to first void was higher on Oral desmopressin for nocturnal polyuria in nocturnal bladder capacity and sleep desmopressin and the nocturia index was in elderly subjects: a double-blind, quality may also influence the results. halved on desmopressin. There was no placebo-controlled randomized correlation between response and plasma exploratory study. BJU Int 1999; 83: The lack of association between response and concentrations during oral treatment with 591–5 absorption might be explained by the high 400 mg desmopressin. Further studies are 8 Carter PG, McConnell AA, Abrams P. dose the patients were given. The plasma needed to determine if this will occur with The safety and efficacy of dDAVP in the levels of desmopressin achieved in this study lower doses of desmopressin. elderly. Neurourol Urodynam 1992; 11: group were probably much higher than the 421–2 threshold for antidiuretic action, which 9 Asplund R, Aberg H. Desmopressin ACKNOWLEDGEMENTS contradicts the previously cited study [10]. in elderly subjects with increased However, they conducted a dose-titration nocturnal diuresis. A two-month The authors thank Ferring Pharmaceuticals based on the dynamic response, whereas the treatment study. Scand J Urol Nephrol for financial support. present patients all received the same dose of 1993; 27: 77–82 desmopressin. Apart from a large inter- 10 Mattiasson A, Abrams P, van individual variation in the plasma CONFLICT OF INTEREST Kerrebroeck P, Walter S, Weiss J. desmopressin at 2 h the patients had a large Efficacy of desmopressin in the treatment intra-individual variation apparently with no A. Riis is a statistician at Ferring of nocturia: a double-blind placebo- effect on the response variables. This study Pharmaceuticals. J.P. Nørgaard is a medical controlled study in men. BJU Int 2002; 89: shows that high doses of desmopressin director and scientific officer. 855–62

11 Eller N, Kollenz CJ, Hitzenberger G. A 15 Callreus T, Hoglund P. Pharmacokinetics desmopressin pharmacokinetics in comparative study of pharmacodynamics and antidiuretic effect of intravenous enuretic children. Pediatrics 1999; 103: and bioavailability of 2 different administration of desmopressin in orally 65–70 desmopressin nasal sprays. Int J Clin overhydrated male volunteers. Pharmacol 19 Asplund R, Sundberg B, Bengtsson P. Pharmacol Ther 1998; 36: 139–45 Toxicol 1998; 83: 259–62 Desmopressin for the treatment of 12 Kohler M, Harris A. Pharmacokinetics 16 Fjellestad-Paulsen A, Hoglund P, nocturnal polyuria in the elderly: a dose and haematological effects of Lundin S, Paulsen O. Pharmacokinetics titration study. Br J Urol 1998; 82: 642–6 desmopressin. Eur J Clin Pharmacol 1988; of 1-deamino-8-D-arginine vasopressin 20 Peters TJ, Donovan JL, Kay HE et al. 35: 281–5 after various routes of administration in The International Continence Society 13 Rittig S, Jensen AR, Jensen KT, Pedersen healthy volunteers. Clin Endocrinol (Oxf) ‘Benign Prostatic Hyperplasia’ Study. the EB. Effect of food intake on the 1993; 38: 177–82 botherosomeness of urinary symptoms. pharmacokinetics and antidiuretic activity 17 Lam KS, Wat MS, Choi KL, Ip TP, Pang J Urol 1997; 157: 885–9 of oral desmopressin (DDAVP) in hydrated RW, Kumana CR. Pharmacokinetics, normal subjects. Clin Endocrinol (Oxf) pharmacodynamics, long-term efﬁcacy Corrrespondence: Gitte M. Hvistendahl, 1998; 48: 235–41 and safety of oral 1-deamino-8-D- Institute of Experimental Clinical Research, 14 Vilhardt H, Lundin S. Biological effect arginine vasopressin in adult patients Aarhus University Hospital-Skejby, Dk-8200 and plasma concentrations of DDAVP with central diabetes insipidus. Br J Clin Aarhus N, Denmark. after intranasal and per oral Pharmacol 1996; 42: 379–85 e-mail: [email protected] administration to humans. General 18 Neveus T, Lackgren G, Tuvemo T, Pharmacol 1986; 17: 481–3 Stenberg A. Osmoregulation and Abbreviations: AUC, area under the curve.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article HEALTH, SADNESS and HAPPINESS IN RELATION TO LUTS ENGSTRÖM et al.

Self-assessed health, sadness and happiness in relation to the total burden of symptoms from the lower urinary tract

GABRIELLA ENGSTRÖM*†‡, LARS HENNINGSOHN§¶, GUNNAR STEINECK¶ and JERZY LEPPERT† *Uppsala University, Department of Public Health and Caring Sciences, Uppsala Science Park, Uppsala, Sweden, †Centre for Clinical Research, Uppsala University, Central Hospital, Västerås, Sweden, ‡Department of Caring Sciences and Pubic Health, Mälardalen University, Västerås, Sweden, §Clinical Cancer Epidemiology, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, ¶Division of Urology, Centre for Surgical Sciences, Karolinska Institutet, Stockholm, Sweden Accepted for publication 15 November 2004

OBJECTIVES by three questions from the Medical men with no ‘other incontinence’, the relative Outcomes Study Short-Form 36 health survey risk (95% confidence interval) of impaired To evaluate the effect of lower urinary tract questionnaire. health was 2.2 (1.8–2.8), while that of a high symptoms (LUTS) on self-assessed health, score for happiness was 0.5 (0.3–0.7) and that sadness and happiness of men. RESULTS of greater sadness was 2.3 (1.7–3.3). Social status, marital status, education, smoking, SUBJECTS AND METHODS Completed questionnaires were returned by physical activity and urinary tract infection all 74.2% of men (748/1008). A low score for affected the impact of LUTS. The study included 504 men (aged health was reported by 34% of men with one 40–80 years) in the rural community of to four LUTS, by 67% with five to eight, and by CONCLUSIONS Surahammar, Sweden, who a year earlier had 75% with nine or more LUTS. The total LUTS reported stress incontinence, urgency or burden correlated with lower scores for The total burden of LUTS is related to self- postvoid dribbling in answer to a postal happiness and with higher scores for sadness. assessed health, sadness and happiness. questionnaire, and 504 age-matched control For each of the 12 specific LUTS, men with the men from the same community. The symptom had lower scores for health and KEYWORDS occurrence of 12 specific LUTS was rated happiness, and higher scores for sadness, than using the Danish Prostatic Symptom Score. men without the symptom. Comparing men health, sadness, happiness, DAN-PSS, lower Health, sadness and happiness were measured with the symptom of ‘other incontinence’ to urinary tract symptoms, SF-36

INTRODUCTION SUBJECTS AND METHODS The respondents completed a self- administered questionnaire, the Danish LUTS affect self-assessed quality of life The study was conducted in the rural Prostatic Symptom Score (DAN-PSS [8], (QoL); in the last decade, the traditional community of Surahammar, Sweden, comprising 12 questions relating to LUTS), way of measuring urinary symptoms where, in 1997, the 11 200 inhabitants and three general questions about health, (frequency, severity) has been supplemented included 2571 men aged 40–80 years. sadness and happiness, from the Swedish by questions relating to the symptom of All of the men invited to take part had version of the Medical Outcomes Study individual distress [1], as well as a sense of participated a year earlier in a self- Short-Form 36 health survey (SF-36) [9]. well-being and self-assessed QoL [2–6]. A administered questionnaire study (‘yes’ or Information was also collected about quick evaluation of the discomfort ‘no’) investigating the prevalence of three potential confounding and effect-modifying caused by LUTS and improvements in common LUTS, i.e. stress incontinence, factors, e.g. social status, education, marital QoL is an important goal [7], as different urgency and post micturition dribbling [1]. All status, smoking, physical activity and UTI treatment strategies depend on symptom 504 men who had reported one or more LUTS during the preceding year. quality and distress, and one major were invited to take part in the present study. therapeutic goal is to improve the QoL As a control group, 504 randomly selected In the DAN-PSS, the severity or frequency of of affected men. To our knowledge, no men from the same community who had speciﬁc symptoms of LUTS were assessed on a published study has reported the effect on reported no LUTS in the previous study four-category scale (no, mild, moderate, QoL in relation to the number of LUTS in men. were matched by age to the group that had much). ‘Urge incontinence’, ‘stress In the present study, we evaluated factors reported LUTS, and they were also invited to incontinence’, ‘other’ incontinence, hesitancy, related to QoL, and the LUTS burden in participate (Fig. 1). These 1008 men were incomplete emptying, straining, dysuria and correlation with self-assessed health, sadness all sent a letter of invitation explaining the urgency were classed as ‘mild’ when the and happiness. This information could be objectives of the study, and a postal reminder symptom was reported to occur rarely, useful for more effective therapeutic was sent twice to those who did not reply ‘moderate’ when the symptom occurred often decisions. within 4 and 6 weeks. and ‘much’ when the symptom occurred

HEALTH, SADNESS AND HAPPINESS IN RELATION TO LUTS

FIG. 1. Flow chart. Men with LUTS (post micturition dribbling, stress incontinence or urgency) who and proportions used to describe the number participated in a previous study [1] (indicated with 1) were investigated in the present study with the DAN- and percentage of men with speciﬁc LUTS. The PSS questionnaire and three questions from the SF-36 (indicated with 2). ethics committee at Uppsala University approved the study. Questionnaire sent to all men aged 40–80 years in the community of Surahammar n = 2571 RESULTS

Not responding In all, 748 (74.2%) men returned the n = 354 questionnaire; a year earlier 411 of these men (55%) had reported stress incontinence, 1 urgency or post micturition dribbling, and 337 Responding (45%) had none of these symptoms. The mean n = 2217 (SD, range) age of the participants at the time of answering the questionnaire was 60 (10.7, 40–80) years. The characteristics of the cohort Post micturition dribbling, No symptoms are shown in Table 1. Stress incontinence or Urgency n = 1681 n = 536 SELF-ASSESSED HEALTH

The risk of obtaining a low score for health Moved/died Reported problems Age-matched was significantly higher in men with LUTS n = 32 504 randomly selected than in men with no LUTS for all the evaluated 504 characteristics, except for unemployed men, men on sick leave and men with self-reported DAN-PSS UTI. Employed men with LUTS had lower n = 1008 scores for health than employed men with no 2 LUTS. For men who went to secondary school, the risk of a low health score was 10 times Not responding n = 260 higher for those with LUTS than for men with no LUTS. Single or widowed men with LUTS reported the same effect on health as those Responding with no LUTS (Table 2). n = 748 When each of the 12 specific LUTS were considered, the risk of a low score for health was higher for men with the symptom than for men without the symptom (Table 3). In always. ‘Weak stream’ was classed as ‘mild’ assessed health, sadness and happiness particular, of men who experienced leakage of when the urinary stream was weak, questions were dichotomised. The response urine with no urge or physical activity (‘other ‘moderate’ when very weak, and ‘much’ when relating to the health question was classed as incontinence’), 59% reported a low score classified as dribbling. ‘Daytime frequency’ ‘low’ if the answer was ‘moderate’ or ‘bad’. for health, compared with 26% of men who was classed as ‘mild’ when the interval Sadness was classed as ‘high’ if the answer experienced no ‘other incontinence’. The RR of between voids was 2–3 h, ‘moderate’ when was ‘all of the time’, ‘most of the time’ ‘some a low score for health was 2.1 (1.7–2.6) for 1–2 h, and ‘much’ when <1 h. ‘Nocturia’ was of the time’ or ‘part of the time’. Happiness men with urge incontinence compared to classed as ‘mild’ when it occurred once or was classed as ‘high’, if the answer was ‘all of men with no urge incontinence. twice at night, ‘moderate’ when three to four the time’ or ‘most of the time’ (Appendix 1). times, and ‘much’ when five or more times. For dichotomised symptom characteristics, SELF-ASSESSED SADNESS ‘Post micturition dribbling was classed as the variables were classified as ‘no symptom’ ‘mild’ when dribbling was reported only to or ‘symptom’. To calculate relative risks (RRs), Of men who had studied at university, a high take place in the lavatory, ‘moderate’ when a the percentage of men reporting a specific score for sadness was reported by 29% of small amount of dribbling occurred in the symptom was divided by the percentage of men with LUTS, compared with 10% of men trousers, and ‘much’ when a large amount of men reporting no levels of the same with no LUTS. Smokers with LUTS had a dribbling occurred in the trousers. symptom. The RRs for background greater risk of obtaining a high score for characteristics were calculated as the sadness than smokers with no LUTS. Of men The questions that were used from the percentage of men with LUTS reporting the living as single/widowers, or married/living general SF-36 questionnaire [9] related to outcome divided by the percentage of men together, the RR of a high score for sadness in self-assessed health, sadness and happiness with no LUTS who reported the same men with LUTS was higher than in men with (Appendix 1). Outcome variables for the self- outcome. The RR and 95% CI were calculated no LUTS (Table 4).

ENGSTRÖM ET AL.

TABLE 1 Characteristics of the studied men TABLE 2 The relative risk of moderate or bad health, with 95% conﬁdence intervals for social status, (n = 748) in the rural community of education, marital status, smoking, physical activity and urinary tract infection (UTI) in men with lower Surahammar urinary tract symptoms vs. no lower urinary tract symptoms

Descriptive statistics N (%) N/total (%) Age in years Characteristic LUTS No LUTS RR (95% CI) mean 60 Social status range 40–80 Employed 45/198 (23) 14/172 (8) 2.8 (1.6–4.9) Social status Retired 64/135 (47) 21/81 (26) 1.8 (1.2–2.7) Employed 393 (53) Unemployed 8/17 (47) 0/6 (0) Unemployed 25 (3) On sick leave 35/45 (78) 16/27 (59) 1.3 (0.9–1.9) Retired 229 (31) Education On sick leave 76 (10) Primary school 110/256 (43) 45/131 (26) 1.6 (1.3–2.2) Missing 25 (3) Secondary school 24/79 (30) 2/65 (3) 9.9 (2.4–40.2) Education University studies 16/58 (28) 4/42 (10) 2.9 (1.0–8.0) Primary school 456 (61) Marital status Secondary school 155 (21) Single/widower 31/64 (48) 8/40 (20) 2.4 (1.2–4.7) University studies 107 (14) Married/living together 125/336 (37) 44/249 (17) 2.1 (1.5–2.8) Missing 30 (4) Other Marital status Smoker 38/81 (47) 12/58 (21) 2.2 (1.3–3.9) Married/living together 618 (83) Non-smoker 17/319 (37) 40/231 (17) 2.1 (1.5–2.9) Single/widower 113 (15) No physical activity 93/218 (43) 31/142 (22) 1.9 (1.4–2.8) Missing 17 (2) Physical activity 62/181 (34) 21/147 (14) 2.4 (1.5–3.7) Other UTI 27/41 (66) 2/7 (29) 2.3 (0.7–7.5) Smoker 146 (20) No UTI 128/358 (36) 49/281 (17) 2.1 (1.5–2.7) Non-smoker 585 (78) Missing 17 (2) Physical activity, > twice/week 354 (47) Physical activity, £ twice/week 376 (51) N/total (%) TABLE 3 Missing 18 (2) DAN-PSS item Symptom No symptom RR (95% CI) The RR of moderate/bad UTI ≥ 1 during the last year 48 (6) Other incontinence* 48/82 (59) 159/606 (26) 2.2 (1.8–2.8) health for men with a No urinary tract infection 680 (91) Stress incontinence 38/77 (49) 169/610 (27) 1.8 (1.4–2.4) specific LUTS vs men Missing 20 (3) Urge incontinence 85/170 (50) 123/519 (24) 2.1 (1.7–2.6) without that specific Urgency 148/380 (39) 59/309 (19) 2.0 (1.6–2.7) symptom. Nocturia 149/385 (39) 60/305 (20) 2.0 (1.5–2.6) Weak stream 122/203 (40) 85/386 (22) 1.8 (1.4–2.3) Daytime frequency 112/337 (36) 68/327 (21) 1.7 (1.4–2.3) The risk of a high score for sadness was Hesitancy 137/363 (38) 72/328 (22) 1.7 (1.3–2.2) significantly higher in men with each of Incomplete emptying 131/348 (38) 75/336 (22) 1.7 (1.3–2.1) 12 specific LUTS. ‘Other incontinence’ Dysuria 51/117 (44) 156/571 (27) 1.6 (1.3–2.0) significantly increased the risk of feeling Postvoid dribbling 166/491 (34) 42/199 (21) 1.6 (1.2–2.2) *Urinary leakage without sad ‘part of the time’ or ‘all the time’ in Straining 119/324 (37) 89/367 (24) 1.5 (1.2–1.9) urge or physical activity. men with ‘mild’, ‘moderate’ or ‘much’ effect from this symptom, compared with men unaffected by ‘other incontinence’. The RR of a high score for sadness in men with happiness score if they had LUTS, compared symptom compared with men unaffected by stress or urge incontinence was 2.1 and with men with no LUTS (Table 4). All 12 LUTS stress incontinence. The relative prevalence of 1.9, respectively. The risk of a high score significantly reduced the happiness score high scores for happiness was 0.6 for men for sadness was higher in men with among men affected mildly, moderately or with ‘mild’, ‘moderate’ or ‘much’ urge ‘mild’, ‘moderate’ or ‘much’ effect from much compared with men with no LUTS. The incontinence compared with men without the symptom of post-micturition dribbling proportion of men with a high score for urge incontinence (Table 5). than in men unaffected by this symptom happiness was lower among those who rarely, (Table 5). often, or always had leakage of urine without SELF-ASSESSED HEALTH AND urge or physical activity than among those SYMPTOM BURDEN SELF-ASSESSED HAPPINESS men who never had ‘other’ incontinence (Table 5). Stress incontinence significantly A low score for health was reported by 30% All men apart from those on sick leave reduced the score for happiness in men with (209 of 692) of the men (Table 6). The self- reported a significant effect on their ‘mild’, ‘moderate’ or ‘much’ effect from this assessed health correlated with the total LUTS

HEALTH, SADNESS AND HAPPINESS IN RELATION TO LUTS

TABLE 4 The RR of sadness (‘all the time’ or ‘part of the time’) and happiness (‘all the time’ or ‘most of the time’) for men with LUTS vs men with no LUTS

Sadness, N/total (%) Happiness, N/total (%) Characteristic LUTS No LUTSRR (95% CI) LUTS No LUTS RR (95% CI) Social status: Employed 35/196 (18) 19/170 (11) 1.6 (0.9–2.7) 93/196 (47) 113/170 (66) 0.7 (0.6–0.8) Retired 28/122 (23) 9/71 (13) 1.8 (0.9–3.6) 48/123 (39) 50/74 (68) 0.6 (0.4–0.7) Unemployed 9/17 (53) 1/6 (17) 3.1 (0.5–20.1) 13/16 (19) 5/6 (83) 0.2 (0.1–0.6) On sick leave 20/46 (43) 5/25 (20) 2.2 (0.9–5.1) 9/45 (20) 8/25 (32) 0.6 (0.3–1.4) Education: Primary school 63/246 (26) 24/164 (15) 1.7 (1.1–2.7) 105/245 (43) 109/166 (66) 0.6 (0.5–0.8) Secondary school 11/76 (14) 5/65 (8) 1.8 (0.7–5.1) 31/77 (40) 43/65 (66) 0.6 (0.4–0.8) University studies 16/56 (29) 4/41 (10) 2.9 (1.1–8.1) 18/56 (32) 23/41 (56) 0.6 (0.3–0.9) Marital status: Single/widower 26/62 (42) 6/38 (16) 2.6 (1.2-5-8) 16/63 (25) 24/39 (61) 0.4 (0.2–0.7) Married/living together 66/323 (20) 28/237 (12) 1.7 (1.1-2-6) 138/322 (43) 154/239 (64) 0.7 (0.6–0.8) Other: Smoker 27/77 (35) 6/58 (10) 3.5 (1.5–7.7) 32/76 (42) 13/20 (65) 0.6 (0.5–0.9) Non-smoker 66/308 (21) 28/217 (13) 1.6 (1.1–2.5) 122/309 (39) 140/220 (64) 0.6 (0.5–0.7) Physical activity, £ twice/week 50/209 (24) 20/137 (15) 1.6 (1.0–2.6) 75/208 (36) 82/138 (59) 0.6 (0.5–0.7) Physical activity, > twice/week 41/175 (23) 14/138 (10) 2.3 (1.3–4.0) 79/176 (45) 96/140 (69) 0.6 (0.5–0.8) UTI 13/38 (34) 0/6 – 7/38 (18) 4/7 (57) 0.3 (0.1–0.8) No UTI 80/346 (23) 34/269 (13) 1.8 (1.3–2.6) 147/346 (42) 174/271 (64) 0.7 (0.6–0.8)

TABLE 5 The RR of sadness and happiness for men for men with a speciﬁc LUTS vs men without that speciﬁc symptom

Sadness, N/total (%) Happiness, N/total (%) DAN-PSS item Symptom No symptomRR (95% CI) Symptom No symptom RR (95% CI) Other incontinence* 29/75 (39) 96/583 (17) 2.3 (1.7–3.3) 20/77 (26) 311/584 (53) 0.5 (0.3–0.7) Stress incontinence 26/71 (37) 101/587 (17) 2.1 (1.5–3.0) 18/72 (25) 314/589 (53) 0.5 (0.3–0.7) Urge incontinence 48/159 (30) 78/500 (16) 1.9 (1.4–2.7) 50/160 (31) 282/502 (56) 0.6 (0.4–0.7) Urgency 90/364 (25) 37/295 (13) 1.9 (1.4–2.8) 145/365 (40) 186/297 (63) 0.6 (0.5–0.7) Nocturia 82/365 (23) 46/295 (16) 1.4 (1.0–2.0) 153/366 (42) 178/297 (60) 0.7 (0.6–0.8) Weak stream 64/286 (22) 64/375 (17) 1.3 (1.0–1.8) 121/286 (42) 209/377 (55) 0.8 (0.7–0.9) Daytime frequency 68/320 (21) 51/316 (16) 1.3 (1.0–1.8) 139/321 (43) 187/318 (59) 0.7 (0.6–0.9) Hesitancy 86/343 (25) 42/318 (13) 1.9 (1.4–2.7) 135/345 (39) 197/319 (62) 0.6 (0.5–0.7) Incomplete emptying 77/330 (23) 46/325 (14) 1.7 (1.2–2.3) 132/330 (40) 196/328 (60) 0.7 (0.6–0.8) Dysuria 37/110 (34) 90/548 (16) 2.0 (1.5–2.8) 32/109 (29) 299/552 (54) 0.5 (0.4–0.7) Post micturition dribbling 107/471 (23) 21/189 (11) 2.0 (1.3–3.2) 199/472 (42) 132/192 (69) 0.6 (0.5–0.8) Straining 70/308 (23) 58/353 (16) 1.4 (1.0–1.9) 120/309 (39) 212/355 (60) 0.7 (0.6–0.8)

*Urinary leakage without urge or physical activity.

burden; 39% (157 of 402) of men with at least for sadness in men with one or more LUTS DISCUSSION one LUTS reported a low score for health, was 2.0 (1.4–2.8). compared with 18% (52 of 290) of men The symptom burden from LUTS determines unaffected by LUTS (RR 2.2, CI 1.7–2.9). A feeling of happiness ‘all of the time’ or ‘most self-assessed health, sadness and happiness. Overall, 19% (128 of 662) of the men felt of the time’ was reported by half (332 of 665) Most LUTS that were measured in the present sadness ‘all of the time’ or ‘part of the time’. of the men. The happiness score was study by the DAN-PSS (12 symptoms) had a Among men unaffected by LUTS, 12% correlated with the total LUTS burden. The negative effect on these factors, and there reported sadness, vs 43% of men with 5–8 prevalence of a high score for happiness was was a strong correlation between the number LUTS. There was no further signiﬁcant higher in men unaffected by LUTS than in of LUTS reported and self-assessed health and increase in reported sadness in men with men affected by LUTS (64% vs 40%; RR 1.6, happiness. A signiﬁcant difference was 9–12 LUTS (Table 6). The RR of a high score CI 1.4–1.9). already apparent in men affected by one LUTS

ENGSTRÖM ET AL.

(RR 1.5), and the prevalence of a low score for TABLE 6 The prevalence of tested scores, as n/N (%) and RR (95% CI) in men with different numbers of health continued to increase with up to eight reported LUTS LUTS. The prevalence of a high score for happiness decreased and that of a high score Number of symptoms for sadness increased in the same way, Group 0 1–4 5–8 9–12 associated with increased LUTS burden. These data are supported by studies of self-assessed Low score for health 52/290 (18) 117/343 (34) 34/51 (67) 6/8 (75) variables of well-being. Henningsohn et al. RR 1 1.9 (1.4–2.5) 3.7 (2.7–5.1) 4.2 (2.6–6.7) [10] reported that the number of chronic High score for sadness 34/275 (12) 73/335 (22) 20/47 (43) 1/5 symptoms after treatment for urinary RR 1 1.8 (1.2–2.6) 3.4 (2.2–5.4) 1.6 (0.3–9.6) bladder cancer determines the risk of a lower High score for happiness 178/278 (64) 144/335 (43) 9/46 (20) 1/6 self-assessed well-being, while Koskimaki RR 1 0.7 (0.6–0.8) 0.3 (0.2–0.6) 0.3 (0.0–1.6) et al. [5] reported that reduced health was associated with an increased LUTS impact, as measured using the DAN-PSS questionnaire. Correlations have also been found when the happiness. It is therefore important to assess population, and we see no indications that impact of LUTS was measured by other not only highly prevalent LUTS but also men in this community differed from men in methods, e.g. the IPSS [11,12]. symptoms with a low prevalence and which the rest of the country. It is always risky to affect QoL in the clinical situation. The generalize results from one study population In the present study, symptom severity was findings by Peters et al. [16], that nocturia to others, but the prevalence of LUTS is associated with negative effects on self- influences ‘everyday life’, supports the present commonly described as being about the same assessed health, sadness and happiness. Other finding that this symptom has negative in other countries of the world. studies have also shown negative effects of effects on perceived health, sadness and increasing symptom severity on different happiness. ‘Weak stream’ was also It is difficult to define when symptoms do not QoL domains (SF-36 and King’s Health significantly correlated with a lower level of merely constitute a normal physical condition Questionnaire) [4,6,13], thus it appears self-assessed health and happiness, and to a or behaviour; LUTS should be evaluated that the same effect can be measured by higher level of sadness. This has also been individually, together with the patient’s extracting key questions from the more discussed previously [17], and could reflect discomfort level from the same symptom. In extensive QoL questionnaires that are often fear of prostate cancer. the present study, we included all LUTS, used. irrespective of discomfort level, and included The differences between men with LUTS and the symptom if it was reported at any level in Different LUTS affect self-assessed health, men with no LUTS with respect to social the DAN-PSS. For some LUTS the reported sadness and happiness in different ways. status, education, marital status, smoking, symptom level might represent a ‘normal’ ‘Other’ incontinence and urge incontinence physical activity and UTI indicate that LUTS condition, rather than a pathological appear to have a greater impact on health have a particular impact on self-assessed condition for that individual. Counting these than stress incontinence. In another health and happiness. Koskimäki et al. [5] low-grade symptoms together with high- population-based Swedish study by Hägglund found that the RR of a reduction in QoL after grade symptoms might dilute the results et al. [14], urge incontinence had a greater adjusting for age and different diseases was obtained. Self-assessments of LUTS have effect on QoL than stress incontinence in higher in men with LUTS than in with men previously shown limitations; Malmsten et al. women. It is reasonable to assume that with no LUTS. Unfortunately, in the present [21] found that self-reported urinary unavoidable urge incontinence that appears study, no specific questions were asked about incontinence could not be verified objectively suddenly is more distressing than an other diseases. in 4.6% of the participants. In the present avoidable symptom such as stress study, self-assessed health, sadness and incontinence. The avoidability of this LUTS were self-reported and the classification happiness were evaluated by three questions symptom could be one explanation for the based on a questionnaire answered in the from a disease-independent questionnaire, results of another study by our group [15], home environment. No clinical investigations the SF-36; we consider that the most reliable which shows that ‘high-severity’ stress were undertaken to validate the reported evaluation of LUTS, as well as quality factors, incontinence causes moderate/much distress LUTS. The use of a questionnaire in the home is the self-assessment of specific questions among a much higher proportion of affected environment probably results in fewer and not a summarized score from many men (67%) than in men with a ‘low-severity’ investigator errors than, for example, a different questions. level of the symptom (21%). Thus, when it personal interview [18,19]. As a result, the occurs, it causes high levels of distress, but misclassifications that might have occurred Bias could have been introduced during the because it is avoidable, the affected person using this method are difficult to assess selection of the study base (Fig. 1). The cohort avoids risky situations and thereby prevents objectively, but the risk should be low, as the in the present study consisted of 1008 men, negative effects on QoL. DAN-PSS is a validated questionnaire i.e. 504 who 12 months earlier reported the designed for self-assessment [20]. The occurrence of one or more of three LUTS [1], Although ‘other’ incontinence was not the Swedish population register provides and 504 age-matched men from the same most prevalent LUTS, it had a considerable information on all residents in the country, community. To minimize misrepresentation, effect on self-assessed health, sadness and the present study is based on a large two postal reminders were sent to those not

HEALTH, SADNESS AND HAPPINESS IN RELATION TO LUTS

responding, but more men who had reported tract symptoms: results from the SF-36. bothersomeness of urinary symptoms. LUTS answered the questionnaire than men Urology 1995; 45: 962–71 J Urol 1997; 157: 885–9 with no earlier reported LUTS. Consequently, 7 Djavan B. Lower urinary tract symptoms/ 17 Brown CT, O’Flynn E, Van Der Meulen J, nothing indicates that the differences benign prostatic hyperplasia: fast control Newman S, Mundy AR, Emberton M. between men with LUTS and the controls are of the patient’s quality of life. Urology The fear of prostate cancer in men with large enough to jeopardise the study results, 2003; 62: 6–14 lower urinary tract symptoms: should but we cannot exclude the possibility that the 8 Hald T, Nordling J, Andersen JT, Blide T, symptomatic men be screened? BJU Int 26% who did not respond biased the results. Meyhoff HH, Walter S. A patient 2003; 91: 30–2 Even if the present results conﬁrmed the need weighted symptom score system in the 18 Steineck G, Ahlbom A. A deﬁnition of to assess QoL questions, most men with LUTS evaluation of uncomplicated benign bias founded on the concept of the study are still unknown to the healthcare system [1]. prostatic hyperplasia. Scand J Urol base. Epidemiology 1992; 3: 477–82 Therefore, the aim of a future study would be Nephrol Suppl 1991; 138: 59–62 19 Steineck G, Kass PH, Ahlbom A. A to focus on the reasons for health-care 9 Sullivan M, Karlsson J, Ware JE. comprehensive clinical epidemiology seeking, which have been poorly documented SF 36 Health survey. Swedish theory based on the concept of the and analysed. Manual and Interpretation Guide. source person-time and four distinct Gothenburg: Sahlgrenska University study stages. Acta Oncol 1998; 37: Hospital 1994 15–23 CONFLICT OF INTEREST 10 Henningsohn L, Wijkström H, Dickman 20 Hansen BJ, Flyger HL, Brasso K et al. PW, Bergman K, Steineck G. Distressful Validation of the patient-administered None declared. symptoms after radical cystectomy with Danish Prostate Symptom Score urinary diversion for urinary bladder Schedule. Ugeskr Laeger 1997; 159: 591– cancer: a Swedish population-based 7 REFERENCES study. Eur Urol 2001; 40: 151–62 21 Malmsten UG, Milsom I, Molander U, 11 Trueman P, Hood SC, Nayak US, Mrazek Norlén LJ. Urinary incontinence and 1 Engström G, Walker-Engström ML, MF. Prevalence of lower urinary tract lower urinary tract symptoms: an Lööf L, Leppert J. Prevalence of three symptoms and self-reported diagnosed epidemiological study of men aged 45 to lower urinary tract symptoms in men - a ‘benign prostatic hyperplasia’ and their 99 years. J Urol 1997; 158: 1733–7 population-based study. Fam Prac 2003; effect on quality of life in a community- 20: 7–10 based survey of men in the UK. BJU Int Correspondence: Gabriella Engström, 2 Bertaccini A, Vassallo F, Martino F et al. 1999; 83: 410–5 Department of Caring Sciences and Public Symptoms, bothersomeness and quality 12 Boyle P, Robertson C, Mazzetta C et al. Health, Mälardalen University, Box325, of life in patients with LUTS suggestive The relationship between lower urinary SE-63105 Eskilstuna, Sweden. of BPH. Eur Urol 2001; 40 (Suppl. 1): tract symptoms and health status: the e-mail: [email protected] 13–8 UREPIK study. BJU Int 2003; 92: 575–80 3 Temml C, Haidinger G, Schmidbauer J, 13 Welch G, Weinger K, Barry MJ. Quality- Abbreviations: DAN-PSS, Danish Prostatic Schatzl G, Madersbacher S. Urinary of-life impact of lower urinary tract Symptom Score; SF-36, Medical Outcomes incontinence in both sexes: prevalence symptoms: results from the Health Study Short-Form 36 health survey; RR, rates and impact on quality of life and Professionals Follow-up Study. Urology relative risk. sexual life. Neurourol Urodyn 2000; 19: 2002; 59: 245–50 259–71 14 Hägglund D, Walker-Engström M-L, 4 Okamura K, Usami T, Nagahama K, Larsson G, Leppert J. Quality of life and APPENDIX 1 Maruyama S, Mizuta E. ‘Quality of life’ seeking help in women with urinary Assessment of urination in elderly incontinence: a population-based study. In general, would you say your health is? Japanese men and women with some Acta Obstet Gynecol Scand 2001; 80: a) Excellent; b) Very good; c) Good; d) medical problems using International 1051–5 Moderate; e) Bad Prostate symptom score and King’s health 15 Engström G, Walker-Engström M-L, questionnaire. Eur Urol 2002; 41: 411–9 Henningsohn L, Lööf L, Leppert J. Have you felt sadness? 5 Koskimaki J, Hakama M, Huhtala H, Prevalence of distress and symptom a) All of the time; b) Most of the time; c) Some Temmela TL. Is reduced quality of life in severity from the lower urinary tract in of the time; d) Part of the time; e) A little of men with lower urinary tract symptoms men: a population-based study with the the time; f) None of the time due to concomitant diseases? Eur Urol DAN-PSS questionnaire. Fam Prac 2004; 2001; 40: 661–5 21: 1–6 Have you been happy? 6 Hunter DJ, McKee M, Black NA, 16 Peters TJ, Donovan JL, Kay HE et al. The a) All of the time; b) Most of the time; c) Some Sanderson CF. Health status and quality International Continence Society ‘Benign of the time; d) Part of the time; e) A little of of life of British men with lower urinary Prostatic Hyperplasia’ Study: the the time; f) None of the time

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 954

Original Article NOCTURIA, HEALTH and PAIN ASPLUND et al.

Nocturia in relation to somatic health, mental health and pain in adult men and women

RAGNAR ASPLUND, SVEN-UNO MARNETOFT*, JOHN SELANDER* and BENGT ÅKERSTRÖM† Family Medicine Stockholm, Karolinska Institute, Huddinge, * Department of Public Health, Division of Rehabilitation Medicine, Karolinska Institute, Stockholm, and Centre for Studies on National Social Insurance, †Department of Nursing and Health Sciences, Mid Sweden University, Östersund, Sweden Accepted for publication 12 November 2004

OBJECTIVE increased in parallel with increasing 10%, 12.4%, 23% and 46.7% (both P < 0.001) frequency of nocturnal voids. In a multiple of the corresponding women, respectively. To assess the relationship of nocturia to logistic regression analysis with sex, age, Life satisfaction decreased in parallel with somatic health, mental health and bodily pain. somatic health, mental health and bodily pain increased nocturia. as the independent variables, signiﬁcant SUBJECTS AND METHODS independent correlates (odds ratios, conﬁdence intervals) of nocturnal micturition CONCLUSION A randomly selected group of men and (two or more episodes vs none or one) were: women aged 20–64 years, living in three age 45–59 vs 20–44 years, 1.9 (1.3–2.7), ≥60 The impairment of both somatic and mental small municipalities in northern Sweden, or in vs 20–44 years, 3.8 (2.4–6.0); somatic health, health was associated with increased the city of Östersund or in Stockholm, were poor vs good, 2.3 (1.4–3.7); mental health, nocturnal voiding. Pain was associated with a sent a postal questionnaire containing poor vs good, 1.9 (1.2–3.0); pain, rather mild substantial increase in nocturia after questions on somatic and mental health, vs very mild or none, 1.5 (1.0–2.3); rather adjusting for age and somatic and mental satisfaction with life, pain, nocturnal voiding, severe vs very mild or none, 1.9 (1.1–3.2); health. Sick-leave was more common in work and sick-listing from work. and very severe vs very mild or none, 6.0 association with more nocturnal voids. (2.5–14.0). Gender was deleted by the logistic RESULTS model. Sick-listing for ≥60 days during the past year was reported by 4.9%, 10.6%, 5.6% KEYWORDS Reports (from 1948 respondents) on poor and 38.9% of the men with none, one, two or somatic and mental health and on pain all ≥ three nocturnal voids, respectively, and by mental health, nocturia, somatic health, pain

INTRODUCTION SUBJECTS AND METHODS 2 weeks after this reminder received a ﬁnal reminder after another 2 weeks. Nocturia is a common complaint in adults, A postal questionnaire with an explanatory especially in elderly people, and both health letter was sent to 3000 men and women aged The questionnaire contained questions on age and quality of life are often impaired in those 20–64 years living in different areas of and sex, somatic and mental health, sleep, with nocturia [1–3]. Somatic disorders such as Sweden and randomly selected from the bodily pain and the number of nocturnal voids cardiac diseases, poorly controlled diabetes, National Population Register on 1 November (Appendix); the question on nocturnal voids sleep apnoea syndrome and chronic pelvic 2003. The selected people were distributed analysed in this study referred to the last few pain are associated with nocturia [4–6]. by residence as follows: 500 from each of days. The question on nocturia has been used Sleep complaints and different nocturnal three small, sparsely populated municipalities extensively in our questionnaire surveys for symptoms, e.g. muscle cramp in the legs and in northern Sweden (Härjedalen, Strömsund exploring nocturia in relation to different leg tingling, are also reported to be increased and Åre) with populations of 11 059, 13 293 diseases and symptoms since the ﬁrst report in parallel with more nocturnal voids [1]. In and 9635, respectively; 500 from the city was published in 1992 [1]. The number of addition, nocturia is also associated with of Östersund (population 58 342); and voids recorded during three consecutive different kinds of medication, e.g. diuretics 1000 from Stockholm, the capital of nights by a large group of men and women and analgesics [4]. Sweden, with a population of 761 949 showed acceptable day-to-day variability (one of the 18 municipalities of the county [1,7]. The aim of the present study was to analyse of Stockholm). the relation between somatic and mental There were also questions about attitudes to health as one factor and nocturnal voids as Those who had not replied within 2 weeks health and disease, sick-listing from work, the other, and to investigate the possible were sent a reminder, those who had not relations with the family, relatives and friends, relationship between nocturnal voiding and replied after 2 further weeks received a and work and unemployment. The subject’s bodily pain in a group of adult men and second reminder with another copy of the somatic health was considered to be good if women. questionnaire, and those who had not replied the response in the questionnaire was ‘Very

NOCTURIA, HEALTH AND PAIN

20–64 years, more nocturnal voids were Age group, Nocturnal voids, % TABLE 1 associated with an impairment of both years N none one two three The number of nocturnal ≥ somatic and mental health, and these two voids in relation to age in Men aspects of health impairment were increased men and women (both 20–29 133 75.8 19.7 3.0 1.5 proportionally with nocturnal voiding P 0.001) 30–44 355 67.5 28.5 3.7 0.3 < frequency (Fig. 1a). In previous studies, elderly 45–59 332 49.5 37.4 10.0 3.1 people with nocturia have impaired general ≥60 102 20.4 58.2 15.3 6.1 health, as well as sleep deterioration, many Women sleep-disturbing somatic symptoms, daytime 20–29 165 60.6 30.0 6.9 2.5 sleepiness and a poor quality of life, and have 30–44 332 57.9 34.4 5.9 1.9 a lower life-expectancy [1,8]. 45–59 387 42.5 44.9 9.1 3.5 ≥60 99 20.8 47.9 18.8 12.5 The present multiple regression analysis showed that the interrelationships of somatic and mental health with nocturia were independent of each other and of age. good’ or ‘Rather good’, and to be poor if the bodily pain as the independent variables, Nocturnal urinary frequency is often response was ‘Rather poor’ or ‘Very poor’. The significant independent correlates, as odds associated with somatic diseases, or with an question on mental health was handled ratios (95% CI) of nocturnal voids (two or age-related increase in nocturnal urine accordingly (Appendix). The study was more vs none or one) were: age 45–59 vs output or a reduced bladder capacity, or a approved by the Ethics Committee of the 20–44 years, 1.9 (1.3–2.7); ≥60 vs 20–44 combination of these two conditions [9,10]. University of Umeå, Sweden. years, 3.8 (2.4–6.0); somatic health, poor vs good, 2.3 (1.4–3.7); mental health, poor vs The use of the term ‘nocturia’ in the present Categorical data among groups were good, 1.9 (1.2–3.0); pain, rather mild vs very study requires clarification; in the compared using the chi-square test, with mild or none, 1.5 (1.0–2.3); rather severe vs standardized urological terminology, nocturia multivariate analysis by logistic regression very mild or none, 1.9 (1.1–3.2); very severe vs is defined as ‘. . . the complaint that the analysis. The Hosmer-Lemeshow test was very mild or none, 6.0 (2.5–14.0). Sex was individual has to wake at night one or more applied for assessing the goodness-of-fit, and deleted by the logistic model. The Hosmer- times to void’ [11]. Among the present in all tests P £ 0.05 was considered to indicate Lemeshow goodness-of-fit test for the final subjects several were probably awake at night significance. model yielded a chi-square of 8.5 on eight as a consequence of different sleep- degrees of freedom (P = 0.553). disturbing symptoms, e.g. musculo-skeletal RESULTS pain, nightmares, sleep apnoea or The statement ‘I am on the whole satisfied menopausal sweating, and thus some Of the 3000 people who received the with my life’ was answered ‘I totally agree’ by nocturnal voids might not have met the questionnaire, in 49 the mailing address was 53.4% of the men with no nocturnal voids above-mentioned criterion. However, in a out of date, 21 were not in Sweden or were and by 46.8%, 32.2% and 11.1% of the men questionnaire survey among 1115 men and unable to respond for medical reasons, 18 with one, two, and three or more, respectively women (39.5% men), in those who reported declined to participate and 17 questionnaires (P < 0.001); among the women the three or more nocturnal voids, the reported were returned uncompleted by the corresponding frequencies were 57.9%, numbers of nocturnal awakenings were 3.4 respondent. The questionnaire was initially 50.9%, 39.5% and 18.2% (P < 0.001). and 3.5 in men and women, respectively, and completed by 1425 subjects; after reminders, there was also reasonably good conformity a further 523 answers were received. Thus Sick-listing for ≥7 days during the past year between few awakenings and fewer voids there were 1948 evaluable questionnaires was reported by 13.4% of the men with no than three per night [7]. Almost all nocturnal (47.7% from men). Among the recipients who nocturnal voids and by 19.9%, 20.4% and voids in the present age group can be could be expected to answer (2930), the 55.6% of the men with one, two, and three or presumed to be associated with waking and response rate was 65.5%. more, respectively (P < 0.001); among the getting out of bed. This supports the women the corresponding frequencies were conclusion that most awakenings at night Good somatic health was reported by 87.5% 24.7%, 25,4%, 44.6% and 50% (P < 0.001). occur in association with voiding, i.e. that the of the men and 84.7% of the women, and Correspondingly, sick-listing for ≥60 days standardized definition of nocturia was met good mental health by 91.3% and 89.4%, during the recent year was reported by 4.9%, for most nocturnal voids. respectively (neither significantly different). 10.6%, 5.6% and 38.9% of the men, and 10%, The number of nocturnal voids increased with 12.4%, 23.0% and 46.7% (both P < 0.001) of The possible cause-effect relationship increasing age in both sexes (Table 1). Reports the women, respectively. between poor mental health and nocturia on poor somatic and mental health and on should be considered. In a study among men pain all increased with increasing number of with LUTS from prostatic obstruction, these nocturnal voids (Fig. 1a,b). DISCUSSION symptoms occurred in association with emotional ill-health [12]. In a recent study, In a multiple logistic regression analysis with In the present study, which comprised major depression was associated with a six- sex, age, somatic health, mental health and randomly selected men and women aged fold increase in the occurrence of two or more

ASPLUND ET AL.

nocturnal voids in men, and a three-fold FIG. 1. A, The frequency (%) of poor somatic health in men and women, and of poor mental health in men and increase in such episodes in women, after women (all P < 0.001), in relation to the number of nocturnal voids. B, The distribution of different numbers age and health had been taken into of nocturnal voids (%) in men and women with no or very mild pain (1), rather mild pain (2), rather severe pain account [13]. This relationship might to (3) and very severe pain (4) (P < 0.001 both for men and women). In both plots the number of voids (none, one, some extent be explained in that there is two, three or more) are represented by the white, light red, green and red bars, respectively. a close relationship between nocturia and sleep impairment, and that sleep impairment A is always present in major depression, as it is 80 one of the diagnostic criteria of such depression [14].

Satisfaction with life on the whole was much 60 less frequent in those who were troubled by nocturnal voids. In a previous study in women aged 40–64 years, more nocturnal voids were associated with more unfavourable reports on

happiness, conﬁdence in the future and % 40 appetite [15].

One surprising finding in the present study was that pain in general was still associated with a substantial increase in nocturnal voids, 20 after adjusting for age and somatic and mental health (Fig. 1b). Other connections between nocturia and painful conditions have also been reported in elderly people, e.g. 0 nocturnal muscle cramps in the legs and spasmodic chest pain [1]. Nocturia is also increased in women with chronic pelvic pain Men Women Men Women [6]. Koskimäki et al. [16] reported a 70% increase in LUTS and a 30% increase in Poor somatic health Poor mental health nocturia among men aged 50–70 years with B arthritis. The authors concluded that arthritis affects both the storage and emptying of the bladder. 60 The relationship between bodily pain and nocturia might be explained in that some analgesics influence renal function. Prostaglandin-inhibiting analgesics reduce 40 urine output by a specific effect on the kidney, and they enhance the propensity for fluid % retention, which can increase urine output at night, when the effect of the analgesic 20 compound has subsided [17]. Another possible reason for the increase in nocturia in association with the use of analgesics is that analgesic use serves as a proxy for pain. 0 The increase in nocturnal voids in subjects with bodily pain may also reflect the increased 1234 1234 propensity for sleep impairment in such Men Women people. This interpretation is supported by findings in a study of elderly men and women (mean age 73 years, SD 6), among whom poor those who very seldom or never experienced was a proportional increase in the prevalence sleep was shown to be 2.7 (1.7–4.3) times such pain [18]. of absence for sickness both in the group with and 4.8 (3.5–6.4) times more common, ≥7 days absent per year and in the group with respectively, in those who were very often Sick-listing was greater in both men and ≥60 days absent per year. Such a relationship troubled by musculo-skeletal pain than in women with more nocturnal voids, and there was previously reported in Swedish women

NOCTURIA, HEALTH AND PAIN

aged 40–64 years, among whom the duration KE. Nocturia and associated morbidity in tract symptoms. Scand J Urol Nephrol of sick-leave was 15 days per year in the a community-dwelling elderly population. 2001; 35: 377–81 group with none and 75 days per year in BJU Int 2003; 92: 726–30 17 Nielsen CB, Sørensen SS, Pedersen EB. those with three or more nocturnal voids. 4 Asplund R, Asplund R. Nocturia in Effects of indomethacin on renal function Women who voided three or more times per relation to sleep, somatic diseases and in normotensive patients with chronic night also consulted a doctor twice as often medical treatment in the elderly. BJU Int glomerulonephritis with preserved renal as those with no nocturnal voids, and were 2003; 91: 302–3 function. Scand J Clin Lab Invest 1994; 54: treated with drugs 2.5 times as often [15]. In a 5 Umlauf MG, Chasens ER. Sleep 523–9 study of productivity, vitality and utility in a disordered breathing and nocturnal 18 Asplund R. Nightmares in relation to group of healthy professionally active polyuria: nocturia and enuresis. Sleep Med health, sleep and somatic symptoms in individuals with nocturia (mean age Rev 2003; 7: 403–11 the elderly. Sleep Hypnosis 2004; 5: 175– 52.9 years, SD 9.8, 48% men), compared with a 6 van Os-Bossagh P, Pols T, Hop WC, 81 randomly selected control group, Kobelt et al. Bohnen AM, Vierhout ME, Drogendijk 19 Kobelt G, Borgström F, Mattiasson A. [19] found that sick-leave for any reason was AC. Voiding symptoms in chronic pelvic Productivity, vitality and utility in a group reported almost twice as often in the nocturia pain (CPP). Eur J Obstet Gynecol Reprod of healthy professionally active group. The productivity and overall work Biol 2003; 107: 185–90 individuals with nocturia. BJU Int 2003; impairment was also lower in this group. 7 Asplund R. Micturition Habits and 91: 190–5 Diuresis in Relation to Sleep and Well- 20 Coyne KS, Zhou Z, Bhattacharyya SK, In the present study the distribution of Being in Elderly Subjects with Emphasis Thompson CL, Dhawan R, Versi E. The nocturnal voids was similar in men and on Antidiuretic Hormone. Stockholm: prevalence of nocturia and its effect on women (Table 1), which is in line with Thesis 1992 health-related quality of life and sleep in previous findings [1,20]. The relation between 8 Asplund R. Mortality in the elderly in a community sample in the USA. BJU Int somatic health and mental health as one relation to nocturnal micturition. BJU Int 2003; 92: 948–54 factor and nocturnal voiding as another 1999; 84: 297–301 showed no gender differences (Fig. 1a). 9 Weiss JP, Blaivas JG. Nocturia. Curr Urol Correspondence: Ragnar Asplund, Tallvägen 3, Rep 2003; 4: 362–6 S-833 34 Strömsund, Sweden. In conclusion, among randomly selected men 10 Rembratt A, Nørgaard JP, Andersson e-mail: [email protected] or and women aged 20–64 years, nocturnal KE. Differences between nocturics and [email protected] voiding was associated with impairment of non-nocturics in voiding patterns: an both somatic and mental health. Pain was analysis of frequency-volume charts from associated with a substantial increase in community-dwelling elderly. BJU Int nocturnal voids after adjusting for age and for 2003; 91: 45–50 APPENDIX somatic and mental health. Satisfaction with 11 van Kerrebroeck P, Abrams P, Chaikin D life was lower and sick-leave more common in et al. The standardisation of terminology Statements in the questionnaire that were association with more nocturnal voids. in nocturia: report from the analysed (original in Swedish). Standardisation Sub-committee of the ACKNOWLEDGEMENTS International Continence Society. Sex: man/woman Neurourol Urodyn 2002; 21: 179–83 Age (years): 20–29 / 30–44 / 45–59 / ≥60 This study was supported by the Social 12 Abramson ZH, Gofin J, Abramson JH. Insurance Office and its co-operative partners Obstructive prostatic symptoms: a My somatic health is: in the project ‘Early and Co-ordinated community survey in Jerusalem. Int J Very good / Rather good / Rather poor / Very rehabilitation’ in the county of Jämtland, Epidemiol 1994; 23: 797–804 poor Sweden. 13 Asplund R, Henriksson S, Isacsson GB, Johansson S. Nocturia and depression. My mental health is: CONFLICT OF INTEREST BJU Int 2004; 93: 1253–6 Very good / Rather good / Rather poor / Very 14 Bech P, Rasmussen NA, Olsen LR, poor None declared. Source of funding: Jämtland Noerholm V, Abildgaard W. The County Council. sensitivity and specificity of the Major I get up . . . times per night for micturition. Depression Inventory, using the Present REFERENCES State Examination as the index of Bodily pain diagnostic validity. J Affect Disord 2001; None or very mild / Rather mild / Rather 1 Asplund R, Åberg H. Health of the elderly 66: 159–64 severe / Very severe with regard to sleep and nocturnal 15 Asplund R, Åberg H. Nocturnal micturition. J Prim Health Care 1992; 10: micturition, sleep and well-being in Sick-listing during the past year (days): 98–104 women of ages 40–64 years. Maturitas 0–6 / 7–29 / 30–59 / 60–179 / ≥180 2 Lose G, Alling-Møller L, Jennum P. 1996; 24: 73–81 Nocturia in women. Am J Obstet Gynecol 16 Koskimäki J, Hakama M, Huhtala H, ‘I am on the whole satisfied with my life’: 2001; 185: 514–21 Tammela TL. Association of non- Agree totally / Agree partly / Disagree partly / 3 Rembratt A, Nørgaard JP, Andersson urological diseases with lower urinary Disagree totally.

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Original Article NOCTURIA, DEPRESSION and SSRI ASPLUND et al.

Nocturia, depression and antidepressant medication

RAGNAR ASPLUND*†, SUSANNE JOHANSSON†, SVANTE HENRIKSSON‡ and GÖRAN ISACSSON‡ *Family Medicine Stockholm, and ‡Neurotec, Division of Psychiatry, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden and †The Research and Development Unit, Jämtland County Council, Östersund, Sweden Accepted for publication 1 December 2004

OBJECTIVE RESULTS yes vs no (2.2; 1.1–4.5). Gender was deleted by the logistic regression model. To assess the possible relationship between The questionnaire was completed by 1375 treatment with selective serotonin-reuptake subjects, of whom 609 (44%) were men; the CONCLUSION inhibitors (SSRIs) and the occurrence of response rate was 69%. Prescription data nocturia. were available for all respondents. The mean Major depression has previously been found (SD) age of the men and women participating to be associated with increased nocturnal SUBJECTS AND METHODS were 48.0 (18.2) and 50.1 (19.1) years, micturition. In the present study, twice as respectively. Two or more nocturnal many men and women treated with SSRIs as An unselected group of adult men and micturition episodes were reported in 15.6% those not so treated had two or more women, living in the city of Östersund, of the men and 16.5% of the women. In a nocturnal voids, after adjusting for major Sweden, were sent a postal questionnaire multiple logistic regression analysis, depression and age. The implication for the containing questions on somatic and mental independent correlates for two or more risk of fall injuries is discussed. health, sleep, sleepiness and nocturia. For nocturnal voids vs no more than one were: depression diagnostics, the Major Depression age 45–59 years vs <45 (odds ratio 2.9; 95% KEYWORDS Inventory (MDI) was used. Prescription data conﬁdence interval 1.9–4.7); age 60–74 on antidepressant drugs were extracted vs <45 (6.0; 3.7–9.8); age > 75 vs <45 (13.4; antidepressants, major depression, nocturia, from a register in the county of Jämtland, 7.9–22.6); major depression, yes vs no (4.6; selective serotonin-reuptake inhibitors, Sweden. 2.8–7.5); and being on treatment with SSRI, SSRI

INTRODUCTION from the urogenital tract are integrated with explanatory letter. Those who had not replied signals from the cortex and hypothalamus within 2 weeks were sent a reminder by Nocturia is a common complaint in adult and that determine whether micturition is socially postcard, and those who had not replied after elderly people; its prevalence increases in and environmentally appropriate [9]. 2 further weeks received a second reminder parallel with increasing age and has a with a new copy of the questionnaire. profound influence on the death rate, health Many people with depression are treated with and quality of life [1,2]. Nocturia is caused by antidepressants and there are reports that The answers to the questions on depression, an increase in the nocturnal urine output, an some antidepressants are associated with an sleep and nocturia were analysed. To obtain impaired bladder capacity or a combination of increased risk of incontinence [10], and that data on nocturnal micturition, the question these two mechanisms [3]. one antidepressant drug, duloxetine, is used ‘I usually get up . . . times for micturition successfully in the treatment of this condition at night’ was included [1]. For depression In a previous study we found that major [11]. The aim of the present study was to diagnostics, the Major Depression Inventory depression (MD) was associated with a six- investigate whether the previously observed (MDI) was used [12]. The MDI contains all nine fold increase in nocturia in men and a three- increase in nocturia in men and women with symptoms of a DSM IV major depression fold increase in women, after age and health depression could be attributed to the episode [13]. The procedure for analysing data had been taken into account [4]. Possible depression per se, to antidepressant from the MDI was described in detail pathogenetic mechanisms of this relationship medication or to both mechanisms. previously [4]. may involve both increased nocturnal diuresis resulting from a disturbed 24-h rhythm of Prescription data on antidepressant drugs vasopressin secretion, and a decreased were extracted from a register in the county nocturnal bladder capacity caused by a SUBJECTS AND METHODS of Jämtland, Sweden, in which all drug central and/or peripheral serotonergic effect prescriptions from 1970 onwards for all [5–8]. Both a bladder contraction and All men and women aged ≥18 years, born on inhabitants with one of four defined birthdays simultaneous relaxation of the urethra are one of two defined days each month of the in all months of the year are recorded. necessary for emptying the bladder [8,9]. In year and resident in any of three defined Prescriptions issued 1 year before the the pontine micturition centre in the brain, it parishes in the city of Östersund, Sweden, distribution of the questionnaire and as long is proposed that impulses indicating urgency were sent a postal questionnaire with an as data were available (mean 6 months,

NOCTURIA, DEPRESSION AND SSRI

Prescription data were available for all those relationship between nocturia and SSRI. The TABLE 1 The distribution (n,%) of major responding or not. result must be interpreted with some caution, depression among men and women of different as there were relatively few subjects taking age groups The mean (SD) ages of the men and women SSRIs, but the good conformity with SSRI participating were 48.0 (18.2) and prescription data between those responding Age, years Men Women 50.1 (19.1) years, respectively; the proportion or not supports the conclusion that the 20–29 0 14 (8.8) of elderly participants (>75 years old) was prescription information was representative 30–44 10 (7.4) 14 (9.9) somewhat larger in the women than in the for the population in the investigated 45–59 10 (5.6) 9 (4.1) men (P < 0.05) (Table 1). geographical area. 60–74 7 (6.1) 5 (3.3) 75 2 (3.8) 6 (6.6) > In all 609 men SSRIs had been used for There were no questions on somatic diseases Total 29 (4.8) 48 (6.3) <3 months before completing the or on symptoms with a possible influence on questionnaire by three (0.5%), for 3–6 months nocturia, e.g. heart diseases, sleep apnoea or by four (0.6%) and for >6 months by 18 BPH, although depression can be expected to (2.9%); the corresponding values in the 766 be more common in association with such women were four (0.5%), seven (0.9%) and 43 diseases [15–18]. Nor did we analyse the maximum 1 year) after this distribution were (5.6%) (P < 0.05). After the questionnaire had possible influence of habits such as alcohol identified for analysis. The period of been completed, 17 (2.8%) of the men and 45 intake, smoking or the intake of coffee or tea, investigation of antidepressant medication (5.9%) of the women received one or more although such habits are associated with covered this duration. SSRI prescriptions (P < 0.01). There was no changes in nocturia and may differ in people significant difference in the prescription with or with no depression [19]. However, we The analysis in this report was restricted pattern between those who had answered the do not think that these factors can explain to selective serotonin-reuptake inhibitors questionnaire and those who had not. more than a minor part of the relationship (SSRIs). Tricyclic antidepressants (e.g. between nocturia and SSRI use. amitriptyline, imipramine, maprotiline) Four (13.7%) of the 29 men with MD and 11 were prescribed to 16 people and other (22.9%) of the 48 women with MD were The analysis was restricted to SSRIs, as this antidepressant drugs (e.g. mianserin, taking an SSRI. Of the 16 men on SSRIs four class of antidepressants has been the nefazodone, mirtazapine and venlafaxine) had MD and of the 565 men not on an SSRI 44 predominant one in the county of Jämtland to nine. The groups treated with either (7.8%) had MD (P < 0.05). The corresponding since 1995 [20]. However, a favourable feature type were considered too small and values for women were 11 of 32 (34%) and 52 with reference to the aim of the study was heterogeneous for further analysis, and of 714 (7.3%) (P < 0.001). Treatment with an that in addition to people with MD treated many of these prescriptions were for low SSRI was 5.4 (1.5–19.7) times more common with an SSRI, the study group included both doses, for occasional use and in several cases in men and 3.6 (1.5–8.6) times more common those with untreated MD and those using an probably for other diseases than depression in women with two or more nocturnal SSRI who did not meet the criteria for MD. [14]. The study was approved by the Ethics micturition episodes than in those with no This improved the possibility of analysing the Committee of the University of Umeå, such episodes. relationship between nocturia and SSRIs Sweden. independently of MD. In the multiple logistic regression analysis Standard methods were used for calculating independent correlates for two or more Most subjects with MD were not being treated the mean (SD); groups of categorical data nocturnal voids vs no more than one episode with an SSRI. Other studies have similarly were compared with the chi-square test, and were: age 45–59 vs <45 years, 2.9 (1.9–4.7); shown that most depressed people in Sweden two numerical variables using Student’s t- age 60–74 vs <45, 6.0 (3.7–9.8); age > 75 are medically untreated or only sporadically test. For comparing frequencies the odds ratio vs <45, 13.4 (7.9–22.6); MD, yes vs no, 4.6 treated [20,21]. Most of those who were (OR) and 95% CI were calculated. For (2.8–7.5); and taking an SSRI, yes vs no, 2.2 treated with an SSRI had been on their multivariate analysis, logistic regression (1.1–4.5). Gender was deleted by the logistic medication for >6 months. The dose of SSRI analysis was used, with the Hosmer- regression model. The Hosmer-Lemeshow was in almost all cases in accordance with Lemeshow test for assessing goodness-of-fit. goodness-of-fit test for the final model current Swedish recommendations for yielded a chi-square of 1.69 on five degrees of treating MD. This suggests that those who freedom (P = 0.89). were on an SSRI but did not meet the criteria for MD were in remission. RESULTS Previous reports on urinary symptoms in The questionnaire was initially completed DISCUSSION association with SSRIs are contradictory. In a by 860 people and after reminders, a further retrospective follow-up study among 450 000 515 answers were received. Thus there The main finding in the present study was residents living in eight Dutch cities, Movig were 1375 evaluable questionnaires, of that treatment with an SSRI was associated et al. [10] identified 13 531 first-time users of which 609 (44%) were from men. Among with greater nocturia, after MD and age had an SSRI between 1994 and 1998. They found recipients who could be expected to answer been taken into account. We found no a 61% increase in the relative risk for urinary (1971 in all), the response rate was 69%. previous report dealing with the possible incontinence caused by the SSRI and also that

ASPLUND ET AL.

sertraline was associated with the highest CONFLICT OF INTEREST Mental Disorders, 4th edn. Washington risk. In contrast, an antidepressant that DC: American Psychiatric Association influences both the serotonin and the None declared. 1994 noradrenaline pathways of the CNS, 14 Henriksson S, Boëthius G, Håkansson J, duloxetine, has been found to reduce Isacsson G. Indications for andoutcome incontinence [11,22]. These divergent results of antidepressant medication in a general may reflect differences in action of the REFERENCES population: a prescriptiondatabase and different antidepressants. medical record study, in Jämtland county, 1 Asplund R, Åberg H. Health of the elderly Sweden, 1995. Acta Psychiatrica Scand MD is a prevalent condition; in a Swedish with regard to sleep and nocturnal 2003; 108: 427–31 study it was found that up to 70 years old, the micturition. Scand J Prim Health Care 15 Asplund R, Aberg HE. Nocturia and cumulative probability of suffering a first 1992; 10: 98–104 health in women aged 40–64 years. episode of depression was 27% in men and 2 Asplund R. Mortality in the elderly in Maturitas 2000; 35: 143–8 45% in women [23]. Many authors have called relation to nocturnal micturition. BJU Int 16 Hajduk IA, Strollo PJ Jr, Jasani RR, attention to the widespread under-diagnosis 1999; 84: 297–301 Atwood CW Jr, Houck PR, Sanders and under-treatment of MD [24,25]. The most 3 Weiss JP, Blaivas JG. Nocturia. Curr Urol MH. Prevalence and predictors of important reason for recognition and Rep 2003; 4: 362–6 nocturia in obstructive sleep apnea– adequate treatment of this condition is that it 4 Asplund R, Henriksson S, Johansson S, hypopnea syndrome – a retrospective causes much suffering and disability, and that Isacsson G. Nocturia and depression. BJU study. Sleep 2003; 26: 61–4 it can be effectively treated [22]. It may Int 2004; 93: 1253–6 17 Veale D, Poussin G, Benes F, Pepin JL, therefore be expected that antidepressant 5 Asplund R, Åberg H. Diurnal variation in Levy P. Identification of quality of life treatment will become more common in the the levels of antidiuretic hormone in the concerns of patients with obstructive future [26]. elderly. J Int Med 1991; 229: 131–4 sleep apnoea at the time of initiation 6 Asplund R, Åberg H. Diurnal rhythm of of continuous positive airway pressure: Nocturia is an important risk factor for falls antidiuretic hormone in elderly subjects a discourse analysis. Qual Life Res 2002; and particularly for hip fractures, with serious with nocturia. Med Sci Res 1991; 19: 765– 11: 389–99 consequences in older people. Mortality after 6 18 O’Sullivan M, Murphy C, Deasy C, a hip fracture is high: a third of patients die 7 Steers WD, Lee KS. Depression and Iohom G, Kiely EA, Shorten G. Effects of within a year after the accident [27]. There is incontinence. World J Urol 2001; 19: 351– transurethral resection of prostate on the also greater depression among elderly people 7 quality of life of patients with benign with hip fracture, and the depression can both 8 de Groat WC. Influence of central prostatic hyperplasia. J Am Coll Surg 2004; be a cause and a consequence of the accident serotonergic mechanisms on lower 198: 394–403 [28,29]. In the present study the occurrence of urinary tract function. Urology 2002; 59 19 Kang D, Andriole GL, Van De Vooren two or more nocturnal voids was reported (Suppl. 1): 30–6 RC et al. Risk behaviours and benign twice as often by men and women on an SSRI 9 Thor KB. Serotonin and norepinephrine prostatic hyperplasia. BJU Int 2004; 93: as by those without such medication, after involvement in efferent pathways to the 1241–5 adjusting for age and MD. The results may urethral rhabdosphincter: implications for 20 Isacsson G, Boethius G, Henriksson S, indicate that elderly people on an SSRI may treating stress urinary incontinence. Jones JK, Bergman U. Selective serotonin run an especially high risk of fall injuries. Urology 2003; 62: 3–9 reuptake inhibitors have broadened the The design of the study did not allow a 10 Movig KL, Leufkens HG, Belitser SV, utilisation of antidepressant treatment in comparison between those on different types Lenderink AW, Egberts AC. Selective accordance with recommendations. of SSRI for the occurrence of nocturia. This serotonin reuptake inhibitor-induced Findings from a Swedish prescription would be an important topic for further urinary incontinence. Pharmacoepidemiol database. J Affect Disord 1999; 53: 15– studies. A greater risk of hip fractures was Drug Saf 2002; 11: 271–9 22 previously reported among antidepressant 11 van Kerrebroeck P, Abrams P, Lange R 21 Isacsson G, Boethius G, Bergman U. Low users, and SSRI and tricyclic antidepressants et al. Duloxetine Urinary Incontinence level of antidepressant prescription for are associated with an increase of similar Study Group. Duloxetine versus placebo in people who later commit suicide: 15 years magnitude [30]. the treatment of European and Canadian of experience from a population-based women with stress urinary incontinence. drug database in Sweden. Acta Psychiatr In summary, previous studies have shown that BJOG 2004; 111: 249–57 Scand 1992; 85: 444–8 MD is associated with an increase in 12 Bech P, Rasmussen NA, Olsen LR, 22 Viktrup L, Bump RC. Pharmacological nocturnal micturition. In the present study, Noerholm V, Abildgaard W. The agents used for the treatment of stress twice as many men and women treated with sensitivity and specificity of the Major urinary incontinence in women. Curr Med SSRIs had two or more nocturnal voids than Depression Inventory, using the Present Res Opin 2003; 19: 485–90 had those without such treatment, after MD State Examination as the index of 23 Rorsman B, Grasbeck A, Hagnell O and age had been taken into account. The diagnostic validity. J Affect Disord 2001; et al. A prospective study of first- results need to be confirmed in a larger study 66: 159–64 incidence depression. The Lundby study, where nocturia in people using different kinds 13 American Psychiatric Association. 1957–72. Br J Psychiatry 1990; 156: of SSRI can be analysed. Diagnostic and Statistic Manual of 336–42

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24 Davidson JR, Meltzer-Brody SE. The epidemiological review. Bull Hosp Jt Dis tricyclic and selective serotonin reuptake underrecognition and undertreatment of 1999; 58: 197–201 inhibitor antidepressants and the risk of depression: what is the breadth and depth 28 Holmes JD, House AO. Psychiatric illness hip fracture. Am J Epidemiol 2003; 158: of the problem? J Clin Psychiatry 1999; 60 in hip fracture. Age Ageing 2000; 29: 77–84 (Suppl. 7): 4–11 537–46 25 Nierenberg AA, Gray SM, Grandin 29 Forsen L, Meyer HE, Sogaard AJ, Correspondence: Ragnar Asplund, Tallvägen 3, LD. Mood disorders and suicide. Naess S, Schei B, Edna TH. Mental S-833 34 Strömsund, Sweden. J Clin Psychiatry 2001; 62 (Suppl. 25): distress and risk of hip fracture. Do e-mail: [email protected] or 27–30 broken hearts lead to broken bones? [email protected] 26 Isacsson G. Suicide prevention – a J Epidemiol Community Health 1999; 53: medical breakthrough? Acta Psychiatr 343–7 Abbreviations: (MD)I, (Major Depression) Scand 2000; 102: 113–7 30 Hubbard R, Farrington P, Smith C, Inventory; SSRI, selective serotonin-reuptake 27 Rose S, Maffulli N. Hip fractures. An Smeeth L, Tattersﬁeld A. Exposure to inhibitor; OR, odds ratio.

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Original Article COMBINED EXTERNAL URETHRAL BULKING and AUS RAHMAN et al.

Combined external urethral bulking and artiﬁcial urinary sphincter for urethral atrophy and stress urinary incontinence

NADEEM U. RAHMAN, THOMAS X. MINOR, DONNA DENG and TOM F. LUE Department of Urology, University of California, San Francisco, USA Accepted for publication 1 November 2004

OBJECTIVE radical prostatectomy were referred for one 84-year-old man who had the replanted recurrent SUI after placing an AUS (four, artificial sphincter removed because of To describe a technique of externally bulking including one with urethral erosion) or a male erosion 14 months after surgery. the urethra with a soft-tissue graft before sling (one, with a resulting atrophic urethra). placing another artificial urinary sphincter Each patient was treated with an external CONCLUSION (AUS), as when placing another AUS for urethral bulking agent (Surgisis® ES, Cook recurrent male stress urinary incontinence Urological, Spencer, Indiana) and had an AUS In cases of severe recurrent SUI from urethral (SUI) other manoeuvres, e.g. placing a tandem placed. atrophy after placing an AUS, externally cuff or transcorporal cuff, must be used to bulking the urethra with Surgisis ES before obtain urinary continence in an atrophic RESULTS placing another AUS is well tolerated, and urethra, and each is associated with gives satisfactory results. morbidity. In each patient the greatest urethral circumference was <4 cm. To place a PATIENTS AND METHODS functional 4 cm cuff, the diameter of KEYWORDS the urethra was enhanced by wrapping From January 2003 to July 2004, five patients it with Surgisis ES. Continence was urethral atrophy, artificial urinary sphincter, (mean age 74 years, range 62–84) treated by significantly improved in all patients except stress urinary incontinence

INTRODUCTION bulking agent, followed by placing another treated with external bulking using four-ply AUS. Surgisis ES derived from porcine small The use of the AMS 800 (American Medical intestinal submucosa, followed by placing an Systems, Minnetonka, Minnesota) artificial AUS. urinary sphincter (AUS) for male stress urinary PATIENTS AND METHODS incontinence (SUI) after radical prostatectomy The defect was repaired with the patient was first popularized in 1972, and has now From January 2003 to April 2004, five patients under general or spinal anaesthesia, with become the ‘gold standard’ treatment, with (mean age 74 years, range 62–84) with intravenous antibiotics given before inducing patients reporting a >90% improvement in recurrent SUI after AUS or a male sling anaesthesia. After sterile genital preparation, quality of life afterward [1]. The absolute operation were treated with external bulking we used either a perineal vertical incision over continence rate after an AUS is 73–90% [2–4], using Surgisis® ES (Cook Urological, Spencer, the bulbous urethra, with the patient in a high but with time some patients have recurrent Indiana) followed by placing an AUS. After lithotomy position, or a transverse incision at incontinence, generally attributed to urethral prostatectomy at an outside institution, four the penoscrotal junction with the patient in a atrophy beneath the cuff. Many surgical patients had an AUS placed 3–10 years earlier supine ‘frog-leg’ position. In the three options have been described to treat such a to treat SUI. All had a 4-cm cuff placed at the patients with a sphincter cuff in place, the condition, including surgically reducing time of their first incontinence operation. corpus spongiosum was exposed and the AUS the cuff size, placing a second tandem AUS Each patient was subsequently referred for activated via the scrotum to monitor the cuff, and recently, a transcorporal cuff the management of recurrent SUI requiring inflation/deflation cuff mechanism. This implantation [5–7]. Each of these methods is more than five pads daily; an evaluation confirmed the cause of the SUI to be urethral associated with some potential complications determined that each had developed urethral atrophy and not mechanical cuff malfunction. and deficiencies. atrophy. Notably, one patient had urethral A pseudocapsule was generally noted around erosion requiring earlier AUS removal. The the cuff, requiring careful dissection to free Herein we describe a simplified treatment fifth patient developed an atrophic urethra the device from the corpus spongiosum. After for severe SUI after an AUS secondary after a male sling was placed following removing the cuff and remaining hardware, to urethral atrophy, using a sterilized prostatectomy. These five patients with the urethral circumference was measured. natural biomaterial as an external urethral recurrent SUI and urethral atrophy were Before bulbar urethral isolation in the

COMBINED EXTERNAL URETHRAL BULKING AND AUS

FIG. 1. size. In this situation, other measures must be Intraoperative photograph taken. Brito et al. [5] described placing a showing the two-layered Surgisis second distal AUS cuff in tandem with a more (blue arrow) surrounding the proximal first (original) cuff for this situation, atrophic urethra and the AUS cuff with a success rate of up to 90%, but the risk (green arrow). of ultimately developing urethral atrophy remains. Future revision will be more difficult because the corpus spongiosum in the more distal portion is even smaller in diameter. Transcorporal placement of either a second tandem cuff or first cuff has also been reported; this technique was also very successful but is more demanding and associated with the potential risk of erectile dysfunction [6].

The use of extracellular matrix as a scaffold for tissue reconstruction has been investigated extensively in the lower urinary tract [8]. Sources have included small intestine submucosa and the urinary bladder itself. Work using animal models Patient TABLE 1 [9–12] of urethral, ureteric, bladder wall Characteristic 123 45 The patients’ and vaginal replacement have resulted in Age, years 80 62 84 66 84 characteristics, with the present use of these materials in Years before AUS failure 10 3 7 5 NA* operative details and humans, with a high success rate. These Prior erosion Yes No No No No current continence status studies showed that the matrix serves as Intraoperative urethral 2.5 3 3.5 2.5 3.0 a temporary, rapidly degraded scaffold circumference, cm *Atrophy from male sling; that is replaced by organized and functional Continence (pads/day) 0–1 0 0/removed 0–1 1–2† †small bladder capacity. smooth muscle and urothelium [8–19]. The rate of resorption of the scaffold has been surprisingly rapid, with as much as 90% of the scaffold replaced within 28 days [11,13,18]. remaining two patients (one had previous of life. Two patients are completely dry, These results indicate that the host cellular cuff erosion and the other a failed male with no pad usage; two had minimal SUI, infiltrate is rapid, diffuse and different from sling operation), urethroscopy was used requiring no or one pad per day. One the typical fibroblastic ingrowth seen with to exclude stricture disease. In all five patient continues to require one or two pads tissue injury or purified collagen scaffold patients the urethral circumference was per day for protection, probably because of materials. <4 cm (2.5–3.5 cm). To provide external his urodynamically confirmed small bladder bulking, a rectangular piece of Surgisis ES capacity. This patient had no leakage during If the same resorption rate were similar in with a width equal to that of the sphincter cough, sneeze or Valsalva manoeuvre in the humans it would be expected that the Surgisis cuff was placed around the urethra (wrapped office setting. There were no complications around the corpus spongiosum would be once or twice, depending on the urethral after surgery (Table 1). After submission of the replaced by host tissue within 3 months. circumference). Finally, an AMS 800 AUS with manuscript, Patient 3, an 84-year-old man That none of the present five patients had a 4-cm cuff was positioned around both the with severe pulmonary disease, had the recurrent urinary leakage after a follow up of urethra and Surgisis ES (Fig. 1). Tubing for the replanted artificial sphincter removed because 4–14 months is certainly encouraging. While reservoir and pump were connected in the of erosion 14 months after surgery. these results remain preliminary, the standard fashion. The system was tested and technique has certain advantages. Placing an cycled to confirm function, and then DISCUSSION external artificial graft around the urethra deactivated. A 12 F urethral catheter was may be protective and delay the onset of placed overnight. The device was activated The AUS is considered to be the ‘gold further urethral atrophy. This technique also 6 weeks later. standard’ for treating severe UI, with patient requires no additional dissection or satisfaction ratings of up to 90%. However, manipulation of the corpus spongiosum or over time, incontinence seems to worsen, corpora cavernosa. A longer follow-up will be RESULTS with the most common mechanism being needed to determine if there is protection urethral atrophy under the cuff, causing a against urethral atrophy in the long term. At a mean (range) follow-up of 11 (4–14) decrease in coaptation of the cuff. If the Studies are also needed to examine whether months, all patients reported a significant current cuff size is 4 cm, reducing it is not a other grafting materials are suitable for the improvement in their continence and quality viable option as this is the smallest available same purpose.

RAHMAN ET AL.

In conclusion, severe recurrent male SUI after requiring revision for erosion and et al. In vivo degradation of 14C-labeled placing an AUS can be adequately managed urethral atrophy. J Urol 2002; 167: small intestinal submucosa (SIS) when with external urethral bulking with Surgisis ES 2075–8 used for urinary bladder repair. and a repeat AUS, with minimal morbidity. 7 DiMarco DS, Elliott DS. Tandem cuff Biomaterials 2001; 22: 2653–9 artificial urinary sphincter as a salvage 15 Kropp BP, Pope JC. Small intestinal procedure following failed primary submucosa. a novel substance for the CONFLICT OF INTEREST sphincter placement for the treatment of study of cellular interaction and post-prostatectomy incontinence. J Urol regeneration in the bladder. Dialogues None declared. 2003; 170: 1252–4 Pediatr Urol 1997; 20: 1–8 8 Badylak SF. Xenogeneic extracellular 16 Grossklaus DJ, Shappell SB, Adams MC, matrix as a scaffold for tissue Brock JW III, Pope JCIV. Small intestinal REFERENCES reconstruction. Transpl Immunol 2004; submucosa as a urethral coverage layer. 12: 367–77 J Urol 2001; 166: 636–9 1 Montague DK, Angermeier KW. 9 Piechota HJ, Gleason CA, Dahms SE 17 Jaffe JS, Ginsburg PC, Yanoshak SJ Postprostatectomy urinary incontinence: et al. Bladder acellular matrix graft. et al. Ureteral segment replacement the case for artificial urinary sphincter in vivo functional properties of the using a circumferential small intestinal implantation. Urology 2000; 55: 2–4 regenerated rat bladder. Urol Res 1999; submucosa xenogenic graft. J Invest Surg 2 Leibovich BC, Barrett DM. Use of the 27: 206–13 2001; 14: 259–65 artificial urinary sphincter in men and 10 Dahms SE, Piechota HJ, Nunes L, 18 Kropp BP, Sawyer BD, Shannon HE women. World J Urol 1997; 15: 316–9 Dahiya R, Lue TF, Tanagho EA. Free et al. Characterization of small intestinal 3 Montague DK, Angermeier KW, ureteral replacement in rats. Regeneration submucosa-regenerated canine detrusor: Paolone DR. Long-term continence of ureteral wall components in the assessment of reinnervation, in vita and patient satisfaction after artificial acellular matrix graft. Urology 1997; 50: compliance and contractility. J Urol 1996; sphincter implantation for urinary 818–25 156: 599–607 incontinence after prostatectomy. J Urol 11 Atala A, Guzman L, Retik AB. A novel 19 Badylak SF, Kropp B, McPherson T, 2001; 166: 547–9 inert collagen matrix for hypospadias Liang H, Snyder PWSIS. A rapidly 4 Elliott DS, Barrett DM. Mayo Clinic repair. J Urol 1999; 162: 1148–51 resorbable bioscaffold for augmentation long-term analysis of the functional 12 Yoo JJ, Meng J, Oberpenning F, Atala A. cystoplasty in a dog model. Tissue Eng durability of the AMS 800 artificial urinary Bladder augmentation using allogenic 1998; 4: 379–87 sphincter: a review of 323 cases. J Urol bladder submucosa seeded with cells. 1998; 159: 1206–8 Urology 1998; 51: 221–5 Correspondence: Tom F. Lue, University of 5 Brito CG, Mulcahy JJ, Mitchell ME, 13 Rickey FA, Elmore D, Hillegonds D, California, San Francisco, 400 Parnassus Adams MC. Use of a double cuff AMS800 Badylak SF, Record R, Simmons-Byrd A. Avenue, Box 0738, San Francisco, CA 94143, urinary sphincter for severe stress Re-generation of tissue about an animal USA. incontinence. J Urol 1993; 149: 283–5 based scaffold: studies of the fate of the e-mail: [email protected] 6 Guralnick ML, Miller E, Toh KL, Webster scaffold. Nucl Instrum Meth Phys Res GD. Transcorporal artificial urinary 2000; 172: 904–9 Abbreviations: SUI, stress urinary sphincter cuff placement in cases 14 Record RD, Hillegonds D, Simmons C incontinence; AUS, artificial urinary sphincter.

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Original Article DAY-CASE SLING SURGERY FOR STRESS URINARY INCONTINENCE GIRI et al.

Day-case sling surgery for stress urinary incontinence: feasibility and safety

SUBHASIS K. GIRI, JOHN DRUMM, JEAN A. SAUNDERS*, JANE MCDONALD and HUGH D. FLOOD Department of Urology, Mid-Western Regional Hospital and National Institute of Health Sciences, and *Statistical Consulting Unit, University of Limerick, Ireland Accepted for publication 29 November 2004

OBJECTIVE time required to achieve an EE of ≥75%, a emptying at 10 h (39% vs 70%). Overall SUI visual analogue scale pain score, perioperative was cured or improved in 90% of patients at To prospectively assess the feasibility for complications, and short-term cure rate of the 6-month follow-up. discharge 10 h after a porcine dermal SUI. Patients were considered suitable for pubovaginal sling procedure (PVS), to examine discharge from hospital when the EE was CONCLUSIONS the surgical factors (postoperative ≥75% or when they were self-catheterizing complications) affecting discharge, and to confidently with adequate pain control and In the present study only 40% of patients measure the short-term cure rate for stress no significant complication. All patients were were suitable for day-case sling surgery. Early urinary incontinence (SUI). followed for 6 months. bladder emptying inefficiency was the main limiting factor. Exclusion of patients with ISD PATIENTS AND METHODS RESULTS and possibly decreasing the EE threshold to 50% would improve the discharge rate. The Between June 2003 and December 2003, 40 The median EE at 10 h was 61%; 16 patients short-term results of this PVS are similar to consecutive patients with SUI and scheduled (40%) achieved efficient emptying and were those obtained with the autologous fascial for treatment using a porcine dermal sling suitable for discharge 10 h after surgery. sling. were enrolled in this prospective study. The median intervals to the first three Patients were admitted with a planned spontaneous voids were 7, 10 and 17 h, and overnight stay and returned to the ward with the median EEs for the first three voids 46%, KEYWORDS no urinary catheter. Outcome measures were 61% and 75%. The median visual analogue bladder emptying efficiency (EE) at 10 h after scale pain score was 3.5. Patients with stress urinary incontinence, minimally surgery, time intervals to the first three intrinsic sphincter deficiency (ISD) were invasive surgery, day-case surgery, spontaneous voids, EE of the first three voids, significantly less likely to achieve efficient pubovaginal sling

INTRODUCTION [5]. However, the Pfannenstiel incision used PATIENTS AND METHODS for harvesting autologous fascia causes Stress urinary incontinence (SUI) is a common considerable postoperative pain and Between June 2003 and December 2003, 40 problem [1] and is usually related to increased morbidity, thereby prolonging the hospital consecutive patients with SUI were enrolled in urethral mobility and/or intrinsic sphincter stay. One solution is to substitute the rectus this prospective study. Ethical approval for deficiency (ISD). However, hypermobility fascia with a ready-made sling material. the study was obtained from the local Ethics and ISD frequently coexist [2]. The degree However, it is important that treatment safety Committee. Patients were recruited after of urethral mobility and leak-point pressure and efficacy are not compromised. The main a decision was made for anti-incontinence are generally directly related. disadvantage of using a synthetic substitute surgery. Definitions conform to the standards is the risk of urogenital tract erosion [6]. recommended by ICS [7], except where Lack of inpatient beds, and patient and Porcine dermal collagen (PelvicolTM, Bard specifically noted. Our inclusion criteria economic demands are driving the concept of Urology, UK), a biological sling material with were that patients had an American minimally invasive, day-case surgery. The virtually no risk of erosion, might be used and Society of Anesthesiologists physical status apparent cost-effectiveness of day surgery implanted as a day-case procedure. Thus the classification of I or II, urodynamically makes this an attractive form of treatment to aims of the present study were to assess the confirmed SUI, and informed consent. purchasers of healthcare. Modifications in suitability for discharge of patients 10 h after Patients with a history of UTI in the previous sling techniques have resulted in broader the a Pelvicol pubovaginal sling (PVS) 6 weeks, neuropathic bladder, uterovaginal indications [3], reduced morbidity and a procedure, the factors (early complications) prolapse, detrusor instability and voiding shorter hospital stay [4]. Autologous rectus affecting time of discharge, and the short- dysfunction (maximum urinary flow rate fascia remains the ‘gold standard’ sling term cure rate. <15 mL/ s, pressure at maximum flow rate of material for the surgical treatment of SUI >40 cmH2O, postvoid residual urine volume,

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PVR, of >50 mL) were excluded from the catheter removed. Cystoscopy was used to confidently with adequate pain control and study. exclude any bladder injury. The sling was then had no significant complications. placed under the proximal urethra at the All patients were evaluated before surgery by urethrovesical junction. The sling sutures Patients were further evaluated at 6 weeks, 3 history, physical examination, urine analysis were then tied loosely over the rectus and 6 months after surgery in the outpatient and urodynamic study. All patients had a sheath on one side after subcutaneous clinic. At each visit, patients were assessed by pelvic examination to assess pelvic floor transfer of one polypropylene suture across history and physical examination, and a defects and bladder neck motion. After free to the other incision. In patients with ISD validated questionnaire [10] (Appendix); they uroflowmetry and measuring the PVR, all the sling was tied with appropriate tension. also completed the KHQ and SF-36 QoL patients had medium-fill subtracted Skin incisions were closed with absorbable questionnaires at the 6-month follow-up. cystometry using a 6 F double-lumen bladder suture and the bladder emptied. Suprapubic Surgery results were classified as ‘cured’ when catheter and a cuffed, air-filled 4 F rectal and vaginal wounds were infiltrated with the patient reported no leakage of urine under catheter. Cystometric variables measured local anaesthetic (20 mL of 5 mg/mL any circumstances and no incontinence on a included sensation, presence of detrusor levobupivacaine). The patients were returned cough-stress test. ‘Improved’ was defined as a stability, compliance and capacity. Urethral to the ward with no urinary catheter and a reduction of half or more in incontinence and sphincter competence was assessed while vaginal balloon pack was used for only 3 h no leakage on cough-stress test. ‘Failure’ was semi-recumbent or standing, using the after the operation. The operative duration defined as a reduction of less than half in Valsalva manoeuvre or cough, at 50 mL and intraoperative blood loss were recorded, incontinence and or leakage on a cough- intervals from 150 mL of filling, to obtain the with any complications. stress test [11]. A full urodynamic study was abdominal leak-point pressure. Patients also only used if the PVS failed. completed the King’s Health Questionnaire After surgery, NSAIDs such as intravenous (KHQ) [8] and the 36-item Short-Form parecoxib 40 mg, paracetamol suppository The primary outcome measure was the Health Survey (SF-36) quality-of-life (QoL) 1 g, diclofenac suppository 100 mg and oral suitability for discharge 10 h after surgery, questionnaire [9]. Explanatory pamphlets nimesulide 100 mg, were used for pain based on the EE, no significant complication were given to each patient, and they were control; opioid analgesia was avoided. and adequate pain control after surgery. counselled about the possible need for clean Intravenous fluid was continued with Secondary outcome measures were the time intermittent self-catheterization (CISC) after solution-18 at 125 mL/h until the patient was intervals to the first three spontaneous voids, surgery, and briefly taught the technique. able to drink fluid freely. All patients were EE of the first three voids, time required Patients were admitted with a planned instructed to report to a nurse as soon as they to achieve an EE of ≥75%, the VAS pain overnight stay. had a sensation to void after the pack was score soon after surgery, perioperative removed. They were then encouraged to void, complications and short-term (6-month) SUI All sling operations were scheduled on a and to use CISC if they failed to void cure rate. morning operating list. Before surgery all spontaneously. In the absence of a patients received thromboprophylaxis with spontaneous void within 6 h after surgery, Data obtained from case report forms were subcutaneous enoxaparin 20 mg and CISC was used to avoid overdistension of the transferred to a computer spreadsheet and antibiotic prophylaxis with intravenous bladder. The catheterized volume was never entries then checked for any errors. All data ceftriaxone 1 g and gentamicin 240 mg. In >500 mL. were tested where appropriate for normality. all procedures patients were under general The statistical significance was assessed using anaesthesia, with surgery by one urologist Patients were assessed at 4, 10 and 24 h after Student’s t-test, Fisher’s exact test or (H.D.F.). surgery for pain intensity using a visual Wilcoxon matched-pairs test where analogue scale (VAS, 0 = no pain, 10 = worst appropriate, with P < 0.05 considered to The patient was placed in the modified pain). The interval to spontaneous voids, indicate significant differences. lithotomy position in Allen’s stirrups. After bladder emptying efficiency (EE) and early antiseptic dressing and draping, a 14 F Foley complications were also recorded. The catheter was inserted. The sling was prepared suitability for discharge was assessed at 10 h RESULTS using a 7 ¥ 2 cm Pelvicol strip secured at each after the procedure. end with a 0 nonabsorbable polypropylene Table 1 shows the baseline characteristics of suture. Two small suprapubic stab incisions Our day-surgery unit opens at 08.00 hours the study population; 13 patients (33%) had were made 5 cm apart just above the (surgery at 09.00 h) and closes at 20.00 hours, ISD. The operation was a primary procedure in symphysis pubis. Then, a vertical 2.5 cm which gives patients 10 h (allowing 1 h for 33 (83%) women and secondary in seven anterior vaginal wall incision was made. After surgery and recovery) in which to void (18%). Previous surgery included one paraurethral dissection, a Yachia needle was efficiently in preparation for discharge. After periurethral collagen injection, two Kelly passed through the suprapubic stab incision each void, the voided volume (VV) and PVR plications, two Stamey vesicopexies, one and guided digitally behind the pubic ramus were measured, the latter using CISC. The EE rectus fascia pubovaginal sling and one Burch into the vaginal incision bilaterally. One end of was calculated as VV/(VV + PVR) ¥ 100. colposuspension. The median (range) the polypropylene suture was then passed Efficient emptying was defined as an EE of preoperative EE was 100 (94–100)%. through the eyelet in the needle, that was ≥75% [3]. Patients were considered suitable then withdrawn upwards. The procedure was for discharge from hospital when emptying The variables assessed during and after repeated on the opposite side and the efficiently or when they could use CISC surgery are shown in Table 2. The median

DAY-CASE SLING SURGERY FOR STRESS URINARY INCONTINENCE

second void within 5 h after surgery. Nearly Characteristics Values TABLE 1 two-thirds of the patients had their second Age, years 48 (28–66) The patients’ void at 6–10 h and 40% achieved efficient Parity 3 (1–7) characteristics, as the emptying; 70% had efficient emptying within Vaginal delivery 38 (95) median (range) or n (%) 24 h. The median (range) duration of hospital Caesarian section 2 (5) stay was 1.5 (1–3) days. Incontinence starting after delivery 25 (62.5) Duration of symptoms, years 5 (1–25) The mean EE 10 h after surgery was Preoperative pad use 3 (1–6) significantly higher in those with no ISD than Postmenopausal 17 (42.5) in those with ISD (70% vs 39%, P = 0.001, Using HRT 8 (20) t-test). Although 15 of 27 (56%) of the Previous hysterectomy 8 (20) patients with no ISD had an EE of ≥75% at Previous incontinence surgery 7 (17.5) 10 h after surgery, only one of 13 of those Abdominal leak-point pressure, cmH O 85 (29–164) HRT, systemic hormone 2 with ISD had (P = 0.014, Fisher’s exact test), Patients with ISD 13 (32.5) replacement therapy. thus patients with ISD are significantly less likely to have an EE of ≥75% at 10 h after surgery. The mean EE 10 h after surgery in patients aged <60 years was greater than in Variable Values TABLE 2 those >60 years old but the difference was Operative duration, min 30 (25–35) Operative and not significant (62% vs 40%, P = 0.113, t- VAS pain score in first 10 h after surgery 3.5 (0–5) postoperative variables, as test). If efficient emptying was defined as a EE at 10 h, % 61 (40–80) median (interquartile EE of 50% then 24 (60%) patients were *Time to EE ≥ 75%, h 13 (10–21) range) or n (%) emptying efficiently 10 h after surgery. *Number of voids to EE ≥ 75% 3 (2–4) Overall, 40% of patients had a pain score of Number of patients with EE ≥ 75% at 10 h 16 (40) 0 (i.e. no pain) 10 h after surgery; one patient had a VAS pain score of 10 at 10 h, but she *Excluding six patients discharged on CISC. was mobile, emptying efficiently and was dischargeable; age and pain score did not affect the EE. FIG. 1. Differences in EE (50–74%, green bars; FIG. 2. Cumulative distribution of time to voiding 75–100%, red bars) for the first, second and third and EE ≥ 75% (light green) for the first (green), There were no major intraoperative voids. second (red) and third (open bars) voids. complications and no bladder perforations. Two patients had a small amount of vaginal 60 120 bleeding immediately after removing the 50 100 vaginal pack (no actions was necessary and both settled on conservative management). 40 80 One patient had significant nausea and 30 60 vomiting soon after surgery and another

% Patients 20 was drowsy even 10 h after surgery. Of % Patients 40 10 the six patients who were discharged on 20 CISC, four achieved an EE of ≥75% within 0 1st Void 2nd Void 3rd Void 0 7 days of discharge, and one each within 0-56-10 11-20 >20 ≥24 10 days and 14 days; no patient required Time, h urethrolysis. (interquartile range) intervals to the first three spontaneous voids were 7 (6–8), 10 (9–14) There was one superficial abdominal wound and 17 (14–21) h, respectively. The median The differences in EE for the first three voids infection and one abdominal wound early EEs for the first three voids were 46 are shown in Fig. 1. The proportion of patients haematoma, both resolving with conservative (30–60)%, 61 (45–75)% and 75 (55–85)%, with an EE of ≥75% increased significantly management. Three patients developed respectively. Although 35 patients (88%) had from the first void to the second (Fisher’s symptoms suggestive of UTI within 6 weeks of their first void within 10 h of surgery, only exact test; P = 0.002), but the proportion discharge and all were successfully treated four (10%) achieved efficient emptying at showed no further significant increase from with antibiotics by their family doctor. Two their first void. While 26 patients (65%) had the second to third void (P = 0.381). patients complained of intermittent left-sided their second void within 10 h after surgery, deep pelvic pain for 3 months, but there was a further 12 (30%) were able to achieve The cumulative distribution of time to voiding no obvious cause for this and both settled efficient emptying at their second void. Thus, and an EE of ≥75% is shown in Fig. 2. spontaneously with time. overall, 16 of 40 (40%) patients achieved Although 20% of the patients had their first efficient emptying and were suitable for void within 5 h, only 2.5% achieved efficient The outcome of the PVS procedure is shown in discharge 10 h after surgery. emptying. None of the patients had their Table 3. All patients were followed for up to

GIRI ET AL.

6 months, and none were lost to follow-up. FIG. 3. The mean KHQ scores before (green) and TABLE 3 Outcome of the PVS for SUI, for the 40 At the 6-week follow-up, there were no 6 months after (red) surgery. *Not significant. The patients assessed, as n (%) failures; at 3 months, three women reported differences in QoL scores were highly significant for further improvement of their condition all domains (Wilcoxon matched pairs test, P < 0.001) Result 6 weeks 3 months 6 months from ‘improved’ to ‘cured’ and four except for general health perception (GH). The Cured 34 (85) 32 (80) 30 (75) reported deterioration of their SUI from domains of the KHQ are: II, incontinence impact; RL, Improved 6 (15) 7 (17.5) 6 (15) ‘complete cure’ to ‘improved’. Two ‘improved’ role limitation; PL, physical limitation; SL, social Failure 0 1 (2.5) 4 (10) women remained the same. One ‘cured’ limitation; PR, personal relationships; E, emotions; woman was reclassified as ‘failure’ because of SL/E, sleep/energy. urgency and urge incontinence at the 3- month follow-up, although a urodynamic 100 study showed no SUI or detrusor instability. other factors such as anaesthesia, pain or 90 80 She was treated with anticholinergic effects of local dissection influence voiding. 70 medication and physiotherapy, with some With the present study protocol the median 60 improvement of continence at the 6-month pain score was low, so pain was unlikely to be 50 review, but was still considered a failure, as the cause of early emptying difficulty. 40 her improvement was less than half. 30

The present data also show that, although Mean Domain Score 20 At the 6-month follow-up, one woman 68% of the patients had their second void 10 reported further improvement of her within 6–10 h after surgery, only 20% had 0 condition and she was reclassified as ‘cured’, their first void within 5 h, and 10% took GH* II RL PL SL PR E SL/E and one had mild worsening of her >10 h for their first void. If the threshold of KHQ Domains continence from ‘cured’ to ‘improved’. Five EE for discharge were reduced to 50%, then women remained unchanged, as ‘improved’. 60% of patients could have been discharged. Three more women were reclassified as However, we do not know if an EE of ≥50% is would not be suitable for discharge as day- failures after being reported as ‘cured’ at an acceptable threshold. The implications of cases. This is almost certainly because of the 6-week and 3-month follow-up. Two these findings for a typical day-surgery unit higher applied sling tension resulting in outlet had pure SUI and a third had pure detrusor open from 08.00 to 17.00 hours is that a obstruction. instability on urodynamic study. At the patient will have only 7 h after surgery in 6-month follow-up, 10 (25%) women which to void efficiently (allowing 2 h for Difficulty in bladder emptying after anti- reported persistent urgency and two (5%) preparation, surgery and recovery). From the incontinence surgery is easily characterized women developed de novo urgency. QoL present data, only four patients (10%) would by measuring the EE. The advantage of measures showed significant improvements be suitable for discharge at 17.00 hours, using EE as the prime measure of emptying in four of the eight domains of the SF-36 and and even if we had chosen a 50% EE as the difficulty is its simplicity and clinical relevance in seven of the eight domains of the KHQ at threshold, only 14 (35%) would be suitable soon after surgery. In contrast to the PVR, the 6-month follow-up (Fig. 3). for discharge on the same day. In the USA, which measures the amount of urine left after medical insurance considerations dictate a void, the EE takes the pre-void bladder <24 h as a threshold for inpatient ambulatory volume into account and is a more objective DISCUSSION surgery; applying that threshold to the way to quantify bladder-emptying difficulty. present patients, then 28 (70%) would have Advances in day-case anaesthesia and been eligible for discharge. Although Ulmsten et al. [15,16] reported that development of minimally invasive surgical most of their patients were discharged one techniques can be expected to continue. Day- A standardized method to measure day after an ambulatory procedure for SUI case surgery has presented a new set of intraoperative sling tension has not yet been (tension-free vaginal tape), Nilson et al. [17] challenges and goals for surgeons. The developed, although many techniques have reported that 80% of the women in their success of day-case surgery depends largely been proposed. These techniques are limited study were discharged on the afternoon of on the nature of the surgery, effective control because of technical difficulties [12,13] or the operation. In another study [18], 17 of 40 of postoperative pain and minimization of because of the questionable relevance of (43%) patients were discharged on the same anaesthetic side-effects, e.g. sedation, nausea procedures such as cough-stress test under day after a porcine dermal sling procedure. In and vomiting. regional anaesthesia. Moreover, in a study by all three studies there was no information on Wang and Chen [14], nearly 45% of patients the time required to first spontaneous void In the present study, 40% of patients emptied were unable to leak urine during a cough test and EE. The difference in the present study for efficiently and were suitable for discharge in the dorsal lithotomy position. As there is no day-case discharge rate reflects our stricter within 10 h of surgery. Only 10% of the exact method of determining how much study protocol and discharge criteria. patients had efficient emptying in their first tension to put on the sling during surgery, the void (Fig. 1). This shows that even with a loose surgeon must rely chiefly on experience to There is wide variation in the use of sling, most patients have early emptying make the judgement [3,4]. However, we found catheters and vaginal packs after sling difficulty. This suggests that either even a that patients with ISD were unlikely to surgery. Although we used a vaginal pack for loose sling is potentially obstructive or that achieve early efficient emptying and thus only 3 h, only two patients reported a small

DAY-CASE SLING SURGERY FOR STRESS URINARY INCONTINENCE

amount of vaginal bleeding soon after minimally invasive day-case sling could erosions after synthetic pubovaginal surgery and neither required intervention. expect a significant risk of an overnight stay, slings: diagnosis and management which might be an unacceptable proposition strategy. Urology 2000; 56: 589–94 Only 10% of the present patients were willing because of increased unplanned hospital 7 Abrams P, Cardozo L, Fall M et al. The to use CISC within 10 h after surgery and readmission. Second, early postoperative standardisation of terminology in lower required assistance from a nurse. More bladder emptying inefficiency is the main urinary tract function: report from the extensive preoperative training might limiting factor; excluding patients with ISD standardisation sub-committee of the improve early ability with CISC and this might and possibly decreasing the EE threshold to International Continence Society. Urology in turn improve the suitability for discharge. 50% would improve eligibility for discharge. 2003; 61: 37–49 Furthermore, sedative side-effects of Third, postoperative pain is not a limiting 8 Kelleher CJ, Cardozo LD, Khullar V, anaesthetic drugs are also an important factor for day-case patient discharge. Finally, Salvatore S. A new questionnaire to hindrance to early patient mobility and CISC. short-term results with the porcine dermal assess the quality of life of urinary Another possible solution would be to sling are similar to those with the autologous incontinent women. BJOG 1997; 104: discharge patients with a short-term fascial sling. 1374–9 indwelling catheter and bring them to the 9 Ware JE, Snow KK, Kosinski M, Gandek day-surgery unit after 2–3 days. This would ACKNOWLEDGEMENTS B. The SF-36 health survey manual and obviously mean another hospital visit and interpretation guide. Boston: Health extra cost. Moreover, many of the present This work was supported by educational grant Institute, New England Medical Centre, women were unwilling to go home with an from the National Institute of Health Sciences 1993 indwelling catheter on the day of surgery. (NIHS), Limerick, Ireland and Pfizer Sales 10 Haab F, Trockman BA, Zimmern PE, Ireland. Leach GE. Results of pubovaginal sling Opioid analgesia after surgery might be for the treatment of intrinsic sphincter associated with nausea, vomiting, increased CONFLICT OF INTEREST deficiency determined by questionnaire time to tolerate oral fluids, sedation and analysis. J Urol 1997; 158: 1738–41 urinary retention [19,20]. To avoid such None declared. Source of funding: National 11 Chaikin DC, Blaivas JG, Rosenthal JE, possible interference after surgery we used Institute of Health Sciences and Pfizer, Ireland. Weiss JP. Results of pubovaginal sling for NSAIDS instead of opioids. With our protocol, stress incontinence: a prospective postoperative pain was never a limiting factor REFERENCES comparison of 4 instruments for outcome for discharge. Only two patients (5%) were analysis. J Urol 1999; 162: 1670–3 unsuitable for discharge because of 1 Hunskaar S, Lose G, Sykes D, Voss S. 12 Kondo A, Kato K, Gotoh M et al. anaesthetic problems, and neither of these The prevalence of urinary incontinence Quantifying thread tension is of clinical emptied efficiently. in women in four European countries. use in Stamey bladder neck suspension: BJU Int 2004; 93: 324–30 analysis of clinical parameters. J Urol Using QoL questionnaires and physical 2 Blaivas JG, Groutz A. Urinary 1989; 141: 38–42 examination, overall SUI was cured or incontinence: pathophysiology, 13 Yamada T, Kura N, Kawakami S, improved in 90% of the present patients at evaluation, and management overview. In Watanabe T, Negishi T, Mizuo T. the 6-month follow-up. These cure rates are Walsh PC, Retik AB, Vaughan ED, Wein AJ Suburethral sling procedure for urinary similar to those of other published series. The eds, Campbells’ Urology, 8th edn, Vol. 2. stress incontinence. With special short-term overall cure rate using the Pelvicol Chap 27. Philadelphia: WB Saunders, reference to determination of tension of sling is comparable with that of the 2002: 1027–43 suspension from posturethrovesical angle autologous rectus fascia sling [21]. 3 Brady CM, Ahmed I, Drumm J, Flood measured by ultrasonography. Nippon HD. A prospective evaluation of the Hinyokika Gakkai Zasshi 1990; 81: 1351– The present surgery was carried out by one efficiency of early postoperative bladder 6 urologist with a special interest in this field, emptying after the Stamey procedure 14 Wang AC, Chen MC. Randomized and this might reduce the external validity. or pubovaginal sling for stress urinary comparison of local versus epidural This bias would rather reinforce our findings incontinence. J Urol 2001; 165: 1601–4 anesthesia for tension-free vaginal tape of limitations to the day-case sling surgery 4 Chaikin DC, Rosenthal J, Blaivas JG. operation. J Urol 2001; 165: 1177–80 approach. This was a prospective Pubovaginal fascial sling for all types of 15 Ulmsten U, Henriksson L, Johnson P, observational study; the objective was to stress urinary incontinence: long-term Varhos G. An ambulatory surgical provide preliminary estimates of variables and analysis. J Urol 1998; 160: 1312–6 procedure under local anesthesia for to generate hypotheses for testing in larger 5 Leach GE, Dmochowski RR, Appell RA treatment of female urinary incontinence. multicentre randomized trials where practical. et al. Female Stress Urinary Incontinence Int Urogynecol J Pelvic Floor Dysfunct Calculations of sample sizes based on this Clinical Guidelines Panel summary report 1996; 7: 81–5 study can be used for further trials. on surgical management of female stress 16 Ulmsten U, Johnson P, Rezapour M. urinary incontinence. The American A three-year follow up of tension free The present findings have four implications Urological Association. J Urol 1997; 158: vaginal tape for surgical treatment of for clinical practice. First, only 40% of patients 875–80 female stress urinary incontinence. BJOG are suitable for Pelvicol day-case sling 6 Clemens JQ, DeLancey JO, Faerber GJ, 1999; 106: 345–50 surgery; even patients considered ideal for a Westney OL, McGuire EJ. Urinary tract 17 Nilsson CG, Kuuva N. The tension-free

vaginal tape procedure is successful in the not ready to go home. In this paper the 5. If you are wearing pads, how many do you majority of women with indications for authors identiﬁed only 40% of patients who use in 24 h? surgical treatment of urinary stress were suitable for day-case sling surgery, but incontinence. BJOG 2001; 108: 414–9 this would not have been the case had the 6. How often do you urinate during the day? 18 Barrington JW, Edwards G, women been taught CISC or sent home with A. More often than once every hour Arunkalaivanan AS, Swart M. The use of an indwelling catheter. What the authors B. Every 1–2 h porcine dermal implant in a minimally showed is that voiding function returns C. Every 3–4 h invasive pubovaginal sling procedure for gradually during the ﬁrst few hours after D. Less often than once every 4 h genuine stress incontinence. BJU Int inserting a sling, and that bladder emptying 2002; 90: 224–7 improves quite rapidly. 7. How many times per night do you wake up 19 Breitfeld C, Peters J, Vockel T, Lorenz from sleep to urinate? C, Eikermann M. Emetic effects of LINDA CARDOZO morphine and piritramide. Br J Anaesth 8. If your incontinence returned after sling 2003; 91: 218–23 operation, how long after surgery was it? 20 Cepeda MS, Alvarez H, Morales O, Carr APPENDIX DB. Addition of ultralow dose naloxone to 9. If your incontinence returned after sling postoperative morphine PCA: unchanged Postoperative questionnaire [10] operation, how did it happen? analgesia and opioid requirement but A. Gradually over months decreased incidence of opioid side effects. 1. How much leakage of urine do you have B. Suddenly over a few days or week Pain 2004; 107: 41–6 now? 21 Cross CA, Cespedes RD, McGuire EJ. Our A. None 10. Do you currently use a catheter to empty experience with pubovaginal slings in B. Mild your bladder? patients with stress urinary incontinence. C. Moderate A. Yes J Urol 1998; 159: 1195–8 D. Severe B. No

Correspondence: Hugh D. Flood, Department 2. If you do now leak urine, how does it 11. Do you get usually the urge to urinate? of Urology, Mid-Western Regional Hospital usually occur? A. Yes and National Institute of Health Sciences, A. Mostly with coughing, sneezing or physical B. No University of Limerick, Ireland. activity e-mail: hfl[email protected] B. Usually not with physical activity, but 12. Since your surgery, do you have problems leakage occurs suddenly with an urge to with pelvic pain? Abbreviations: SUI, stress urinary urinate before it can be controlled A. Yes incontinence; ISD, intrinsic sphincter C. Leakage of urine often occurs in both of the B. No deficiency; PVR, postvoid residual urine situations described above volume; KHQ, King’s Health Questionnaire; D. Not sure when leakage occurs 13. If you are having intercourse, is it painful? SF-36, The 36-item Short-Form Health A. Yes Survey; QoL, quality of life; CISC, clean 3. How much improved is your urinary leakage B. No intermittent self-catheterization; EE, bladder compared to before sling operation? C. Not sexually active emptying efficiency; VAS, visual analogue a. 100% better scale; VV, voided volume. b. 90% better 14. Overall, how satisfied are you with the c. 80% better results of your sling surgery? EDITORIAL COMMENT d. 70% better 0_1_2_3_4_5_6_7_8_9_10 e. 60% better Not satisfied The authors concluded that only 40% of f. 50% better Very satisfied patients were suitable for Pelvicol day-case g. 40% better sling surgery. Unfortunately the underlying h. 30% better 15. Knowing what you know now, would you principle reported here is not new. Sling i. 20% better have the sling surgery again? surgery (even conventional sling surgery) has j. 10% better A. Yes been used on a day-case basis, and usually is k. the same B. No in North America, and the introduction of l. worse than before the surgery mid-urethral tapes has meant that a very 16. Would you recommend the sling surgery large proportion of sling surgery is on day- 4. Do you wear any protective pads for urine to your friend? cases. To facilitate this, patients may need to leakage? A. Yes learn CISC or be prepared to go home with an A. Yes B. No indwelling catheter; sometimes patients are B. No C. Not sure.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article STEREOLOGICAL ANALYSIS OF SYNTHETIC SLINGS THIEL et al.

A stereological analysis of ﬁbrosis and inﬂammatory reaction induced by four different synthetic slings

MARCELO THIEL, PAULO C. RODRIGUES PALMA, CÁSSIO L.Z. RICCETTO, MIRIAM DAMBROS and NELSON R. NETTO Jr Division of Urology, Universidade Estadual de Campinas, and Hospital Estadual Sumaré, Campinas, SP, Brazil Accepted for publication 22 November 2004

OBJECTIVES copolymers and monofilament polypropylene and polylactic acid copolymers than before (PLP) implanted the abdominal subcutaneous but it was less than with PLP and silicone, To analyse quantitatively, using stereological layer; while a control group of 10 rats had which again were no different. During this methods, the density of the collagen fibres dissection and suturing with 5/0 Nylon in the period the inflammatory reaction induced by induced by four types of sling materials, and abdominal subcutaneous layer, as used to fix SIS was greater. The stereological analysis verify by a histopathological analysis the the strips in the other rats. Picro-Sirius indicated that collagen fibres induced by corresponding inflammatory reaction, as staining was used to assess collagen polycaprolactone and polylactic acid fibrosis secondary to sling implantation is fibres, and haematoxylin-eosin for the copolymers and PLP were less dense (61% considered responsible for restoring urethral histopathological study. At 7, 30 and 90 days and 65%, respectively), and significantly less support and re-establishing continence in after surgery, 10 rats from each group were than with silicone (85%) and SIS (86%). women with stress urinary incontinence, and killed and assessed. new synthetic materials that promote CONCLUSION adequate fibrosis with the least intensity and RESULTS duration have been proposed to substitute PLP was the best nonabsorbable material as it the aponeurotic sling. After 7 days all the materials induced a induced a less intense inflammatory reaction moderate inflammatory reaction that did not than the other tested materials. As porcine SIS MATERIALS AND METHODS differ from that in the control group. At 30 was completely absorbed the intense fibrosis days there was no difference between the induced is useful, as it is exclusively The study comprised 70 isogenic white Wistar control and polycaprolactone and polylactic responsible for the urethral support later after rats divided into three groups: group A (30 acid copolymers, having the least surgery. rats) had 8 ¥ 4 mm strips of silicone and inflammatory reaction. PLP and silicone porcine small intestine submucosa (SIS) produced a moderate inflammatory reaction, KEYWORDS implanted in the abdominal subcutaneous while the porcine SIS induced a more intense tissues; group B (30 rats) had 8 ¥ 4 mm strips reaction. At 90 days there was a more intense fibrosis, sling, materials, stress urinary of polycaprolactone and polylactic acid inflammatory reaction in polycaprolactone incontinence

INTRODUCTION compared the intensity of fibrosis produced a controlled environment (25 ± 2 ∞C; exposed by different materials. Fibrosis is considered a to a daily light cycle for 12 h) and with free Suburethral slings initially used for treating good indicator of suburethral support, that access to water and food. The study was stress urinary incontinence were created from substitutes for weakened natural ligaments conducted in accordance with the Guide for grafts taken from patients, and promoted and promotes the coaptation of the urethra the Care and Use of Laboratory Animals organized fibrosis that reinforced the under stress. published by the US National Health Institute sphincter mechanism through improved (Publication 85–23, revised 1985) and the suburethral support [1]. Currently, several The purpose of the present study was to Animal Protection Committee of our materials are available [1,2] for this purpose, experimentally assess the intensity of fibrosis University approved the protocol. e.g. mono- and multifilament polypropylene based on the volumetric density of the (PLP) mesh, porcine small intestinal collagen fibres induced by four different Four types of material were compared; PLP, submucosa (SIS), human dermal matrix, and materials used in the manufacture of slings, porcine SIS, silicone, and copolymers of other materials being continuously developed. and to qualitatively determine the polylactic acid and polycaprolactone (GAL). Some of these materials have been tested and characteristics of the inflammatory reaction The animals were randomly divided into three rejected, e.g. PTFE and bovine pericardium. that occurs during its integration with the groups and had materials implanted into the host tissue. abdominal submucosa, as follows: group A The material that provides the best adequate (30 rats) had 8 ¥ 4 mm strips of silicone and long-lasting suburethral support with a low MATERIALS AND METHODS porcine SIS; group B (30 rats), strips of GAL risk of local complications, e.g. sclerosis, and PLP of the same dimensions, and a infection and extrusion, has still not been The study comprised 70 female virgin Wistar control group (10 rats) had dissection of the defined. To date no study has objectively rats (8 weeks old, mean 250 g), maintained in subcutaneous tissue and suturing with

THIEL ET AL.

5/0 Nylon. The strips were attached in all the TABLE 1 The degree of inflammatory infiltration (absent/mild/moderate/severe) for each material after 7, animals at their extremities to the superficial 30 and 90 days. At 7 days there was no significant difference among the groups, at 30 and 90 days the fascia of the abdomen with two 5/0 Nylon SIS produced the most intense inflammatory reaction sutures.

Inflammatory infiltrate, n at The rats were anaesthetized with a solution of Group 7 days 30 days 90 days chloral hydrate injected into the caudal vein. The animals were then placed in the dorsal Control 0/2/7/1 1/8/1/0 7/3/0/0 decubitus position, their abdomens shaved A SIS 0/1/8/1 0/1/4/5 0/4/2/4 and antisepsis applied as a solution of A silicone 0/3/6/1 0/4/5/1 0/6/4/0 polyvinylpyrrolidone. A 5-cm median incision B GAL 0/2/5/3 0/7/3/0 4/4/2/0 was made in the lower abdominal region and B PLP 0/2/5/3 0/3/7/0 2/3/5/0 dissected up to the subcutaneous tissue. After implanting and fixing the strips, the incision was sutured with 5/0 Nylon. in this case). The quantitative measure was inflammatory reactions. Of all the materials The animals in Groups A and B were divided obtained using a light microscope and the tested, SIS produced the most intense into subgroups of 10 animals that were killed fibres counted at ¥400 magnification in 10 inflammatory reaction. after 7, 30 and 90 days, using an intravenous random microscopic fields in each group [4]. injection with sodium thiopental. The animals After 90 days, the implanted materials were then totally dissected, which included The intensity of the inflammation was produced significant differences (P < 0.001; the skin, subcutaneous layer, superficial assessed statistically at each sample time and Table 1). The control group had the least fascia, musculature and deep fascia. These expressed as the absolute frequency, using reaction, followed in increasing order by GAL, were stretched on a support to avoid nonparametric tests as this variable was PLP and silicone, the last two being very retraction during specimen processing. measured using a nominal (infiltration) or similar. SIS induced a more intense ordinal (the rest) scale. Because comparing inflammatory reaction similar to that at Picro-Sirius staining was used for the the materials produced independent samples 30 days. histological analysis of fibrosis, and for the (obtained from different rats), the Kruskal– remaining histological features the slides Wallis test was used to assess differences The stereological assessment was used only at were stained with haematoxylin and eosin. between the variables and the chi-square 90 days to determine collagen deposited The inflammatory reaction was qualitatively test to verify the hypothesis, involving around each implant (Fig. 1). This showed that classified according to its intensity as absent contingency tables (presence or absence of all the implants induced changes in the (no inflammation or £5% of the slide area), inflammation). ANOVA was used to evaluate distribution of collagen fibres in the light (inflammatory reaction in 5–25% of the the volumetric density of the collagen fibres abdominal walls, and there were significant area), moderate (25–70% of the area) and around the implanted material; in both tests differences in the volumetric density of the intense (≥70% of the area). All the samples P < 0.05 was considered to indicate collagen fibres around the implants. The were evaluated by the same pathologist. significant differences. collagen fibres induced by SIS occupied 86% of the area of the abdominal wall around the Collagen fibres were quantified using the implant. Likewise silicone induced collagen stereological method in rats killed at 90 days, RESULTS fibres in 85% of the total area, PLP in 65% and to determine the three-dimensional features GAL in 61%. of the anatomical structures based on bi- There was no significant difference in the dimensional sections. This theory is based on intensity of the inflammatory reaction DISCUSSION Delesse’s principle [3], which states that the induced by the various materials in rats relationship between the surface area of the killed after 7 days (P = 0.784) (Table 1). All the Slings are used to provide urethral support organ and the section of the structure is materials produced a moderate reaction, even in patients with stress urinary incontinence, the same as that between the volume of the in the control group. Intense inflammatory because the pubourethral ligaments that structure and volume of the entire organ. The reactions were more frequent in group B, but usually provide this support are weak [5]. volumetric density of collagen fibres was not significantly so. Therefore, long-lasting suburethral support quantified stereologically by superimposing depends on the biomechanical characteristics the M-42 grade system (Tonbridge, UK) on the There were significant differences in all the of the material used to make the sling, as well morphological image of the slide. The rats assessed after 30 days (P < 0.001; as its capacity for inducing a reaction in the volumetric density corresponds to the relative Table 1), most of the rats (86%) having an host that produces fibrotic support, which concentration of the structure or tissue of the inflammatory reaction that was either represents the main element of long-term study sample. The formula V = (Pp/Pt) ¥ 100% moderate or mild. There was no significant support, especially in biological or absorbable was used to calculate the volumetric density difference between the control and GAL, in synthetic slings [6]. (V) of the collagen fibres, where Pp is the which there was a less intense inflammatory number of points in the structure (collagen reaction, and no differences between the Slings not only fulfil physiopathological fibres) and Pt the number of points tested (42 silicone and PLP implants, both with moderate requirements but are also less invasive and

STEREOLOGICAL ANALYSIS OF SYNTHETIC SLINGS

FIG. 1. Microscopic aspect of the implants after 90 days. SIS, silicone, PLP and GAL induced collagen ﬁbres in antibiotics against anaerobes, and antisepsis 86%, 85%, 65% and 61% of the analysed area, respectively. (A) porcine SIS; (B) silicone; (C) monoﬁlament PLP; with chlorhexidine acetate, there were fewer (D) GAL (haematoxylin and eosin, ¥400). complications. There was no relationship between rejection and sling material, age or ABconcomitant prolapse [10]. Except for the usual antisepsis procedures, no prophylactic antibiotics were used in the present study, to Collagen fibre silicone avoid any interference in the diagnoses of subsequent infections.

Collagen fibre The main characteristic of porcine SIS is its behaviour as a collagen matrix for the growth of host tissue. After a prolonged SIS period it induces remodelling and complete substitution of the surrounding recipient tissue, differing from simple random post- traumatic ﬁbrosis. Preclinical studies of this biomaterial indicated that it has a greater C D resistance to bacterial infection than synthetic grafts [11], because of rapid Collagen fibre neovascularization soon after implanting [12]. GAL A SIS pubovaginal sling was used in 152 patients [13]; after 4 years of follow-up, 93.4% were still continent. However, 50.7% polypropylene Collagen fibre had urge incontinence, and the frequency was variable and persistent in some until much later. There were no reports of infection, erosion or rejection.

A sling material developed using biodegradable polycaprolactone and polylactic acid copolymers with a structure similar to absorbable surgical suture was also help the patient to rapidly return to normal is no consensus about the safest material. analysed. The substitution of the host fibrous activities, with a favourable outcome in the Theoretically, it is recommended that any tissue during scarring is a characteristic of medium-term. A previous study [7] aimed to sling should induce a minimum inflammatory this material. A previous unrandomized study determine the biomechanical characteristics reaction related to the capacity of promoting assessed the use of this sling in 11 patients of slings, including those of synthetic (Gore- urethral support, which may depend to and an early follow-up assessment showed TexTM and PLP), cadaveric (decellularized and greater or smaller degree on local fibroid that eight of the patients were continent, in frozen skin, g-ray irradiated fascia) and reaction [8]. A previous study comparing accordance with the subjective assessment autologous materials (skin, rectus fascia and the changes in patients who had autologous, criteria [14]. vaginal mucosa). When the entire strip of aponeurotic and PLP slings implanted material was tested, the cadaveric fascia had concluded that although the outcomes Although silicone has been widely used in the best performance, followed by the related to urinary incontinence were prostheses for several years, very little is synthetic materials and last the autologous similar, the synthetic material triggered known about its behaviour when used in tissues (P < 0.05). When used as a patch, the a greater reaction in the local tissue, slings. Only one previous study has reported a synthetic materials were significantly better which was probably the result of a delayed case of a urethrovaginal fistula attributed to than the autologous and cadaveric fascia hypersensitive immune reaction that could the use of silicone [15]. (P < 0.05). Although this analysis is important, be extensive or not, depending on the it cannot be considered conclusive, as the biocompatibility of the material being used The present histopathological assessment of final biomechanical characteristics of the [9]. the samples showed clearly that the intensity sling may significantly change after of the inflammatory reaction induced by the incorporation by the host. As there are many To identify factors associated with synthetic various implant materials differed. The materials now available with several different sling rejection, 428 sling were implanted by analysis at 7 days represented the early characteristics, the present study aimed to gynaecologists who used PTFE or PLP slings. reaction to the implant, while those at 30 and verify the tissue reactions induced by each The minimum follow-up in these 386 women 90 days mimic late and final integration material after implantation. Nonabsorbable was 24 months. Rejection or associated stages, respectively. The results showed that synthetic materials generally present a symptoms occurred in 47 women (12.2%). during the first 7 days all materials induced greater risk for urethral erosion, but there After introducing preoperative prophylactic a similar response and did not differ

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significantly from the control group, but at 30 use of silicone in slings characterize it as procedure, an indispensable characteristic for and 90 days this changed. After 30 days, the having the highest rate of graft complications a sling that is completely absorbed after some response to GAL was similar to that in the and rejection [16], and a high rate of urethral time. control for the inflammatory reaction, or vaginal wall erosion, abscess or pseudocyst suggesting that there are unlikely to be formation involving the graft [18]. These Currently, more intensive research aimed at inflammatory exudates and extrusion during findings are attributed to the surface reducing complications is being conducted in this phase. PLP and silicone produced a more characteristics; silicone is smooth and not the area of implantable urinary tract intense reaction than in the control and GAL, porous, contrary to polypropylene mesh. biomaterials, whether for use in endoluminal but less intense than that induced by SIS. Nonetheless, the present analysis indicated catheters, slings or even for partial or total After 90 days, there was a more intense that most of these features in clinical use are organ substitution. With the development of reaction to all implanted materials; the probably caused by the intense inflammatory in vitro cell culture techniques and tissue stereological analysis showed that GAL response induced by the graft and the recovery through gene therapy, research on had the least capacity for stimulating the consequent local exudation and necrosis this aspect has changed recently. Therefore, production of collagen fibres. This is a that make the site more susceptible to similar experimental and prospective studies long-term absorbable material, and thus complications. Despite the high rejection on biocompatibility have become increasingly this characteristic represents a potential rates for this type of implant, the same necessary before these materials can be made disadvantage because the main element that studies report high cure rates for urinary available for general use. Hence, biomaterials provides long-lasting support is the fibrous incontinence during a prolonged follow-up, may be associated in future with a low risk of tissue newly formed in response to the even in women who have had the sling infection, erosion, mineral deposition, implant. removed, and in those who had early removal migration of particles, secondary reactions, of the implant at 4 weeks after initial surgery but with better durability. PLP stimulated an intermediate inflammatory [18]. These apparently contradictory data are reaction, greater than that of GAL and less explained by the intense deposition and In conclusion, urethral support, the main than that of SIS and silicone. As it is currently organization of collagen fibres around the objective of any sling, depends on its specific the most used material, it is also the most graft, as noted here. These findings also resistance, determined by its physicochemical studied for use in slings. Despite there being reinforce the idea that acute stimulation of properties and the response induced in the several clinical studies they rarely discuss fibrosis around the implant is one of the host by the sling, represented by new local aspects related to sling integration and factors responsible for the effectiveness of fibrous tissue. Therefore, the lower the reactions induced in the host tissue. A recent this technique, even with materials associated persistence and specific resistance of the study [16] conducted on humans used tissue with a high rate of complications after material, the greater its capacity for inducing biopsy to compare polypropylene with surgery. a resistant support at the site. From the another synthetic material, Mersilene, and present study, PLP and SIS represent materials verified minimal changes in the connective The most inflammation was provoked by that combine these characteristics in a tissue at the site, which was in accordance SIS; the stereological analysis indicated balanced and synergistic manner. The former with the findings of the present study. The that of all the tested materials, it was the is the most adequate nonabsorbable material advantage of using propylene instead of the greatest stimulus for the formation of because it induces an inflammatory reaction other synthetic materials is its low rate of collagen fibres (86% volumetric density), a that is less intense than with other materials. complications, which can be explained by the little more than that of silicone and much As the SIS was completely absorbed after low intensity of tissue reaction to the implant, more intense than the GAL or monofilament some time, the intense fibrosis is as confirmed here. Considering the good PLP. Although there are few clinical studies advantageous, as it is responsible for urethral clinical results with PLP slings and the on this material, the results showed that support after surgery. Thus, in relation to incorporation of this material, another treatment with this type of sling was highly the histopathological and stereological conclusion suggested is its independence effective and had the lowest complication characteristics of the host integration from newly formed local collagen in the long- rate [13]. This material can be considered process, PLP and SIS are the best alternatives term maintenance of continence. Hence, it an allograft, representing the only natural for manufacturing slings, and better than can be inferred that the nonabsorbable PLP material analysed in the present study. The silicone and GAL. mesh is important in late postoperative SIS surface is wrinkled and has pores, urethral support. There has been speculation characteristics that differentiate it from about the possible influence of PLP mesh silicone and more like PLP. However, it differs pores (quantity and dimension) in relation to from the latter because after promoting the ACKNOWLEDGEMENTS the predisposition to local infection and induction of new collagen tissue by the host biocompatibility [17]. tissue, it is completely absorbed later. The This study was supported by grants from importance of these differences in clinical Coordenação de Aperfeiçoamento de Pessoal The degree of inflammatory reaction induced practice should be assessed by clinical assays de nível superior (CAPES) and the Foundation by silicone is similar to that of PLP. before reaching a conclusion. Nevertheless, for Research Support, State of Sáo Paulo – Nevertheless, the stereological analysis this material produced the highest stimulus FAPESP (Proc 01/11205–5). This paper forms showed that the capacity to promote fibrosis for the formation of collagen fibres around part of a thesis submitted to the Department around the graft (mean 85% volumetric the graft, that might guarantee long-term of Surgery of the Faculty of Medical Sciences, density) was intense. Overall, reports on the maintenance of continence after the State University of Campinas, UNICAMP, in

STEREOLOGICAL ANALYSIS OF SYNTHETIC SLINGS

partial fulfilment of the requirements for the 7 Choe JM, Kothandapani R, James L, 14 Palma PCR, Riccetto CLZ, Herrmann V, PhD degree in surgery. Bowling D. Autologous, cadaveric, and Thiel M, Dambros M, Netto NR Jr. synthetic materials used in sling surgery: Sabre. experiência inicial com um novo comparative biomechanical analysis. modelo de sling sintético autofixável e CONFLICT OF INTEREST Urology 2001; 58: 482–6 absorvível, para tratamento da 8 Bemelmans BL, Chapple CR. Are slings incontinência urinária de esforço None declared. now the gold standard treatment for the feminina. Urodin Uroginecol 2002; 5: management of female urinary stress 14–20 incontinence and if so which technique? 15 Shobeiri SA, Echols KT, Franco N. Sinus REFERENCES Curr Opin Urol 2003; 13: 301–7 formation after insertion of a silicone- 9 Debodinance P, Cosson M, Burlet G. coated suburethral sling. Int Urogynecol J 1 Cardozo L, Bidmead J. Sling Tolerance of synthetic tissues in touch Pelvic Floor Dysfunct 2003; 14: 356–7 techniques in the treatment of genuine with vaginal scars: review to the point of 16 Morgan JE, Heritz DM, Stewart FE. stress incontinence. BJOG 2000; 107: 287 cases. Eur J Obstet Gynecol Reprod The polypropylene pubovaginal sling 147–56 Biol 1999; 87: 23–30 for the treatment of recurrent stress 2 Morgan TO Jr, Westeney L, McGuire 10 Persson J, Iosif C, Wolner-Hanssen P. urinary incontinence. J Urol 1995; 154: EJ. Pubovaginal sling: 4-year outcome Risk factors for rejection of synthetic 1013–4 analysis and quality of life assessment. suburethral slings for stress urinary 17 Staskin DR, Plzak L. Synthetic slings. J Urol 2000; 163: 1845–8 incontinence: a case-control study. Obstet pros and cons. Curr Urol Rep 2002; 3: 3 Delesse M. Procédé mécanique pour Gynecol 2002; 99: 629–34 414–7 déterminer la composition des roches. 11 McGuire EJ, Lytton B. Experience with 18 Duckett JRA, Constantine G. Ann Mines 1848; 13: 379–88 pubovaginal slings for urinary Complications of silicone sling insertion 4 Hally A. A counting method for incontinence at the University of for stress urinary incontinence. J Urol measuring the Volumes of tissue Michigan. J Urol 1987; 138: 525–6 2000; 163: 1835–7 components in microscopical sections. 12 Palma P, Dambros M, Riccetto C, Quart J Microsc Sci 1964; 105: 503–17 Herrmann V, Netto NR. Pubovaginal Correspondence: Marcelo Thiel, Rua Barão de 5 Petros PE, Ulmsten U. An integral theory sling using the porcine small intestine Jaguara, 601, apto 122, Campinas SP Brazil of female urinary incontinence. Acta submucosa for stress urinary CEP 13015–001. Scand Obstet Gynecol Suppl 1990; 153: incontinence. Braz J Urol 2001; 27: 483–8 e-mail: [email protected] 7–31 13 Rutner AB, Levine SR, Schmaelzle JF. 6 Cardozo L, Bidmead J. Sling techniques Processed porcine small intestine Abbreviations: SIS, porcine small intestinal in the treatment of genuine stress submucosa as a graft material for submucosa; PLP, multifilament incontinence. Br J Obstet Gynecol 2000; pubovaginal slings. durability and results. polypropylene; GAL, copolymers of polylactic 107: 147–56 Urology 2003; 62: 805–9 acid and polycaprolactone.

Blackwell Science , LtdOxford , UKBJUBJU International1464 -410XBJU International 95

Original Article SACRAL MAGNETIC STIMULATION FOR CPPS IIIB LEIPPOLD et al.

Sacral magnetic stimulation in non-inﬂammatory chronic pelvic pain syndrome

THOMAS LEIPPOLD, RAETO T. STREBEL, MIRJAM HUWYLER, HUBERT A. JOHN, D. HAURI and DANIEL M. SCHMID Department of Urology, University Hospital Zurich, Switzerland Accepted for publication 29 November 2004

OBJECTIVES and quality-of-life index were determined CONCLUSIONS before and after treatment. To prospectively evaluate sacral magnetic High-frequency sacral magnetic stimulation high-frequency stimulation as a treatment RESULTS in patients with CPPS IIIB only reduces option for patients with non-inﬂammatory pain during stimulation, with no sustained chronic pelvic pain syndrome (CPPS, category All patients tolerated the stimulation well relief of symptoms. Therefore, intermittent IIIB). and 12 of 14 reported agreeable sensations sacral magnetic stimulation cannot be during stimulation. There were no recommended as a treatment option for PATIENTS AND METHODS complications; only one patient did not CPPS IIIB. complete the treatment course. The mean Fourteen men with CPPS IIIB were treated (range) total NIH-CPSI score did not change KEYWORDS with high-frequency sacral magnetic with treatment, at 27 (18–38) before and stimulation, with 10 treatment sessions 27 (4–40) after treatment. Moreover, there chronic pelvic pain syndrome, chronic once a week for 30 min at a frequency of was no sustained effect on the mean scores prostatitis, sacral magnetic stimulation 50 Hz. The National Institutes of Health for pain, micturition complaints or quality of Chronic Prostatitis Symptom Index (NIH-CPSI) life.

INTRODUCTION prostatitis [7,8]. Non-inflammatory CPPS PATIENTS AND METHODS (according to NIH definition, CPPS IIIB) is Pelvic pain is the predominant symptom in characterized by a painful syndrome of the From September 2003 to May 2004, 14 men patients with chronic prostatitis. In 1995, pelvis with no evidence of inflammation in (mean age 49 years, range 26–65) and the American National Institute of Diabetes prostatic secretions or seminal fluid [9]. with a clinical diagnosis of CPPS IIIB were and Digestive and Kidney Diseases Working Usually patients present with protracted prospectively studied, after being evaluated Group on prostatitis proposed the term pelvic pain, perineal discomfort and using the NIH-CPSI. The mean (range) chronic pelvic pain syndrome (CPPS) [1]. substantial LUTS. Most patients report a duration of prostatitis was 3 (1–8) years, and The new classification according to the history of multiple antibiotic treatments patients had consulted an average of two National Institutes of Health (NIH) supports with no improvement and, consequently, other urologists or general physicians. They the diagnosis and management of these have serious psychological disturbances had been treated with antibiotics for 10 patients, being: I, acute bacterial prostatitis; [10]. The NIH Chronic Prostatitis Symptom (4–18) weeks during their history of CPPS. II, chronic bacterial prostatitis; IIIA, Index (CPSI) is a validated tool to evaluate inflammatory CPPS; IIIB, non-inflammatory symptoms of pain, voiding and impact on Samples of the first-voided urine, midstream CPPS; IV, chronic asymptomatic prostatitis. quality of life [9]. urine, expressed prostatic secretion and It has been estimated that about half of men voided urine after massage were cultured. A have prostatitis at some time in their life To date, no evidence-based prostatic swab or first-void and midstream [2], and recently published epidemiological pathophysiological cause of CPPS IIIB has urine were tested for Chlamydia trachomatis, studies show that the prevalence is 5–12% been suggested, and thus many therapies Neisseria gonorrhoeae, Mycoplasma hominis [3,4]. have been proposed, some of them with a and Ureaplasma urealyticum. The men were doubtful rational basis. However, none of diagnosed with CPPS IIIB according to NIH Prostatitis is the most common reason for a them has shown any permanent major relief criteria [2], i.e. high-power microscopy man aged <50 years to consult a urologist, of symptoms. It is generally thought that (¥1000) of expressed prostatic secretion accounting for 8% of all urology visits in the CPPS IIIB is a neuromuscular disorder of the showed <10 leukocytes, bacterial growth was USA [5]. The effect on a patient’s quality of life pelvic floor/perineal complex [11]. Therefore, <104/mL of expressed prostatic secretion, and is substantial, with similarities to patients we determined the possible therapeutic effect seminal fluid showed no significant bacterial who have had a recent myocardial infarction of sacral high-frequency neuromodulatory growth and leukocyte counts. Urodynamic [6]. Bacterial infection of the prostate is the magnetic stimulation on patients with CPPS evaluation or anal rectoscopy were used when cause in only 5–10% of patients with chronic IIIB. indicated.

SACRAL MAGNETIC STIMULATION FOR CPPS IIIB

FIG. 1. placed on major nerves innervating the area The patient prone with the of pain. Novak and Mackinson [21] implanted magnetic stimulating coil placed peripheral nerve stimulators in 17 patients lumbosacrally. following injury to a peripheral nerve, with excellent results in five and a good response in six. Siegel et al. [22] showed that transforamenal S3 and S4 sacral nerve stimulation could have beneficial effects on the severity and frequency of chronic intractable pelvic pain; nine of 10 patients had a decrease in severity of pain at a median follow-up of 19 months. John et al. [23] introduced a high-frequency electrostimulation device to treat CPPS IIIB, with temporary success in 10 of 12 patients. Urethro-anal stimulation was applied once a week for 10 sessions. Peters and Konstandt Magnetic stimulation was applied with a MAG significantly decrease, from 6 (3–10) before to [24] showed a decrease in narcotic PRO X100 (Medtronic A/S, Skovlunde, 5 (3–9) after treatment (P = 0.226). The mean requirements by long-term sacral Denmark) device. The magnetic stimulating (range) quality-of-life scores showed no neuromodulation in 18 of 21 patients with coil was placed lumbosacrally on the patient beneficial effect, at 9 (6–12) before and 9.5 refractory interstitial cystitis using an while prone (Fig. 1), the final exact position of (3–12) after treatment. implanted device. the coil being defined by the patient reporting a crawling feeling and muscle contraction An electrical current through a coil induces a during magnetic stimulation in the area of DISCUSSION magnetic field and a changing magnetic field pain. Repetitive magnetic biphasic high- in turn induces an electric field. This physical frequency stimulation was delivered for 30 CPPS is a common and debilitating problem law can be applied to allow noninvasive min (50 Hz, 100 pulses in a train and an inter- that significantly impairs quality of life stimulation of the sacral roots using a train interval of 2 s). Patients had 10 [12–16], but no evidence-based therapies magnetic field. Based on the cited reports, treatment sessions once or twice a week. The are available. These patients usually we postulated that repeated sacral high- NIH-CPSI was determined before and after consult several physicians and are often frequency magnetic stimulation of afferent the 10 treatment sessions. treated with different unsuccessful antibiotic nerves supplying the pelvic floor and pelvic trials. Furthermore, they can experience organs might temporarily or permanently psychological problems and sexual relieve chronic pelvic pain. This hypothesis is RESULTS dysfunction. Absence from work is extensive, supported by the observation that electrical and some patients never return to work sacral neuromodulation is successful for CPPS IIIB was diagnosed in all 14 men; the [10]. However, the cause of CPPS remains treating urgency and frequency syndromes magnetic stimulation was well tolerated and unclear. Many procedures to treat CPPS or [25]. Similarly, Yamanishi et al. [26] there were no side-effects. Twelve of 14 chronic prostatitis have been reported; successfully treated six of eight patients with patients reported a distinct, agreeable and the International Prostatitis Collaborative mainly neurogenic urge incontinence, using crawling feeling in the area of pain during Network published a listing in order of priority sacral magnetic neuromodulation. stimulation. Thirteen men finished the 10 of therapies that have at least some evidence treatment sessions and one man stopped or theoretical basis for treatment [17]. The Patients with CPPS have an altered sensation after the fourth, as he was unwilling to pain-suppressive effect of low- (2 Hz) and of perineal pain elicited by heat, which might continue because the treatment was high- (50–100 Hz) frequency peripheral represent a C-fibre mediated effect [27]. ineffective. Only one patient (who completed electrical stimulation was evaluated in 1976 Equally, neurogenic and idiopathic forms the 10 treatment sessions) reported an by Andersson et al. [18] in patients with of bladder overactivity are thought to be improved NIH-CPSI score, from 19 before chronic pain in the legs or back. High- mediated by C-fibres [28,29]. In the present treatment to 4 afterward; in 12 patients there frequency electrical stimulation of afferent study, sacral magnetic neuromodulation in was no overall benefit. nerve fibres is hypothesized to control pain by patients with CPPS IIIB did not improve pain, modulating the transmission of pain impulses symptoms of micturition or quality of life. The mean total NIH-CPSI scores did not [19]. High-frequency stimulation was Although most patients reported agreeable change with treatment, but remained at a reported to be more successful, although the sensations during stimulation, this effect did similar level, with a mean (range) score of effect was short lasting. Campbell and Long not translate into a sustained relief of 27 (18–38) before treatment and 27 (4–40) [20] implanted nerve-stimulating devices for symptoms. Only one patient did not complete afterward. The mean (range) pain score did pain control in 33 patients with various the whole treatment course, although 12 of not change significantly, at 12.4 (6–20) before disabling chronic pain conditions; eight had 14 had no benefit from the sacral magnetic and 12.7 (1–19) after treatment. The mean excellent pain suppression and seven had stimulation. Presumably this low withdrawal (range) voiding-complaint scores did not intermediate success. The electrodes were rate can be explained by the ease of

LEIPPOLD ET AL.

application, the lack of side-effects and most 5 Collins MM, Stafford RS, O’Leary MP, chronic pain conditions. Acta Orthop importantly, the desire for cure of this Barry MJ. How common is prostatitis? A Scand 1976; 47: 149–57 debilitating condition. national survey of physician visits. J Urol 19 Wall PD, Melzack R. Textbook of Pain, 1998; 159: 1224–8 4th edn. Edinburgh: Churchill Livingstone Interestingly, in a pilot study, sacral magnetic 6 Wenninger K, Heiman JR, Rothman I, 1999 stimulation temporarily eliminated the pain in Berghuis JP, Berger RE. Sickness impact 20 Campbell JN, Long DM. Peripheral five patients with pudendal neuralgia, the of chronic nonbacterial prostatitis and its nerve stimulation in the treatment of effect lasting from 30 min to 56 days [30]. correlates. J Urol 1996; 155: 965–8 intractable pain. J Neurosurg 1976; 45: This pain-reducing effect might be explained 7 Weidner W, Schiefer HG, Krauss H, 692–9 by the different causes of the overlapping Jantos C, Friedrich HJ, Altmannsberger 21 Novak CB, Mackinnon SE. Outcome symptoms of CPPS and pudendal neuralgia. M. Chronic prostatitis: a thorough search following implantation of a peripheral By contrast, peripheral afferent electrical for etiologically involved microorganisms nerve stimulator in patients with chronic nerve stimulation produced no symptom in 1,461 patients. Infection 1991; nerve pain. Plast Reconstr Surg 2000; relief in patients with chronic prostatitis or 19(Suppl. 3): S119–25 105: 1967–72 intractable interstitial cystitis [31,32]. The 8 Krieger JN, McGonagle LA. Diagnostic 22 Siegel S, Paszkiewicz E, Kirkpatrick C, failure to obtain sustained symptom relief by considerations and interpretations of Hinkel B, Oleson K. Sacral nerve magnetic sacral stimulation in CPPS does not microbiological findings for evaluation of stimulation in patients with chronic exclude a role for high-frequency magnetic chronic prostatitis. J Clin Microbiol 1989; intractable pelvic pain. J Urol 2001; 166: neuromodulation in treating pain in general. 27: 2240–4 1742–5 Indeed, during stimulation patients reported 9 Litwin MS, McNaughton-Collins M, 23 John H, Ruedi C, Kotting S, Schmid DM, an agreeable feeling, i.e. less pain, so there Fowler FJ Jr et al. The National Institutes Fatzer M, Hauri D. A new high frequency might be some benefit from permanent of Health Chronic Prostatitis Symptom electrostimulation device to treat chronic stimulation with internal or external devices. Index: development and validation prostatitis. J Urol 2003; 170: 1275–7 The present results need to be interpreted of a new outcome measure. Chronic 24 Peters KM, Konstandt D. Sacral cautiously because of the small, although Prostatitis Collaborative Research neuromodulation decreases narcotic homogenous, patient population and the lack Network. J Urol 1999; 162: 369–75 requirements in refractory interstitial of a control group treated with a sham device. 10 Becopoulos T. Chronic prostatitis. Eur cystitis. BJU Int 2004; 93: 777–9 Urol Update Ser 1994; 3: 74–9 25 Bemelmans BL, Mundy AR, Craggs High-frequency sacral magnetic stimulation 11 Barbalias GA, Meares EM Jr, Sant GR. MD. Neuromodulation by implant for in patients with CPPS IIIB only reduces pain Prostatodynia: clinical and urodynamic treating lower urinary tract symptoms during stimulation without producing a characteristics. J Urol 1983; 130: 514–7 and dysfunction. Eur Urol 1999; 36: sustained relief of symptoms. Therefore, 12 Hitchcock LS, Ferrell BR, McCaffery M. 81–91 intermittent sacral magnetic stimulation The experience of chronic nonmalignant 26 Yamanishi T, Yasuda K, Suda S, cannot be recommended as a treatment pain. J Pain Symptom Manage 1994; 9: Ishikawa N, Sakakibara R, Hattori T. option in CPPS IIIB. 312–8 Effect of functional continuous magnetic 13 Latham J, Davis BD. The socioeconomic stimulation for urinary incontinence. CONFLICT OF INTEREST impact of chronic pain. Disabil Rehabil J Urol 2000; 163: 456–9 1994; 16: 39–44 27 Lee JC, Yang CC, Kromm BG, Berger RE. None declared. 14 Poulsen DL, Hansen HJ, Langemark Neurophysiologic testing in chronic pelvic M, Olesen J, Bech P. Discomfort or pain syndrome: a pilot study. Urology REFERENCES disability in patients with chronic pain 2001; 58: 246–50 syndrome. Psychother Psychosom 1987; 28 Fowler CJ, Jewkes D, McDonald WI, 1 National Institutes of Health Summary 48: 60–2 Lynn B, de Groat WC. Intravesical Statement. NIH/ NIDDK workshop on 15 Russo CM, Brose WG. Chronic pain. capsaicin for neurogenic bladder chronic prostatitis. Executive Summary. Annu Rev Med 1998; 49: 123–33 dysfunction. Lancet 1992; 339: 1239 Bethesda, Maryland, December 1995 16 Watt-Watson JH, Graydon JE. Sickness 29 Silva C, Ribeiro MJ, Cruz F. The effect of 2 Stamey T. Urinary tract infection in impact profile: a measure of dysfunction intravesical resiniferatoxin in patients males. In Stamey T ed. Pathogenesis and with chronic pain patients. J Pain with idiopathic detrusor instability Treatment of Urinary Tract Infections. Symptom Manage 1989; 4: 152–6 suggests that involuntary detrusor Baltimore: Williams & Wilkins, 1980: 342– 17 Nickel JC, Nyberg LM, Hennenfent M. contractions are triggered by C-fiber 9 Research guidelines for chronic input. J Urol 2002; 168: 575–9 3 Moon TD, Hagen L, Heisey DM. Urinary prostatitis: consensus report from the 30 Sato T, Nagai H. Sacral magnetic symptomatology in younger men. Urology first National Institutes of Health stimulation for pain relief from pudendal 1997; 50: 700–3 International Prostatitis Collaborative neuralgia and sciatica. Dis Colon Rectum 4 Rizzo M, Marchetti F, Travaglini F, Network. Urology 1999; 54: 229–33 2002; 45: 280–2 Trinchieri A, Nickel JC. Prevalence, 18 Andersson SA, Hansson G, Holmgren E, 31 Zurkirchen MA, Joller-Jemelka H, Tenti diagnosis and treatment of prostatitis in Renberg O. Evaluation of the pain G, Hauri D, John H. Peripheral afferent Italy: a prospective urology outpatient suppressive effect of different frequencies nerve stimulation in the treatment of practice study. BJU Int 2003; 92: 955–9 of peripheral electrical stimulation in chronic pelvic pain syndrome: a new

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therapeutic option? Eur Urol 2001; 39 Correspondence: Thomas Leippold, Abbreviations: CPPS IIIB, non-inﬂammatory (Suppl. 5): 13 Department of Urology, University Hospital chronic pelvic pain syndrome; NIH-CPSI, The 32 Zhao J, Nordling J. Posterior tibial nerve Zurich, Frauenklinikstr. 10, 8091 Zurich, National Institutes of Health Chronic stimulation in patients with intractable Switzerland. Prostatitis Symptom Index. interstitial cystitis. BJU Int 2004; 94: 101– e-mail: [email protected] 4

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Original Article COMBINED INTRACORPORAL INJECTION and PDE-5 INHIBITOR AFTER RP MYDLO et al.

Associate Editor Use of combined intracorporal Michael G. Wyllie injection and a phosphodiesterase-5 Editorial Board inhibitor therapy for men with a Ian Eardley, UK Jean Fourcroy, USA suboptimal response to sildenaﬁl Sidney Glina, Brazil Julia Heiman, USA and/or vardenaﬁl monotherapy after Chris McMahon, Australia radical retropubic prostatectomy Bob Millar, UK Alvaro Morales, Canada JACK H. MYDLO, ROSALIA VITERBO and PAUL CRISPEN Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA Michael Perelman, USA Accepted for publication 8 November 2004 Marcel Waldinger, Netherlands

OBJECTIVE these patients used ICI therapy only intermittently, instead of regularly, as they felt To report experience with combined therapy that this was adequate enough for good using intracorporal injection (ICI) of results. alprostadil and oral phosphodiesterase 5 (PDE-5) inhibitors for the minimally invasive CONCLUSIONS treatment of erectile dysfunction (ED) after radical prostatectomy (RP), as PDE-5 PDE-5 oral pharmacotherapy is the most inhibitors are effective but a few patients may commonly used effective therapy for ED but have a suboptimal response. may not be as effective in patients who have radical surgery; the addition of testosterone PATIENTS AND METHODS patches may have side-effects or be considered a risk in patients with a history of In a retrospective study, 34 men (aged prostate cancer. The use of ICI therapy as an 46–66 years) had a nerve-sparing retropubic adjunct or maintenance therapy to their oral RP and subsequent ED. Patients were titrated medication may be another alternative in on sildenaﬁl citrate or vardenaﬁl to maximum these patients. doses. All had a suboptimal response after a maximum of eight doses of oral therapy and KEYWORDS were then treated with ICI therapy using 15 or 20 mg alprostadil. Erectile function was erectile dysfunction, combined therapy, assessed with the Sexual Health Inventory for injection, prostate cancer Men (SHIM).

RESULTS INTRODUCTION

Of the 32 patients who continued combined Current therapy for erectile dysfunction (ED) therapy, 22 (68%) had an improvement in includes penile re-vascularization, semi-rigid erectile function after ICI therapy, as assessed and inﬂatable penile prostheses, transurethral by the SHIM score. On follow-up, 36% of alprostadil urethral suppositories,

MYDLO ET AL.

intracavernosal injection (ICI) therapy and and of £21 as associated with some degree of TABLE 1 The SHIM scores before and after ICI oral pharmacotherapy. The use of the ED. The assessment of improved erectile therapy for the two monotherapy groups phosphodiesterase (PDE) type 5 inhibitors is function was based on an improved SHIM currently the main effective and simple score. We also determined how long the Variable Sildenafil Vardenafil treatment, and they are the most commonly patients continued on ICI therapy, and any Sample size 12 10 used agents. They result in increased levels of side-effects and other issues related to its SHIM cyclic GMP and, combined with nitric oxide, use. No other pharmacotherapeutic agents before ICI 14.3 14.9 lead to the relaxation of the corporal smooth were used in these patients, e.g. MUSE after ICI 23.4 24.1 muscle and consequent erection [1,2]. suppositories or devices such as the penile occlusive ring. Recent data show that 18% of the prescriptions for PDE-5 inhibitors are written by urologists, while 82% are written by other RESULTS After 7 months, eight patients (36%) stopped physicians. Therefore, effective treatment for using ICI therapy regularly because they ED is now available to many physicians and Of the original 49 men who had nerve-sparing claimed they had good erections with patients, who previously perhaps may not RP and oral therapy for ED, 15 were satisfied intermittent use. The regular users continued have entertained invasive therapies [1–7]. with their response to oral therapy; the ICI monthly, after their third or fourth PDE-5 PDE-5 inhibitor therapy has had a major remaining 34 patients (aged 46–66 years) dose. Although several patients stated they impact on the effective and noninvasive were included in the study. Oral PDE-5 had some soreness at the site of injection, treatment of ED, and these drugs have now therapy led to some improvement in erectile they alternated the sides and continued ICI been in use long enough to evaluate their function in most patients but we also ensured therapy. effectiveness in real situations. Several that the patients were re-educated in the reports now show that there is a small but proper use of their medication, i.e. that their significant proportion of men with a pills were being taken on an empty stomach, DISCUSSION suboptimal response [7–10]. at up to eight doses for the desired effect, and that the men were sufficiently aroused. Normal erectile physiology involves Combined therapy for men with a suboptimal contributions from several organ systems; the response to PDE-5 inhibitor therapy was The patients tried PDE-5 therapy at home, vascular, endocrine and neuronal systems are reported previously, and consists of sildenafil first in private with erotic material instead crucial for normal erectile function [1]. Often and intraurethral alprostadil (MUSE), or of using it immediately with their partner. more than one of these systems is deficient or sildenafil and androgen supplementation if We find that this approach eliminates the damaged in men with ED. There are several the patient has subtherapeutic levels of psychological aspects of the pressure and potential ways to approach a patient with a testosterone [11–15]. However, androgen expectations of the partner. Once this suboptimal response to PDE-5 inhibitors. supplementation after prostate cancer confounding variable is eliminated, it is Combined therapy involving a PDE-5 inhibitor surgery may be considered controversial. Thus easier to assess the efficacy of the drug and a second agent, which targets another we assessed the efficacy of sildenafil and/or for the couple. Those patients who were vascular, endocrine or neuronal pathway, may vardenafil with the booster effect of ICI still dissatisfied with a less than optimal provide a better outcome in this selected therapy using alprostadil in men with ED after response were then re-evaluated with group of patients. Several supplemental/ radical prostatectomy (RP). the SHIM questionnaire; there were no combined therapies for men with a differences between sildenafil and vardenafil suboptimal sildenafil response have been failures. described. These combined therapies include PATIENTS AND METHODS testosterone supplementation, a centrally Initially the ICI therapy was administered by acting dopamine agonist, intraurethral and ICI The study started with 49 men who had good the physician and then patients were taught therapies [11–18]. erections before surgery, who had a nerve- to inject themselves. Two patients withdrew sparing retropubic RP and who sought from ICI treatment because of painful The role of testosterone in men with ED is not treatment for ED afterwards. These men were injections. Surprisingly, cost was not a factor clear; replacing testosterone alone in men treated with either sildenafil or vardenafil. to discontinue its use, especially if the results with normal or low-to-normal levels of After having a suboptimal response from the were beneficial. For several patients where testosterone does not significantly improve maximum dosage of eight doses (100 mg for health insurance did not cover both therapies, erectile function. However, in patients sildenafil, 18 men, and 20 mg for vardenafil, free samples were given. with low levels of serum testosterone, 16 men), these 34 patients were titrated to supplementing testosterone in combination their maximum benefit from ICI therapy with In all, 22 of the 32 men (68%) reported with oral sildenafil is beneficial in those with a alprostadil (either 15 or 20 mg). Once taught having a much better erection with PDE-5 suboptimal response to sildenafil alone [15]. in the office, they used ICI at home. inhibitors after starting ICI therapy, based on responses from the SHIM questionnaire Although serum testosterone levels and the The Sexual Health Inventory for Men (SHIM) (Table 1). They also stated that ICI was helpful incidence of prostate cancer have not been was used before starting treatment with oral in maintaining the effectiveness of the PDE-5 shown to be associated risks, in the present therapy; a score of 25 was considered normal inhibitor. medicolegal climate supplementing with

COMBINED INTRACORPORAL INJECTION AND PDE-5 INHIBITOR AFTER RP

testosterone should be used cautiously in there is a high discontinuation rate of pilot for a larger, randomized sample study of patients who have a history of, or are at an 37–76% caused by local side-effects or patients. increased risk for, prostate cancer [19–21]. aversion to self-injection. McMahon et al. [14] Moreover, the testosterone dermal patches studied the ability of sildenafil to salvage The management of ED after RP is especially have been associated with a severe dermatitis patients failing ICI therapy. They reported challenging; nerve-sparing techniques have in up to 35% of patients [22]. Patients with a 66% salvage rate in patients receiving improved potency rates after RP, but ED still Parkinson’s disease, cerebral vascular sildenafil combined with ICI, but the effect of occurs at a high rate. The response to accidents, Alzheimer’s disease and depression combined therapy was no better in them than sildenafil after RP is strongly influenced by may also have ED [1,2,17]. for sildenafil alone. However, Shabsigh nerve status at the time of surgery. Several and Anastasiadis [15,16] reported an 88% reports show a significantly lower response The relationship between CNS pathology and response rate in patients using ICI in whom to sildenafil monotherapy in patients ED may involve central neurotransmitters and sildenafil alone had failed. Other investigators undergoing RP than in controls [20–25]. neural hormones. Dopamine agonists are reported the ‘booster’ effect of intermittent Combined therapy may have a role in these currently being investigated in the treatment ICI in the office for patients with a suboptimal patients. of ED [16]. Apomorphine, a D1 and D2 response to sildenafil [16–18]. Kaplan et al. receptor agonist, combined with sildenafil has [19] reported on the beneficial use of an a- In conclusion, in patients with ED after RP and been shown to increase intracavernosal blocking agent combined with ICI, suggesting with a suboptimal response to PDE-5 pressure in the rat model [1,2]. that the synergistic effects of vascular monotherapy, ICI and PDE-5 combined dilatation and blockade of sympathetic therapy may be a safe and effective Peripheral nervous system pathology is well inhibition may explain this response. This alternative, using minimally invasive known to adversely affect erectile function. additional pharmacotherapy may be treatment. The importance of an intact cavernosal considered in future studies in those patients innervation is shown by the high rate of ED we are treating with combined PDE-5 after non-nerve sparing RP [21]. Medical inhibitors and ICI. However, this would further CONFLICT OF INTEREST treatment that directly addresses peripheral add to the cost of combined therapy, which nervous system lesions is lacking. may be prohibitive for the patient. Even more None declared. important is to consider the side-effects that Cavernosal smooth muscle relaxation is can occur with the synergy of combined instrumental in erectile physiology; this is therapy, e.g. hypotension, priapism, headache, REFERENCES regulated by cytosolic Ca2+ levels, and these curvature of the shaft from repeated are regulated by two second-messenger injections, etc. Each patient must be made 1 Lue TF. Erectile dysfunction. N Eng J Med systems involving cGMP and cAMP. aware that combined therapy has greater 2000; 342: 1802–13 Pharmacological manipulation of these risks and side-effects because of the synergy. 2 Walsh PC, Retik AB, Vaughn ED, eds. second-messenger pathways is currently used Campbell’s Urology, 8th edn. Philadelphia: in the treatment of ED, in that PDE-5 Last, we noted that in patients with no WB Saunders, 2002: 1653–5 inhibitors target the cGMP pathway, while the prostate cancer who complain of ED resulting 3 Williams G, Abbou CC, Amar ET et al. cAMP pathway is targeted by agents such as from their antidepressant medication, Efficacy and safety of transurethral alprostadil. Targeting both second-messenger successful treatment with combined therapy alprostadil therapy in men with erectile pathways with combined therapy may be led to less depressed patients, and dysfunction. Br J Urol 1998; 81: 889–94 beneficial in patients who have a suboptimal consequently less antidepressant medication, 4 Padma-Nathan H, Hellstrom WJ, Kaiser response to PDE-5 inhibitors alone [1,2,7]. which reversed their ED-antidepressant FE et al. Treatment of men with erectile medication ‘cycle’ [17]. dysfunction with transurethral Mydlo et al. [11] reported on the use of MUSE alprostadil. N Eng J Med 1997; 336: 1–7 and sildenafil combined for those patients There were several limitations to the present 5 Werthman P, Rajfer J. MUSE therapy: who had a suboptimal response with study. First, there were relatively few patients preliminary clinical observations. Urology monotherapy. They reported an overall and the study was not randomized or 1998; 50: 874–82 improvement of 114% using MUSE and controlled. Therefore, no statistically 6 Costabile RA, Spevak M, Fishman IJ sildenafil over either alone, using the significant conclusions can be drawn from the et al. Efficacy and safety of transurethral International Index of Erectile Function data. Second, although all these nerve- alprostadil in patients with erectile questionnaire to assess the improvement in sparing RPs were performed by one surgeon dysfunction following radical erectile function. Subsequently, they reported (J.H.M.) there may still have been variation in prostatectomy. J Urol 1998; 160: 1325–8 a high attrition rate because of the the trauma to the nerves, either unilaterally or 7 Marks LS, Duda C, Dorey FJ et al. cumbersomeness of using different bilaterally. This could account for some Treatment of erectile dysfunction with medications 30 min apart, the urethral variability in the results after surgery. Last, the sildenafil. Urology 1999; 53: 19–24 discomfort and the cost [12]. follow-up was insufficient to determine how 8 Zippe CD, Jhaveri FM, Klein EA et al. many more patients would stop taking ICI Role of Viagra after radical prostatectomy ICI is an effective alternative because it acts because of the side-effects, cost, loss of with sildenafil citrate (Viagra). Urology locally with no major systemic side-effects. efficacy, loss of motivation or partner support. 1998; 52: 963–6 The efficacy is reportedly 72–87% [13,14] but However, this small analysis should serve as a 9 Gralnek D, Wessells H, Cui H, Dalkin BL.

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Differences in sexual function and quality 16 Shabsigh R, Anastasiadis AG. Erectile treatments for erectile dysfunction in of life after nerve sparing and nonnerve dysfunction. Ann Rev Med 2003; 54: 153– patients with prostate cancer after radical sparing radical retropubic prostatectomy. 68 retropubic prostatectomy. BJU Int 2001; J Urol 2000; 163: 1166–70 17 Nurnberg HG, Seidman SN, Gelenberg 88: 58–62 10 Zagaja GP, Mhoon DA, Aikens JE et al. AJ, Fava M, Rosen R, Shabsigh R. 23 Rhoden EL, Morgentaler A. Testosterone Sildenafil in the treatment of erectile Depression, antidepressant therapies, and replacement therapy in hypogonadal men dysfunction after radical prostatectomy. erectile dysfunction: clinical trials of at high risk for prostate cancer. Results of Urology 2000; 56: 631–4 sildenafil citrate in treated and untreated 1 year of treatment in men with prostatic 11 Mydlo JH, Volpe MA, Macchia RI. patients with depression. Urology 2002; intraepithelial neoplasia. J Urol 2003; Initial results utilizing combination 60: 58–66 170: 2348–51 therapy in patients with a suboptimal 18 Nehra A, Steers WD, Althof SE et al. 24 Atiemo HO, Szostak MJ, Sklar GN. response to either alprostadil or Third International Conference on the Salvage of sildenafil failures referred from sildenafil monotherapy. Eur Urol 2000; Management of Erectile Dysfunction: primary care physicians. J Urol 2003; 170: 38: 30–4 linking Pathophysiology and Therapeutic 2356–8 12 Mydlo JH, Volpe MA, Macchia response. J Urol 2003; 170: S3–5 25 Jaffe JS, Antell MR, Greenstein M, RJ. Results from different patient 19 Kaplan SA, Reis RB, Kohn IJ, Shabsigh Ginsberg PC, Mydlo JH, Harkaway RC. populations using combined therapy R, Te AE. Combination therapy using oral Use of intraurethral alprostadil in patients with alprostadil and sildenafil: predictors alpha-blockers and intracavernosal not responding to sildenafil citrate. of satisfaction. BJU Int 2000; 86: 1–6 injection in men with erectile dysfunction. Urology 2004; 63: 951–4 13 McMahon CG. Erectile dysfunction. Med Urology 1998; 52: 739–43 J Australia 2000; 173: 492–7 20 Carter BH et al. Longitudinal evaluation Correspondence: Jack H. Mydlo, Department 14 McMahon CG, Samali R, Johnson H. of serum androgen levels in men with and of Urology, Temple University Hospital, 3401 Treatment of intracorporal injection non- without prostate cancer. The Prostate North Broad Street, Philadelphia, PA 19140, response with sildenafil alone or in 1995; 27: 25–31 USA. combination with triple intracorporal 21 Anastasiadis AG, Ghafar MA, Burchardt e-mail: [email protected] injection therapy. J Urol 1999; 162: 1992– M, Shabsigh R. Economic aspects of 8 medical erectile dysfunction therapies. Abbreviations: ED, erectile dysfunction; ICI, 15 Shabsigh R. Hyogonadism and erectile Expert Opinion Pharmacotherapy 2002; 3: intracavernosal injection; PDE-5, dysfunction: the role of testosterone 257–63 phosphodiesterase type 5; MUSE, therapy. Int J Impotence Res 2003; 15: 22 Baniel J, Israilov S, Segenreich E, Livne intraurethral alprostadil; SHIM, Sexual Health S9–13 PM. Comparative evaluation of Inventory for Men; RP, radical prostatectomy.

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Original Article ERECTILE FUNCTION and BRACHYTHERAPY PONHOLZER et al.

The effect on erectile function of 103palladium implantation for localized prostate cancer

ANTON PONHOLZER*†, RENÉE OISMÜLLER‡¶, CANATAY SOMAY‡¶, FELIX BÜCHLER‡, ULRICH MAIER*†A, ROBERT HAWLICZEK‡¶, MICHAEL RAUCHENWALD*† and STEPHAN MADERSBACHER*† *Department of Urology and Andrology, †Ludwig Boltzmann Institute for Urological Oncology, ‡Institute of Radio-oncology and ¶Ludwig Boltzmann Institute for Applied Research in Radiation Oncology, Donauspital, Vienna, Austria Accepted for publication 1 December 2004 ADied March 2003

OBJECTIVE (neo)adjuvant antiandrogen therapy for up to moderate/severe ED. In a multivariate 3 months. analysis, neither age nor preoperative To determine in a prospective study the effect prostate-speciﬁc antigen level, prostate on erectile function of 103Pd brachytherapy for RESULTS volume, D90, hormonal treatment, diabetes, localized prostate cancer, using a validated smoking or hypertension were predictive of questionnaire. At baseline, 27 (35%) patients had no erectile preserving potency (P > 0.05). dysfunction (ED; EF domain score 26–30), 24 PATIENTS AND METHODS (31%) had mild/moderate ED (score 11–25) CONCLUSIONS and 27 (35%) severe ED (score 6–10). The Between July 1999 and April 2003, 113 men mean EF domain score decreased from 17 to There was a high prevalence of pre-existing with localized prostate cancer were treated by 12 (P 0.001) after 30 months. Overall, 52 < ED in these men; 57% of men fully potent or permanent implantation of 103Pd seeds, of men (67%, including those with severe ED at with mild ED at baseline remained so whom 78 with a follow-up of 30 months were baseline) remained in the same ED category at 30 months after brachytherapy. included in this study. No patient received 30 months after therapy as before, 12 (15%) supplemental external beam radiation deteriorated by one category, 14 (18%) by two therapy. At baseline and 3-month intervals, or more, and no patient improved. Of the 27 KEYWORDS erectile function (EF) was assessed by the EF patients fully potent (score 26–30) at domain score of the International Index of baseline, 37% remained so after 30 months, prostate cancer, therapy, sexuality, Erectile Function-15 (IIEF-15); 77% received 19% developed mild and the remaining 44% radiotherapy, brachytherapy

INTRODUCTION particular there is a paucity of prospective volume of £50 mL (Table 1). Preoperative data using validated instruments [7,8]. staging included TRUS of the prostate, pelvic In the absence of randomized trials showing CT and dynamic MRI of the prostate with an that a particular treatment is better than To address this important issue we devised a endorectal coil. In addition, a detailed medical another for localized prostate cancer (in terms prospective study by using the EF domain of history, including an assessment of factors of cause-speciﬁc survival) patients may value the International Index of Erectile Function with known effects on erectile dysfunction their quality of life as much as quantity of life (IIEF questions 1–5 and 15) to investigate the (ED), e.g. smoking habits, diabetes, [1]. Urinary continence and erectile function effect of 103Pd brachytherapy on EF. In all, 78 hypertension and medication, was obtained. (EF) are considered to be the most important consecutive patients with a follow-up of The partnership status was ascertained but determinants of quality of life after treatment 30 months entered this study and completed more detailed information on this issue for prostate cancer [1]. the IIEF-15 at baseline and every 3 months (e.g. partner interested in sexual activity, thereafter. motivated partner, etc.) was not collected. For There is a wide range of reported potency the current analysis, all 78 patients who rates after deﬁnitive therapeutic options for completed a 30-month follow-up were patients with localized prostate cancer. The PATIENTS AND METHODS analysed. reported potency after nerve-sparing prostatectomy is 20–90% when patients were Between July 1999 and April 2003, 113 The 103Pd seeds were implanted under followed long enough to account for the consecutive men with newly diagnosed ultrasonographic guidance using an return of EF after surgery [2–4]. After external localized prostate cancer were treated by intraoperative computed planning template. beam radiation therapy (EBRT), potency was permanent 103Pd seed implantation, with no 103Pd was used exclusively (half-life 17 days, preserved in 45–80% [5,6]. The results for EBRT, at our hospital. Inclusion criteria were initial dose rate 24 cGy/h, activity 51.8 MBq). preserving potency after permanent prostate clinical stages T1–T2, a PSA level of £15 ng/ From July 1999 to December 2000 a brachytherapy are less forthcoming; in mL, Gleason score of £7 and a prostate prescription dose of 115 Gy to the prostate,

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maintaining a safety margin (3–5 mm) Characteristic All Full follow-up TABLE 1 around the prostate, was delivered. From N11378 The baseline characteristics January 2001 to date, all patients received Median (range) age, years 72 (49–83) 71 (56–83) of the patients a prescription dose of 125 Gy according N: to the recommendations of the American 60 11 7 Brachytherapy Society [9]. All procedures < 61–70 40 31 were performed by two physicians (A.R. and 71–80 58 38 R.O.) in cooperation between the Department 81 4 2 of Urology and Andrology and the Institute of ≥ Median (range) PSA, ng/mL 7.4 (2.3–17) 7.4 (31–15) Radio-oncology. The median (range) number N: of seeds implanted was 84 (45–122) and the 463 number of needles used 37 (22–46). Post- < 4–10 80 60 planning after 1 month was standardized, 10 27 15 revealing a median D90 (radiation dose ≥ Median (range): delivered to 90% of the prostate target TRUS prostate volume, mL 27 (12–58) 26.2 (12.9–58) volume) of 112.8 (55.5–188) Gy. N: 30 86 55 To reduce the prostate, or as adjuvant < 30–50 27 23 treatment if the waiting time was >6 weeks, Gleason score 65% of men received LHRH-antagonists, 3–4 37 25 5% antiandrogen monotherapy and 7% 5–6 65 50 combined therapy for up to 3 months (all 7113 therapy started before 103Pd implantation, and no patient had therapy for >3 months). Only 23% of men were treated with no concomitant antiandrogen therapy. All 100 FIG. 1. baseline assessments (IIEF, quality-of-life The distribution of ED category score, PSA assay) were conducted before 80 according to EF domain score over starting antiandrogen therapy. time (no ED, white, score 26–30; 60 mild ED, green, 22–25; moderate To assess the effect of brachytherapy on EF ED, light red, 11–21; severe ED, red, and quality of life, the IIEF-15 questionnaire 6–10).

% of men 40 [10,11] and the EORTC QLQ C30 were completed before and every 3 months after 20 brachytherapy by the patients. Questions 1–5 and 15 of the IIEF-15 were used as the EF 0 domain score, and all patients had a routine Baseline 6 18 30 oncological follow-up by a DRE, serum PSA Time, months assay, a measurement of postvoid residual volume and the IPSS at 3-month intervals; 78 men who reached the 30-month follow-up volume, PSA and Gleason score. The domain score improved slightly over time were analysed. distribution of men in the various categories after a sharp decline 3 months after therapy. of ED before brachytherapy is shown in Fig. 1; Differences in IIEF scores over time were the median age for those with no, mild or Overall, 52 men (78%; including those with calculated using the paired Student’s t-test moderate and severe was 68, 71 and 73 years, severe ED at baseline) remained in the same and Wilcoxon signed-rank test. A multivariate respectively. Table 2 compares the age, serum ED category as before therapy, 12 (15%) regression analysis was used to identify PSA level, prostate volume and comorbidity of deteriorated by one category, seven (9%) independent factors predictive of preserved the 27 fully potent men (IIEF >25) to the 51 by two and a further seven (9%) by three potency; in all tests, statistical signiﬁcance with ED (IIEF <26) at baseline. Potent men categories; no patient improved. The was set at P < 0.05. were on average 4 years younger and had a distribution of men in ED categories at lower incidence (P < 0.05) of diabetes baseline and 30 months is shown in Table 3; mellitus. overall, 57% of patients with mild or no ED RESULTS before treatment maintained that level Within the study population of 78 men there 30 months afterward. The baseline characteristics of all 113 patients was a signiﬁcant reduction of the mean IIEF treated within the study period, and of the 78 score, from 43.2 before to 33.0 (-23.6%) In a multivariate analysis, neither age nor with a follow-up of 30 months who entered 30 months after brachytherapy, and in the EF preoperative PSA, prostate volume, D90, the present analysis, are shown in Table 1. domain score, from 16.5 to 12.2 (-26.1%) hormonal treatment, diabetes, smoking or Both groups were comparable in age, prostate (both P < 0.001) (Fig. 2). The IIEF and EF hypertension were predictive factors for the

ERECTILE FUNCTION AND BRACHYTHERAPY

FIG. 2. Changes of the mean IIEF-15 total score (A) Mean (sd) no ED (IIEF 25) ED (IIEF 25) P TABLE 2 > £ and the mean EF (B) domain score with time. The N2751 Clinical variables and bars indicate the SD (78 men). Age, years 68.3 (6.7) 72.4 (4.4) <0.05 comorbidities of men with PSA, ng/mL 9.3 (7.7) 9.6 (4.4) >0.05 and without ED at baseline A Prostate volume, mL 26.2 (7.6) 28.3 (10.6) >0.05 70 N with: 60 Hypertension 30 41 >0.05 50 Diabetes mellitus 4 12 <0.05 40 Nicotine consumption 34 22 >0.05 30 20 10 0

N (%) in ED category TABLE 3 B none mild moderate severe The distribution of ED status 25 Before therapy 27 (35) 8 (10) 16 (20) 27 (35) according to EF score at 20 At 30 months: baseline and after 15 None 10 (37) 0 0 0 30 months depending on Mild 5 (19) 6 0 0 the ED status at baseline, 10 and the changes in the IIEF Moderate 5 (19) 1 10 0 5 Severe 7 (25) 1 6 27 (100) and EF score over time with IIEF score initial ED category 0 Baseline 6 18 30 before 65.3 59.4 47.0 14.5 Time, months after 44.0‡ 43.0† 29.4‡ 12.5 EF score before 28.7 24.0 16.2 6.0 *P < 0.05; †< 0.01; ‡< 0.001 after 18.2‡ 16.7† 9.7† 4.0* before vs after. prostate brachytherapy as a result of differences in follow-up, various definitions of ED and method of data collection. preservation of potency (P > 0.05). However, brachytherapy are scant. To address this There was a high incidence of ED before data for the effect of hormonal treatment important issue several study prerequisites brachytherapy in the present men; only 35% must be interpreted cautiously as there were must be fulfilled, i.e. a prospective design, were fully potent at baseline, largely as a few untreated men, which reduced the use of validated study instruments, an result of patient selection, underlined by a statistical power. homogeneous study population and identical median age of 72 years at baseline. Younger treatment, a reasonable sample size and men were treated by brachytherapy in our The proportion of men using any medication sufficient follow-up. The present study meets institution if they refused radical for ED increased from 5% at baseline to 23% these criteria and is, to our knowledge, the prostatectomy or if there was serious after 30 months. The EORTC-QLQ C30 scores first prospective study exclusively using comorbidity. did not change during the study period. brachytherapy with 103Pd, no EBRT and a validated questionnaire before and after The present prospective data show that treatment. To avoid any bias from different permanent prostate brachytherapy with DISCUSSION follow-up periods, only men who had 103Pd results in a decline in EF in about half 30 months of follow-up were included; the men. The steep decrease in EF at Within the past decade prostate patients with short-term survival therefore 3–6 months after therapy, which recovers brachytherapy has become a popular did not affect the data. This is particularly partly thereafter, is not only caused by definitive treatment option for localized important for assessing ED after 103Pd implantation but also by antiandrogen prostate cancer. In the USA it is almost as brachytherapy. The patient-administered IIEF therapy. More important is that 57% of the common as radical prostatectomy, and is used in the present study has been evaluated men potent or with mild ED before therapy becoming increasingly popular in Europe. The as a sensitive and specific tool for evaluating remained so 30 months afterward. preservation of potency is an important ED. Penson et al. [1] reported that physicians’ consideration for many (particularly young) ratings of patients’ symptoms do not There is one other large-scale study on the men with localized prostate cancer when correlate well with patients’ self-assessment effect of brachytherapy on ED which used a choosing among the three major definitive of quality of life, and reported significant validated questionnaire; Merrick et al. [12] treatment options, i.e. radical prostatectomy, differences between physician and patient reported that potency was preserved at EBRT or brachytherapy. While the effect of assessment of all quality-of-life domains, 6 years after therapy in half of 125 men radical (retropubic, perineal, laparoscopic) including EF. Similar to the situation after initially potent and treated with 125I or 103Pd, prostatectomy and EBRT on EF has been radical prostatectomy or EBRT, a wide range with or with no supplemental EBRT. That extensively assessed [2–6], data after of ED has been reported after permanent study was initiated before the IIEF became

PONHOLZER ET AL.

available and is thus hampered as the IIEF CONFLICT OF INTEREST (IIEF): a multidimensional scale for score was not obtained before therapy. assessment of erectile dysfunction. Valicenti et al. [13] assessed 34 men after 103Pd None declared. Urology 1997; 49: 822–30 brachytherapy (with/with no EBRT), reporting 11 Cappelleri JC, Rosen RC, Smith MD, a 44% reduction in EF at 1 year after REFERENCES Mishra A, Osterloh IH. Diagnostic implantation. In that study the authors also evaluation of the erectile function domain analysed the role of short-term neoadjuvant 1 Penson DF, Litwin MS, Aaronson NK. of the international index of erectile endocrine therapy on the return of EF; there Health related quality of life in men with function. Urology 1999; 54: 346–51 was no apparent long-term effect on EF, and prostate cancer. J Urol 2003; 169: 1653– 12 Merrick GS, Butler WM, Galbreath RW, no clear negative effect of neoadjuvant 61 Stipetich RL, Abel LJ, Lief JH. Erectile therapy in the short term [13]. Two other 2 Siegel T, Moul JW, Spevak M, Alvord function after permanent prostate series with sufficient men but no validated WG, Costabile RA. The development of brachytherapy. Int J Radiat Oncol Biol questionnaires reported potency rates of 64% erectile dysfunction in men treated for Phys 2002; 52: 893–902 after 3 years in 313 men [14] and 76% after prostate cancer. J Urol 2001; 165: 430–5 13 Valicenti RK, Bissonette EA, Chen C, 5 years in a subgroup of men with no EBRT or 3 Catalona WJ, Basler JW. Return of Theodorescu D. Longitudinal comparison androgen deprivation, from 482 patients [15]. erections and urinary continence of sexual function after 3-dimensional following nerve sparing radical retropubic conformal radiation therapy or prostate ED after definitive local treatment for prostate prostatectomy. J Urol 1993; 150: 905–10 brachytherapy. J Urol 2002; 168: 2499– cancer represents a multifactorial process, 4 Katz R, Salomon L, Hoznek A et al. 504 including neurogenic compromise, vascular Patient reported sexual function 14 Stock RG, Kao J, Stone NN. Penile insufficiency, local trauma and psychogenic following laparoscopic radical erectile function after permanent causes. After radical prostatectomy, ED has prostatectomy. J Urol 2002; 168: 2078–82 radioactive seed implantation for been correlated with the surgical trauma 5 Robinson JW, Moritz S, Fung T. treatment of prostate cancer. J Urol 2001; to the neurovascular bundles, although Meta-analysis of rates of erectile function 165: 436–9 potency rates even after nerve-sparing after treatment of localized prostate 15 Potters L, Torre T, Fearn PA, Leibel SA, prostatectomy are unlikely to exceed 30–50% carcinoma. International J Radiat Oncol Kattan MW. Potency after permanent [16]. However, some series reported potency Biol Phys 2002; 54: 1063–8 prostate brachytherapy for localized preservation rates of up to 90% after bilateral 6 Shipley WU, Zietman AL, Hanks GE et al. prostate cancer. Int J Radiat Oncol Biol nerve-sparing prostatectomy, depending Treatment related sequelae following Phys 2001; 50: 1235–42 upon the erectile status before surgery, and external beam radiation for prostate 16 Montorsi F, Briganti A, Salonia A, age [17]. cancer: a review with an update in Rigatti R, Burnett AL. Current and future patients with stages T1 and T2 tumor. strategies for preventing and managing In contrast, after permanent prostate J Urol 1994; 152: 1799–805 erectile dysfunction following radical brachytherapy, the radiation dose to the 7 Stone NN, Stock RG. Complications prostatectomy. Eur Urol 2004; 45: 123–33 neurovascular bundles does not correlate following permanent prostate 17 Walsh PC, Marschke P, Ricker D, with the development of ED. However, there brachytherapy. Eur Urol 2002; 41: 427–33 Burnett AL. Patient-reported urinary seems to be a strong correlation between the 8 Merrick GS, Wallner KE, Butler WM. continence and sexual function after dose of radiation delivered to the bulb of the Permanent interstitial brachytherapy for anatomic radical prostatectomy. Urology penis and the subsequent development of ED the management of carcinoma of the 2000; 55: 58–61 in EBRT. In addition, patient age, preoperative prostate gland. J Urol 2003; 169: 1643– ED, supplemental EBRT, and the choice of 52 Correspondence: Robert Hawliczek, Chairman, isotope and antiandrogen therapy, may have a 9 Beyer D, Nath R, Butler W, Merrick G. Institute for Radiooncology, Donauspital– significant effect on the results. The American Brachytherapy Society SMZO, Langobardenstrasse 122, 1220 Vienna, continued documentation and elucidation of Recommendations for clinical Austria. the causes of ED after permanent prostate Implementation of Nist-1999 Standards e-mail: [email protected] brachytherapy, and advanced imaging of for Palladium 103 Brachytherapy. IJROBP tumour location, may provide refined 2000; 47: 273–5 Abbreviations: ED, erectile dysfunction; EF, treatment techniques, lower rates of ED, and 10 Rosen RC, Riley A, Wagner G, Osterloh erectile function; IIEF, International Index of ultimately a better quality of life for the IH, Kirkpatrick J, Mishra A. The Erectile Function; EBRT, external beam patients. international index of erectile function radiation therapy.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article LAPAROSCOPIC VS OPEN DONOR NEPHRECTOMY SIMFOROOSH et al

Authors from Iran compare various Comparison of laparoscopic and open outcomes between laparoscopic and open donor nephrectomy in donor nephrectomy: a randomized kidney transplantation; they controlled trial carried out a large comparative trial, and found that laparoscopic NASSER SIMFOROOSH, ABBAS BASIRI, ALI TABIBI, NASSER SHAKHSSALIM and donor nephrectomy gave better SEYED M.M. HOSSEINI MOGHADDAM donor satisfaction and morbidity, Department of Urology and Renal Transplantation, Urology and Nephrology Research Center, Shahid Labbaﬁ Nejad Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran with equivalent graft outcome. Accepted for publication 15 November 2004

OBJECTIVE signiﬁcantly different between ODN and LDN. Long-term graft survival was 93.8% for LDN To compare the graft survival, donor and and 92.7% for ODN. recipient outcome, donor satisfaction, and complications of laparoscopic (LDN) and open CONCLUSIONS donor nephrectomy (ODN) in kidney transplantation. Compared to ODN, LDN was associated with greater donor satisfaction, less morbidity and equivalent graft outcome. PATIENTS AND METHODS KEYWORDS In a randomized controlled trial, 100 cases each of LDN and ODN were compared. We laparoscopy, nephrectomy, kidney modiﬁed the standard LDN procedure to make transplantation, living donor, randomized it less expensive. controlled trials

RESULTS INTRODUCTION

The mean (SD) operative duration was Laparoscopic donor nephrectomy (LDN) 152.2 (33.9) min for ODN and was developed in an attempt to increase 270.8 (58.5) min for LDN, and the mean the frequency of kidney donation by reducing duration of kidney warm ischaemia was the disincentives to donation, capitalising 1.87 min for ODN and 8.7 min for LDN. Only on the associated reduced morbidity [1]. one LDN required conversion to ODN because Ratner et al [2] reported the first successful of bleeding. The mean follow-up in the LDN human LDN in 1995. Later descriptive studies and ODN groups was not significantly reported that the morbidity of LDN was different (406.1 vs 403.8 days). The mean (SD) less than with open DN (ODN) and that the score for donor satisfaction was 17.3 (3.5) for long-term renal graft function of LDN was ODN and 19.6 (1.0) for LDN. The rate of equivalent to that of ODN [2–4]. To our ureteric complications was 2% for ODN and knowledge, the present study is the first none for LDN. As determined by serum randomized clinical trial comparing LDN and creatinine levels at 3, 21–30, 90, 180 and 365 ODN. Preliminary results were reported days after surgery, graft function was not previously [5].

SIMFOROOSH ET AL.

PATIENTS AND METHODS TABLE 1 Patient characteristics and complications during and after ODN and LDN (both 100 patients) The present prospective study began after Characteristics/complications ODN LDN P gaining experience from 90 cases of LDN, and Mean (SD): includes 100 cases of LDN and 100 of ODN age, years 29.2 (5.2) 27.8 (3.9) 0.06 performed between July 2001 and September weight, kg 67.3 (9.7) 64.4 (9) 0.03 2003. Eligibility criteria were as follows: height, cm 172.2 (8.5) 170.5 (7.4) 0.15 donor body mass index (BMI) <28 kg/m2; BMI, kg/m2 22.67 (2.7) 22.2 (2.9) 0.19 no complexity in the donor kidney Donor sex (M/F) 92/8 86/14 0.17 vessels; recipient aged 18–65 years; and Mean (range): no haemolytic uraemic syndrome or focal follow up, days 403.8 (18–787) 406.1 (11–791) 0.9 segmental glomerulosclerosis and oxalosis in operating time, min 152.2 (80–260) 270.8 (165–490) 0.001 the recipient. All donors were evaluated at an < hospital stay, days 2.2 (2–8) 2.26 (2–5) 0.5 outpatient visit 7–10 days after surgery. A haematocrit difference, % before and day 3.7 ( 2.3–12.4) 4.1 ( 3.7–11.4) 0.21 telephone interview was conducted for - - after surgery donors at the closing date of study. The LDN [median] inpatient parenteral analgesic, mg 10.8 (11–80) [5] 11.5 (0–85) [5] 0.7 or ODN was performed by two co-surgeons Intraoperative donor complications, n (68 ODN and 69 LDN by N.S. and 32 ODN and None 82 96 31 LDN by A.B.) on the left kidney in all Pneumothorax 18 0 patients. The kidney was transplanted by the Splenic laceration 0 2 same urologist who did the nephrectomy. Cardiac arrhythmia 0 1 Bowel serosal injury 0 1 The authors’ institution has adopted codes Postoperative donor complications, n of ethics to guide human experimentation. None 91 83 After patients had been recruited and Bleeding 1 4 signed an informed consent form, they Retention 0 1 were assigned randomly to ODN and LDN Ileus 4 7 groups, using a balanced randomization Thigh numbness 1 1 method [6]. UTI 2 1 Scrotal swelling 0 3 The BMI was calculated; the warm ischaemia Subcutaneous collection 1 2 time was defined as the time from renal artery occlusion to kidney immersion in ice-slush, and operating time as the time from the initial skin incision to the final skin suture. Cold donors with multiple renal arteries were Whitney, Kaplan–Meier and chi-square tests ischaemia time was defined as the time excluded. as appropriate, with significance considered between kidney immersion in ice-slush and to be indicated at P < 0.05. graft revascularization. Serial creatinine levels The surgical technique used for ODN was the were measured in the recipient and recorded standard retroperitoneal flank approach. For at 3 and 21–30 days, and 3, 6 and 12 months LDN, under general anaesthesia and using a RESULTS after transplantation. The definition of transperitoneal approach in the modified delayed graft function varies in different flank position, a video laparoscope was The patient demographics and surgical studies [7]; we defined delayed graft function introduced through a 12-mm umbilical port; outcomes in the ODN and LDN groups are as serum creatinine levels of >35 mg/L on the 12-mm pararectal and 5-mm epigastric ports shown in Table 1. All nephrectomies were third day after transplantation. Using a were used for the dissecting instruments. We completed as scheduled, except for one LDN 20-point visual analogue scale (0 = no used the following modifications to the that required conversion to ODN because of satisfaction to 20 = full satisfaction), we conventional LDN: (i) the first trocar was bleeding. The mean (range) kidney warm assessed donor satisfaction for discomfort introduced in an open technique using an ischaemia time was 1.87 (1–5) min for ODN and cosmetic result; the validity of this ordinary non-disposable trocar (no Hasson’s and 8.7 (4–17) min for LDN (P < 0.001). The scaling method has not been assessed in trocar was used); (ii) we used three medium- mean interval between the beginning of previous studies. large metal clips instead of an Endo-GIA surgery and cold washing of the kidney stapler for ligating the renal veins and was 205 (123–320) min in the LDN and All potential donors had an extensive medical arteries; (iii) no organ-extracting device (e.g. 89.13 (40–209) min in the ODN group and psychological evaluation, and received a Endo-catch bag) was used; the kidney was (P < 0.001), and the mean cold ischaemia light mechanical bowel preparation 12 h extracted manually via an 8–10 cm time 48 (20–106) min and 49.4 (15–118) min, before surgery. Donors underwent suprapubic incision. respectively. conventional angiography or digital subtraction angiography to evaluate the The results were assessed statistically using No patients in the ODN group and only one in anatomy of the kidney vasculature, and all Student’s t-test, nonparametric Mann– the LDN group required a blood transfusion

LAPAROSCOPIC VS OPEN DONOR NEPHRECTOMY

(P < 0.001). Eighty-five patients in the ODN TABLE 2 Delay (in days) to resumption of ‘normal’ activities in donors group and 83 in the LDN group were discharged within 48 h of surgery. Table 2 Mean (median, range) shows the delay to resumption of ‘normal’ Activities ODN LDN P activities after LDN or ODN. Light activities 7.9 (5.5, 2–40) 5.9 (4, 2–30) 0.05 Heavy activities 56.6 (60, 5–210) 34 (30, 7–90) 0.002 Three kidney recipients in the ODN group but Driving a vehicle 20.8 (15, 2–150) 11.6 (7, 2–60) 0.004 none in the LDN group were donors’ first Receiving analgesia, after discharge 7.8 (5, 0–40) 3.3 (3, 0–20) <0.001 relatives. Two recipients in the LDN group and three recipients in the ODN group died, the reasons for death being given in Table 3. Long-term recipient survival was 96.9% Cause of death Group Months after transplantation TABLE 3 in the ODN group and 97.9% in the LDN Cardiovascular LDN 0 (day of transplantation) Recipient deaths in each group (no significant difference; Wilcoxon Pulmonary emboli LDN 3 group statistic). Uraemia and pneumonia ODN 11 Cardiovascular ODN 6 Ten recipients in the ODN and five in the Uraemia and infection ODN 12 LDN group had a history of previous kidney transplantation. The rate of recipient urological complications in the LDN and ODN groups was none and 6%, respectively. In the Recipient variable N Mean (range) P TABLE 4 ODN group they included vein thrombosis in Age, years Demographic one patient (1%), stricture of the ureteric ODN 100 38.6 (18–61) 0.07 characteristics and serum anastomosis in one (1%), lymphocele in two LDN 100 35.6 (18–61) creatinine levels of (2%), and both ureteric anastomosis leakage Weight, kg recipients and lymphocele in one (1%). The rate of ODN 100 63.5 (32–102) 0.9 ureteric complications was none in the LDN LDN 100 63.45 (34–106) group and 2% in the ODN group. Male to female ratio ODN 61/39 0.6 Delayed graft function was diagnosed in eight LDN 65/35 patients in the ODN and 11 in the LDN group. Serum creatinine, mg/L, days after surgery Within 3 months after transplantation, acute 3 tubular necrosis was diagnosed in seven ODN 100 18.5 (5–136) 0.23 patients in the ODN and in 11 in the LDN LDN 100 20.1 (7–125) group; and acute rejection in 11 in the ODN 21–30 and in two in the LDN group. Graft function ODN 100 14 (5–30) 0.35 was not significantly different between the LDN 100 16 (7–123) LDN and ODN groups, as determined by serum 90 creatinine levels after surgery (Table 4). Long- ODN 77 14.1 (6–47) 0.46 term graft survival was 93.8% in the LDN and LDN 78 14.7 (7–40) 92.7% in the ODN group. Three recipients in 180 the ODN and two in the LDN group were lost ODN 69 14.5 (7–43) 0.11 to long-term follow-up. LDN 64 14.1 (5–91) 365 ODN 48 13.0 (7–24) 0.94 DISCUSSION LDN 53 13.2 (8–28) Kuo et al. [8] reported that obese donors (BMI > 31 kg/m2) have similar outcomes with LDN as non-obese donors, but other studies during surgery. Two patients who had an chest tube was inserted for all cases with have found that increasing patient weight ODN and one who had a LDN required re- intraoperative pneumothorax. The rate of correlates with longer operative duration [9]. operation. The reasons for re-operation were postoperative donor complications was 17% To minimize the impact of obesity as an effect surgical site bleeding (one patient in each in the LDN group and 9% in the ODN group modifier, we narrowed the inclusion criteria of group) and pleural haemorrhage (one patient (Table 1). There were no major complications the present study to only include donors with in the ODN group). There were no cases of in either group. a BMI of <28 kg/m2. malfunction of vascular clips on major vessels in the LDN group. Minor intraoperative The mean (SD) score for donor satisfaction Some researchers showed a halving in complications are also shown in Table 1. A was 17.3 (3.5) for ODN and 19.6 (1.0) for LDN hospital stay for LDN and a more rapid return

SIMFOROOSH ET AL.

to work [1,10–12]. Lind et al. [3] stressed that increasing experience should be less common. REFERENCES LDN is associated with a shorter hospital stay In previous studies, the conversion rate from than is ODN (2.2–2.7 vs 3.8–5.7 days). In our LDN to ODN was 1.6–13% [11,19], but such 1 Ratner LE, Hiller J, Sroka M et al. transplantation centre, the policy is to favour conversion was required in only one patient in Laparoscopic live donor nephrectomy reducing the hospital stay, regardless of the present study. removes disincentives to live donation. surgical technique. In the present study, the Transplant Proc 1997; 29: 3402–3 mean hospital stay in the LDN group was There is a different pattern of complications 2 Ratner LE, Ciseck LJ, Moore RG, similar to that in other studies, but the mean and morbidity in ODN. Although one report Cigarroa FG, Kaufman HS, Kavoussi LR. hospital stay in the ODN group was shorter [10] showed that ODN has a higher incidence Laparoscopic live donor nephrectomy. than in other reports. of pneumothorax, flank nerve entrapment Transplantation 1995; 60: 1047–9 and flank hernia, in the present study one 3 Lind MY, Ijzermans JN, Bonjer HJ. Open Compared with ODN, LDN results in a shorter patient in each of the groups had thigh vs laparoscopic donor nephrectomy in time until patients are able to drive, take care numbness which might be a result of nerve renal transplantation. BJU Int 2002; 89: of the home, and return to full activity, work entrapment in the flank. Patients in both the 162–8 and regular exercise [11]. We divided the present groups had no major intraoperative 4 Fabrizio MD, Ratner LE, Kavoussi LR. ordinary activities into ‘light activities’, ‘heavy complications. In a recent series from the Laparoscopic live donor nephrectomy: activities’ and ‘ability for driving’. Donors in University of Maryland [19] among 738 LDNs pro. Urology 1999; 53: 665–7 the LDN group had a significantly shorter 15 major complications, including 13 vascular 5 Simforoosh N, Bassiri A, Ziaee SA et al. delay to resuming each type of activity. injuries and two bowel injuries, were reported. Laparoscopic versus open live donor Advantages of LDN thus include less loss of In the present study, two patients who had an nephrectomy: the first randomized income and thus a lower financial burden for ODN and one who had LDN required clinical trial. Transplant Proc 2003; 35: donors [13]. The cosmetic result of LDN is also reoperation. 2553–4 better than that of ODN [14–16] and this 6 Peto R, Pike MC, Armitage P et al. Design seems to be important for the present In the present study, recipients after LDN had and analysis of randomized clinical trials patients’ reported satisfaction. no ureteric complications. We performed a requiring prolonged observation of each wide dissection around the ureter, patient. I. Introduction and design. Br J Using a 20-point visual analogue scale, there maintaining adequate peri-ureteric fat; this Cancer 1976; 34: 585–612 was significantly less reported pain in the LDN wide dissection might explain the relatively 7 Danovitch GM, Nast C. Diagnosis and group, although the mean dose of parenteral low incidence of recipient ureteric therapy of graft dysfunction. In Owen WF, analgesic delivered in hospital was not complications. We also had no complications Pereira BJ, Sayegh MH eds. Dialysis and significantly different between the groups. from trocar entry; this success probably Transplantation – a Companion to The mean number of days receiving analgesia reflects the policy of simple open access, Brenner and Rector’s the Kidney, 1st edn. after discharge was lower in the LDN group. In whereby we introduced a regular reusable Philadelphia: WB Saunders, 2000: 568–83 the study of Waller et al. [17], donors were trocar from a 1.5-cm incision above the 8 Kuo PC, Plotkin JS, Stevens S, Cribbs A, managed after surgery with a patient- umbilicus (a modification of Hasson’s Johnson LB. Outcomes of laparoscopic controlled analgesia system and LDN was technique). The success of this LDN donor nephrectomy in obese patients. associated with less postoperative pain and a modification lowers the financial burden Transplantation 2000; 69: 180–2 lower analgesic requirement. upon donors, which might be particularly 9 Ratner LE, Smith P, Montgomery RA, important for donors in developing countries. Mandal AK, Fabrizio M, Kavoussi LR. The present study showed that warm Further efforts should be made to simplify Laparoscopic live donor nephrectomy: ischaemia time (within the range of our data) laparoscopic instrumentation and lower pre-operative assessment of technical did not significantly affect graft function. the cost of surgical instruments used for difficulty. Clin Transplant 2000; 14: 427– Buzdon et al. [18] reported on 640 LDNs and LDN. 32 found no effect of warm ischaemia time on 10 Flowers JL, Jacobs S, Cho E et al. recipient graft function within the range of LDN seems to be an attractive alternative to Comparison of open and laparoscopic live 35–720 s. In the present study the longest ODN. Our modification to LDN is technically donor nephrectomy. Ann Surg 1997; 226: time of warm ischaemia was 1020 s, longer feasible and, compared to ODN, gives greater 483–90 than that recommended as a safe limit by donor satisfaction, a faster return to work and 11 Brown SL, Biehl TR, Rawlins MC, Hefty Buzdon et al. [18]. Warm ischaemia time ordinary activities, and less pain after surgery. TR. Laparoscopic live donor nephrectomy: (within the present range) had no correlation Kidneys harvested by LDN have equivalent a comparison with the conventional open with recipient serum creatinine levels at the function to those harvested by ODN, graft approach. J Urol 2001; 165: 766–9 measured intervals, suggesting that any survival is similar with the two approaches, 12 Hiller J, Sroka M, Holochek MJ, damage from warm ischaemia might be and the warm ischaemia time (within the Morrison A, Kavoussi LR, Ratner LE. reversible. range of our data) appears to be safe. Functional advantages of laparoscopic live-donor nephrectomy compared with In the present study, there was no significant CONFLICT OF INTEREST conventional open-donor nephrectomy. difference in postoperative complications J Transpl Coord 1997; 7: 134–40 between the groups. Donor complications in None declared. Source of funding: Urology 13 Ratner LE, Kavoussi LR, Sroka M the LDN group seem to be declining, and with Nephrology Research Center (UNRC). et al. Laparoscopic assisted live donor

LAPAROSCOPIC VS OPEN DONOR NEPHRECTOMY

nephrectomy: a comparison with the organ loss? Curr Opin Urol 1999; 9: 219– nephrectomy: the University of Maryland open approach. Transplantation 1997; 22 6-year experience. J Urol 2004; 171: 47– 63: 229–33 17 Waller JR, Hiley AL, Mullin EJ, Veitch 51 14 Kim FJ, Ratner LE, Kavoussi LR. Renal PS, Nicholson ML. Living kidney transplantation: laparoscopic live donor donation: a comparison of laparoscopic Correspondence: Nasser Simforoosh, Urology nephrectomy. Urol Clin North Am 2000; and conventional open operations. Nephrology Research Centre, Shahid 27: 777–85 Postgrad Med J 2002; 78: 153–7 Labbaﬁnejad Hospital, Boostan 9th St., 15 Sasaki TM, Finelli F, Bugarin E et al. Is 18 Buzdon MM, Cho E, Jacobs SC, Jarrell Pasdaran Ave, PO Box 1666679951, Tehran, laparoscopic donor nephrectomy the new B, Flowers JL. Warm ischemia time does Iran. criterion standard? Arch Surg 2000; 135: not correlate with recipient graft function e-mail: [email protected] 943–7 in laparoscopic donor nephrectomy. Surg 16 Chan DY, Ratner LE, Kavoussi LR. Endosc 2003; 17: 746–9 Abbreviations: L(O)DN, laparoscopic (open) Laparoscopic donor nephrectomy: 19 Jacobs SC, Cho E, Foster C, Liao P, donor nephrectomy; BMI, body mass standard of care or unnecessary risk of Bartlett ST. Laparoscopic donor index.

Blackwell Science , LtdOxford , UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article TIMING FOR CHEMICAL DE-EPITHELIALIZATION OF AN ILEAL SEGMENT BAKHTIARI et al.

Another group of authors from Iran Determination of the time required attempted experimentally to determine the required time for for appropriate chemical de- the appropriate enzymatic epithelialization of an ileal segment treatment of the ideal segment to complete de-epithelialization, thus for cystoplasty: an animal model reducing its absorptive function. They found that 25 min of JALAL BAKHTIARI, HAMID REZA FATTAHIAN, MOHAMMAD JAVAD GHARAGOZLOU*, ABDOLMOHAMMAD KAJBAFZADEH† enzymatic treatment of the ideal and SEYED REZA JAFARZADEH segment was adequate for this, and Departments of Clinical Sciences and *Pathobiology, Faculty of Veterinary Medicine, University of that it was recommended from Tehran, and †Department of Paediatric Urology, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran their experimental study for Accepted for publication 12 November 2004 cystoplasty.

OBJECTIVES blood glucose level (BGL) for the groups at different times after the glucose-absorption To determine the time required for the test, but a pair-wise comparison showed appropriate enzymatic treatment of an ileal signiﬁcant differences in BGL between group segment to de-epithelialize its mucosa and to 1 and the other groups, except group 7. The reduce its absorptive function for cystoplasty degree of histopathological change was in dogs. associated with the duration of enzymatic treatment, in that changes were more MATERIALS AND METHODS prominent in group 7. There was no shrinkage or collagen deposition. Twenty-one adult female Persian mixed-breed dogs were divided into seven equal groups: CONCLUSIONS group 1 (negative control group) had no ileocystoplasty; group 2 (positive control In these conditions, 25 min of enzymatic group) had a routine ileocystoplasty with no treatment of the ileal segment is sufﬁcient to enzymatic treatment of the ileal segment; and remove the absorptive function of the groups 3–7 had an ileocystoplasty with 5, 10, augmented bladder, and is recommended for 15, 20 or 25 min, respectively, of enzymatic cystoplasty in dogs. treatment of the ileal segment with collagenase and trypsin. The seven groups KEYWORDS were then compared for haematological, biochemical and histological changes, and de-epithelialization, cystoplasty, enzymatic glucose reabsorption assessed using a treatment, glucose absorption test, dog glucose-absorption test.

RESULTS INTRODUCTION

No dogs showed any signs of metabolic Ileocystoplasty is used often to reconstruct disturbances, biochemical and haematological the bladder in patients with end-stage changes. There were signiﬁcant differences in bladder dysfunction when other more

BAKHTIARI ET AL.

conservative management fails. Almost all intravenous) was administered as a fluids for 24 h and cefazolin (20 mg/kg, parts of the gastrointestinal system have been prophylactic antibiotic before inducing intramuscular for 8 h) for 3 days. successfully incorporated into the urinary anaesthesia. The anaesthetic protocol was by bladder for urinary diversion, to increase atropine sulphate (0.02 mg/kg, subcutaneous) Blood samples were drawn from the cephalic capacity, improve compliance, or abate as premedication, and diazepam (0.27 mg/kg) vein at 0, 14 and 35 days to assess uncontrollable detrusor contractility, and and ketamine hydrochloride (5.5 mg/kg, both haematological and biochemical changes, and for intractable interstitial cystitis [1–5]. intravenous) to induce, and 1% halothane to ultrasonography used at 14 and 35 days to Complications include the metabolic maintain, anaesthesia. After the abdominal evaluate the augmented bladder wall disturbances secondary to electrolyte skin was shaved and disinfected with thickness. The absorptive capacity of the ileal reabsorption, metabolic acidosis because of povidone-iodine, the surgery was through a segment epithelium was determined using a the absorptive function of epithelial tissue on midline incision. A 20-cm long ileal segment glucose absorption test; 5 weeks after the ileal segment, asymptomatic chronic at least 10 cm proximal to the ileocaecal valve surgery, 60 mL of 50% dextrose was instilled bacteriuria, UTIs, vitamin B12 and nutritional and before the ileocaecal ligament, with an through a 12 F Foley catheter into the bladder. deficiencies in children, urinary obstruction adequate mesentery to reach the native The blood glucose level (BGL) was then secondary to mucus formations of goblet bladder, was selected. The mesentery was measured in each group before anaesthesia cells, diarrhoea after neural stretch reflexes, cleared from the bowel at each end for a short (T1), after anaesthesia to assess glucose osteomalacia and osteopenic changes, distance to create a window, and the bowel absorption (T2) and at 5-min intervals for up adenocarcinoma, bladder rupture after divided at these ends. Intestinal continuity to 25 min (T3 to T7, respectively). ischaemia or scar tissue formation along the was re-established with an ileo-ileostomy anastomosis, which may question the created using an end-to-end anastomosis Epithelial loss, as assessed on beneficial effects of the procedure [6]. Several with a single-layer simple interrupted 3–0 histopathological sections on the day of techniques have been introduced for polyglactin 910 suture. The ileal segment for surgery, was graded on a scale of +1 to +4, mechanical gastrointestinal mucosal ablation, augmentation was irrigated clear with 0.9% representing £25% 25–50% 50–75% and with different clinical results [6]. Enzymatic normal saline and 0.25% neomycin sulphate 75–100% loss of epithelium, respectively. The treatment of the ileal segment has been solution. The ileal segment was treated histology of the augmented bladder was suggested for de-epithelialization of its enzymatically according to the predetermined assessed at the end of the follow-up. After mucosa and reducing its absorptive and time, and ª5 mm of the ileal segment anaesthesia, the abdomen was re-opened secretive functions [7]. Thus the purpose of surgically resected and assessed to determine and the general aspect of the augmented the present study was to determine the the degree and extent of enzymatic effects on bladder and vascularization of the graft required time for appropriate enzymatic de- the intestinal epithelium. The intestinal evaluated, with special attention to epithelialization of an ileal segment for segment ends, which were clamped during appearance, texture and elasticity. The cystoplasty. the enzymatic treatment, were cut to ensure augmented bladder was removed, opened, equal enzyme contact throughout the fixed in 10% buffered formalin and embedded segment. Then 15 cm of the ileal segment was in paraffin wax. Random histological sections opened on its antimesenteric border, of 5 mm thick were stained with haematoxylin MATERIALS AND METHODS detubularized and reconstructed as a U shape. and eosin (H&E) and Masson’s trichrome. The bladder was then incised in the sagittal Animals were killed 35 days after surgery The study included 21 female Persian mixed- plane, extending near the bladder neck with an overdose (intravenous) injection of breed dogs (aged 1–2 years, 15–24 kg), ventrally and near the trigone dorsally. The thiopental sodium solution. All layers in the vaccinated and prescribed anti-helminth ileal segment was the anastomosed to the bladder, the ileal segment and in the vesico- agents before surgery. The dogs were given native bladder using a two-layer closure (an enteric junction were evaluated by light neomycin sulphate (0.5 mg/kg, orally) for 24 h inner layer of running 3–0 polyglactin 910 microscopy. and were fasted for 12 h before surgery. The and an outer layer of running Cushing 3–0 dogs were divided into seven equal groups polyglactin 910). The mesenteric window at A mixed-model (repeated-measures) ANOVA (randomly assigned): in group 1 (negative the bowel anastomosis was closed. The water- was used to compare BGL among the groups control group) the dogs had sham surgery tightness of the ileo-ileostomy and and within each group at different times with no ileocystoplasty; in group 2 the dogs ileocystoplasty were checked by injecting (T1–T7), with P < 0.05 considered to indicate had a routine ileocystoplasty with no 0.9% normal saline solution into the significance [8,9]. enzymatic treatment of the ileal segment; in augmented bladder, to detect any leakage groups 3–7 the dogs had an ileocystoplasty from the suture lines. The abdominal cavity with an ileal segment treated for 5, 10, 15, 20 was irrigated with 0.9% normal saline RESULTS or 25 min, respectively, with 100 mL of a solution. The peritoneum and abdominal 0.125% enzymatic cocktail, consisting of muscles, and subcutaneous layers were There was no difference in serum electrolytes, collagenase and trypsin. separately closed with a single-layer of blood urea nitrogen, creatinine, total protein, running 3–0 polyglactin 910 suture, and the albumin, blood gases, triglycerides, For the surgical procedure, an intravenous skin closed with simple interrupted 3–0 cholesterol, anion gap and haematological line was started beforehand and all dogs polyamide sutures. The skin was bandaged to profiles in all groups. Ultrasonography received 5% dextrose-lactate-Ringer’s prevent self-mutilation and contamination. showed a mean wall thickness of 2.30 mm in solution at 60 mL/kg. Cefazolin (20 mg/kg, After surgery all dogs received intravenous the ileal segment, 2.41 mm in the native

TIMING FOR CHEMICAL DE-EPITHELIALIZATION OF AN ILEAL SEGMENT

FIG. 1. 200 Macroscopically, the adventitia, the Glucose absorption in groups 1–7 mesenteric vasculature, smooth muscle at different times; T1, before 180 layers, transitional and ileal mucosa were anaesthesia; T2–T7, 5-min normal in appearance. The internal surface of 160 GROUP intervals after anaesthesia. the augmented bladder was completely 1 140 covered with apparently healthy mucosa. 2 Compared with other parts of the bladder, the 120 vesico-enteric junction was uniformly 3 thickened and elevated.

Glucose, g/dL 100 4 The native bladder tissues, including 80 5 transitional cell layer, submucosal, muscle 60 6 layers and adventitia, were normal in 40 7 appearance but in some cases there was a T1 T2 T3 T4 T5 T6 T7 mild to moderate oedema of the submucosal Time connective tissues.

In the vesico-enteric junction, the FIG. 2. A few smooth muscle fibres within the FIG. 3. Narrow filiform villi composed of two layers histopathology showed transitional cell healing mature granulation tissues at the junctional of adjacent modified epithelial cells, with no hyperplasia, metaplasia and transitional zone. Masson’s trichrome ¥ 100. discernible lamina propria. H&E ¥ 250. epithelium growing and migrating over the intestinal villi, which formed a urothelial-like layer over the intestinal epithelium (urothelialized to the top of the villi). There was fairly mature granulation tissue and fibrosis, and focal and diffuse infiltration of lymphocytes at the junctional zone.

On Masson’s trichrome staining a few smooth muscle fibres were found within the healing mature granulation tissues at the junctional zone (Fig. 2). Heterotropic bone formation was found in the vesico-enteric junction in two of 18 dogs, and in one there was a bladder and 6.00 mm in the vesico-enteric mucocele lined by attenuated epithelial cells, zone. containing mucus material and desquamated cells. There were significant differences in BGL among the groups and at different times; In the ileal segment, the smooth muscle pair-wise comparison showed significant layers, myenteric plexus, Peyer’s patches differences in BGL between group 1 and the and serosa of the ileal tissue were intact. other groups, except group 7, which indicated The mucosa showed atrophic changes that the acceptable enzymatic treatment time characterized by blunting and a reduction in was 25 min (i.e. in groups 1 and 7 there was a both villus height and crypt depth. In some similar amount of glucose absorbed via the animals the atrophic changes were very bladder). Although the BGL was lower in (+1) while 10 min caused 33% denudation of marked, in which the crypts were absent and group 6 than 2–5, it was not statistically the villi epithelium (+2) with partial crypt the villi originated from the vicinity of the significant, indicating that 20 min of lysis. At 15 min of treatment about half the muscularis mucosa. Some villi showed severe enzymatic treatment of the ileal segment was villi were de-epithelialized (+2) while 20 min atrophic changes, appeared as very narrow not enough to completely abolish the caused 75% denudation (+3) with more crypt filiform villi composed of two layers of absorptive capacity of the bladder to a level lysis, and almost complete denudation of villi adjacent modified epithelial cells, with no similar to that in group 1, as occurred in epithelium (+4) at 25 min. The lamina propria, discernible lamina propria (Fig. 3). There were group 7 (Fig. 1). The pair-wise comparison stratum compactum, Peyer’s patches, fewer goblet cells. The intervilli space was also showed significant differences in BGL in muscular layers and serosa were intact in wider, and in some animals the crypts were T1 or T2 with the other times (T3–T7). all sections except those treated for dilated and contained a mixture of mucus and 25 min. Mild vascular damage, petechial proteinaceous eosinophilic material. At the Histological sections taken on the day of haemorrhage in the villi apex and villi sites of the enzymatic interactions where the surgery showed that 5 min of treatment separation were apparent in a few epithelial cells of villi had been lysed and denuded focally 20% of the villi epithelium histopathological sections. desquamated, the lost epithelial cells were

BAKHTIARI ET AL.

replaced by hyperplastic, attenuated, protamine sulphate at 10 mg/mL and urea at FIG. 4. The hyperplastic and deformed regenerated deformed regenerated uniform cells which, 200 g/L for 15 min in a volume of 50–60 mL uniform cells are parallel to the basement in contrast to the normal epithelial cells [14]. membrane. H&E ¥ 400. of the villi, had the long axis of their nuclei parallel to the basement membrane. In In the present study, except for mild to addition there were no goblet cells among the moderate oedema in some cases, all layers of regenerated epithelial cells (Fig. 4). Collagen native bladder were of normal appearance. A deposition (fibrosis) was not seen in all groups urothelial-like layer of migrating transitional (Masson’s trichrome staining). epithelium, with hyperplasia and metaplasia, was evident on top of the intestinal villi, as The histopathological changes seen in all the previously seen in rats [17]. The few smooth experimental groups were relatively constant, muscle fibres apparent within the healing but the degree of change was associated with mature granulation tissues at the junctional the duration of enzymatic treatment, so that zone may originate from the muscularis layers the changes were more prominent in group 7. of the native bladder or ileal segment. It was There was no necrosis, dysplastic changes, stated that they are the result of hypertrophy, granulomatous reactions and fibrosis or any migration and differentiation from undesirable tissue alterations in the connective tissue cells [18,19]. In two cases, augmented bladder. heterotopic bone formation was apparent in the vesico-enteric junction, which was previously seen at the junctional zone of DISCUSSION bladder and bovine amniotic membrane [20].

Gastrointestinal segments are a very useful In the present study, enzymatic treatment had source for reconstructing and augmenting no significant adverse effects on the ileal the urinary bladder in the management of layers, consistent with other studies [7]. various problems. Unfortunately, no intestinal The atrophic changes consisting of reduced segment is a physiological substitute for villous height and crypt depth were also indicating that enzymatic treatment for the native bladder. The complications of documented by some [21] although others 25 min was sufficient; both groups 1 and 7 augmentation cystoplasty may persist and reported increases in height and crypt length, absorbed a similar amount of glucose via the are significant for some patients [6]. The or markedly reduced height of villi with bladder, showing that 25 min of enzymatic magnitude of the complications depends normal crypt depth in a rat model [22,23]. treatment can reduce the absorptive capacity on the type of intestinal segment used, the In the present model there were also severe of an ileal segment to that of a normal amount of functional mucosa, the duration of atrophic changes of villi which gave them a bladder. Enzymatic treatment for 20 min was the contact of urine with epithelium, and narrow filiform appearance. insufficient to properly abolish the absorptive renal functional capacity [10,11]. There are capacity of the bladder to a level similar to many suggestions for de-epithelializing Enzymatic treatment of an ileal segment by that in groups 1 and 7. This confirms that the intestinal mucosa, and reducing its collagenase and trypsin was previously 25 min of enzymatic treatment of the ileal absorptive and secretive functions, to fulfil successful in rats [7]; the epithelium was segment for ileocystoplasty is enough to the requirement of an ideal substitute, atrophied in the control and treatment remove the absorptive capacity of the bladder, including mechanical, seromuscular groups, and it completely abolished the and not increase the BGL for up to 25 min enterocystoplasty, chemical destruction of absorptive function of the epithelium, while after glucose absorption in dogs. A shorter the intestinal mucosa by hypertonic normal the BGL increased to twice the baseline values duration (5–20 min) of enzymatic treatment saline solution, hemi-acidrin, photochemical in the control group. did not significantly reduce the absorptive ablation using haematoporphyrin derivatives function of the bladder. and red light, collagenase and trypsin, In the present model, glucose was gradually protamine sulphate and urea solution, silver absorbed from the bladder with Glucose is basically transported through the nitrate solution and HEPES-buffered saline autotransplanted ileum, but the absorption intestinal membrane in a co-transport mode [6,12–16]. rate of the augmented bladder using a with the active transport of sodium. In the standard ileocystoplasty procedure was rapid. first stage, sodium is actively transported The absence of significant changes in the The malabsorption of an intestinal segment through the basolateral membranes of the biochemical data reflects the absence of used as the urinary bladder seems to be intestinal epithelial cells into the paracellular renal damage and significant metabolic favourable, because hyperchloric acidosis spaces. In the second stage, sodium combines disturbances secondary to bladder and caused by urine reabsorption cannot occur. with a transport protein in the interior of the intestinal surgery [14]. We found that 25 min However, studies show that carbohydrate cell, but this protein does not transport the of enzymatic treatment could completely absorption is not generally impaired [24]. sodium until it also combines with some other de-epithelialize ileal mucosa. One study appropriate substances, e.g. glucose [24]. showed that >90% of the epithelium was There was no statistically significant Normal bladder has neither absorptive nor removed when bladders were treated using difference in BGL between groups 1 and 7, secretive ability [23]. The reduction of

TIMING FOR CHEMICAL DE-EPITHELIALIZATION OF AN ILEAL SEGMENT

absorptive function of an enzymatically 6 Rink RC, Adams MC. Augmentation injection in the porcine model. Tech Urol treated ileal segment was probably a result of cystoplasty In Walsh PC, Retik AB, 2001; 7: 70–4 changes in the ultrastructure of cellular Vaughan ED, Wein AJ eds, Campbell’s 17 Guan Z, Richard G, Charest-boule L, membranes [7]. Although the present study Urology, 7th edn. Vol. III. Chapt 102. Nelson K, Kiruluta G. Augmentation showed that glucose absorption through the Philadelphia: WB Saunders, 1998: 3167– cystoplasty in rats. Development of an ileal membrane was abolished after 25 min of 89 animal model. J Urol 1990; 144: 461–5 enzymatic treatment, some extrapolation is 7 Turkeri LN, Simek F, Sav A, Ilker YN, 18 Ueno K, Yamanaka N, Kimura S, possible for the associated electrolyte Akdas A. Enzymatic treatment of ileal Arakawa S, Kamidono S, Hara I. Bladder movements. segment used for urinary tract reconstruction with autotransplanted reconstruction. Int Urol Neph 1996; 28: ileum in the dog: better functional results 655–63 than standard enterocystoplasty. BJU Int ACKNOWLEDGEMENTS 8 Petrie A, Watson P. Statistics for 2001; 87: 703–7 Veterinary and Animal Sciences. London: 19 Probst CW. Small intestines. In Slatter D The authors thank Drs Iradj Nowrouzian, Blackwell Sciences, 1999: 90–100 ed. Textbook of Small Animal Surgery. Vol. Abbas Veshkini and Dariush Shirani for their 9 Shannon DM, Davenport AM. Using 1. Philadelphia: WB Saunders, 1993: 53– kind assistance during the study. This study SPSS to Solve Statistical Problems. 63 was supported by the Research Council, New Jersey: Merrill Prentice Hall, 2001: 20 Bakhtiari J, Saberi-Afshar F, Noorbala University of Tehran (Grant # 218/3/512). 273–84 H, Gharagozlo MJ, Veshkini A. Urinary 10 Goldwasser B, Barret DM, Benson RC. bladder reconstruction using fresh and Bladder replacement with use of a formalin-preserved bovine amnion in CONFLICT OF INTEREST detubularized right colonic segment: dogs. MJIRI 2000; 14: 277–81 preliminary report if a new technique. 21 Kojima Y, Asaka H, Ando Y, Takanashi None declared. Source of funding: Mayo Clin Proc 1986; 61: 615 R, Kohri K. Mucosal morphological Research Council, University of Tehran 11 Narayan P, Broderick GA, Tanagho EA. changes in the ileal neobladder. Br J Urol (Grant 218/3/512). Bladder substitution with ileocecal 1998; 82: 114–7 (Mainz) pouch. Clinical performance over 22 Burnett AL, Donowitz M, Marshall 2 years. Br J Urol 1991; 68: 588 FF. Inhibition of transport processes REFERENCES 12 Brandell RA, Hall MC, Koch MO, Braren of intestinal segment following HV. Exposure of intestinal segments to augmentation enterocystoplasty in rats. 1 Rowland RG, Mitchell ME. Perspective hemiacidrin: analysis of metabolic and J Urol 1996; 156: 1872–5 on cystectomy and diversion. In: AUA histological effects using a rat model. 23 Davidson T, Carlen B, Bak-Jensen E, Update Series 1985; IV: Lesson 29 J Urol 1994; 152: 725–7 Willen R, Mansson W. Morphologic 2 Klimberg IW, Wajsman Z. Treatment for 13 Haselhuhn GD, Kropp KA, Keck RW, changes in intestinal mucosa with urinary muscle invasive carcinoma of the bladder. Selman SH. Photochemical ablation contact-effects of urine or disuse? J Urol J Urol 1986; 136: 1169 of intestinal mucosa for bladder 1996; 156: 226–32 3 Hendern HW, Hendern RB. Bladder augmentation. J Urol 1994; 152: 24 Guyton AC, Hall JE. Digestion and augmentation. Experience with 129 2267–71 absorption in the gastrointestinal tract. In children and young adults. Follow-up in 14 Niku SD, Scherz HC, Stein PC, Parsons Textbook of Medical Physiology, 10th edn. 129 cases. J Urol 1987; 139: 579 CL. Intestinal de-epithelialization and Chapter 65. Philadelphia: WB Saunders 4 Mitchell ME, Piser JA. augmentation cystoplasty: an animal 2000: 754–63 Intestinocystoplasty and total bladder model. Urology 1995; 46: 36–9 replacement in children and young adults. 15 Demirbilek S, Aydin G, Ozardali HI, Correspondence: Jalal Bakhtiari, Department Follow-up in 129 cases. J Urol 1987; 138: Baykara S. Chemically induced intestinal of Clinical Sciences, Faculty of Veterinary 579 de-epithelialization using silver nitrate for Medicine, University of Tehran, PO Box 5 Melchior H, Spehr C, Knop-Wagemann bladder augmentation. Urol Res 2001; 29: 14155–6453, Tehran, Iran. I. The continent ileal neo-bladder for 29–33 e-mail: [email protected] urinary tract reconstruction after 16 Liu IJ, Lee AM, Terris MK. cystectomy. A survey of 44 patients. Effectiveness of denuding the Abbreviations: H&E, haematoxylin and eosin; J Urol 1988; 139: 714 intestinal mucosa by submucosal BGL, blood glucose level.

Blackwell Science , LtdOxford , UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article LAPAROSCOPIC MANAGEMENT OF INTERSEX PATIENTS DÉNES et al.

In the world’s largest series of The laparoscopic management of patients with intersex treated by laparoscopy, authors from Sao intersex patients: the preferred Paulo found that this technique approach allowed easy identiﬁcation and removal of gonads. They also found FRANCISCO T. DÉNES, MARCELO A.S. COCUZZA, that other organs could be EDISON D. SCHNEIDER-MONTEIRO, FREDERICO A.Q. SILVA, removed and genitoplasty ELAINE M.F. COSTA*, BERENICE B. MENDONCA* and SAMI ARAP Divisions of Urology and *Clinical Medicine and Endocrinology, University of São Paulo School of performed. Medicine Hospital, São Paulo, Brazil Accepted for publication 30 November 2004

OBJECTIVE approach to complete its removal, together with masculinizing genitoplasty. There To present possibly the largest series of the were no intraoperative complications or use of laparoscopy for treating intersex conversions; two patients had complications patients. after surgery.

PATIENTS AND METHODS CONCLUSIONS

Fifty intersex patients (34 with male and two Laparoscopy allows the straightforward with female pseudohermaphroditism, nine identiﬁcation and removal of gonads. All with gonadal dysgenesis, four with true abnormal ductal structures must be removed, hermaphroditism, and one with complex as this increases the chance of resecting hypospadias), aged 0.5–46 years (mean 18.3), unidentiﬁed gonads. Removing the uterus underwent laparoscopy to remove gonads and vaginal component of the urogenital and/or ductal structures incompatible with sinus in patients with male social sex is the social gender, or for gonadal tumour or a feasible, with low morbidity. Genitoplasty, potential risk for malignancy. When necessary, according to the social sex, can be performed genitoplasty was performed concomitantly. in the same procedure.

RESULTS KEYWORDS

At the laparoscopic evaluation, 10 gonads of intersex, laparoscopy, treatment, gonads, six patients were absent, while four were ovary identiﬁed as ‘vanishing’; 72 gonads (46 dysgenetic, 17 normal testes, one normal ovary, one ovotestis, seven gonadoblastomas INTRODUCTION or dysgerminomas) were removed; two ovotestes were replaced in the scrotum after The management of patients with intersexual removing the ovarian segment, as was one states is clinically demanding. Only with a normal testis. Twelve patients with a careful clinical evaluation can the correct urogenital sinus had its vaginal component diagnosis be established, therefore reducing removed, 11 including a hysterectomy. Three the probability of therapeutic misconduct of these patients had a combined perineal (mainly for sex assignment). The therapeutic

DÉNES ET AL.

TABLE 1 Guidelines for the laparoscopic management of the gonads and Müllerian derivatives in intersex patients

Clinical intersex diagnoses Possible ﬁndings Social sex Laparoscopic management FPH Normal gonads, MDD Male Gonadectomy resection of MDD

MPH Normal gonads and/or Female Gonadectomy dysgenetic gonads; MDD Male Gonadectomy (when dysgenetic)/orchidopexy (when normal) Resection of MDD

TH Normal gonads, ovotestis Female Orchidectomy/resection of testicular tissue from ovotestis MDD Male Resection of ovarian tissue from ovotestis/orchidopexy Resection of MDD

GD Dysgenetic gonads, MDD Female Gonadectomy (Y chromosome) Male Gonadectomy (Y chromosome), resection of MDD

MDD, Müllerian duct derivatives.

objective is to offer the best quality of life, of the inguinal area [1]. Hormonal, resected, most often together with the ductal reconciling structural limitations with the cytogenetic and radiological investigation structures. In the presence of a normal testis functional potential of the external genital (pelvic ultrasonography and retrograde in a patient with a male social sex, organs, and adjusting them to the genitography) were also used. laparoscopic orchidopexy can be performed psychological characteristics and gender [2]. preferences of the patient, whenever defined The patients had a general anaesthetic with [1,2]. endotracheal and nasogastric intubation. The MPH represents the most frequent indication external genitals were re-evaluated under for therapeutic laparoscopy [1]. As the patient Laparoscopy was recently introduced as a anaesthesia, to plan the extent of the eventual with an underdeveloped phallus is generally method of evaluating and treating intersex reconstruction in the same procedure. The orientated to the female gender, the testes patients with impalpable gonads [1,3]. The entire abdomen and the genital area were must be resected. When present, the objective of the present study was to report cleansed and prepared. When combined hypoplastic uterus should be left, to allow the the results of what is, to our knowledge, the genitoplasty was planned, the patient was possibility of menstruation and pregnancy largest series of laparoscopic procedures in placed in the semi-lithotomy position, or [4,5]. When the testes are palpable, intersex patients. otherwise supine. The video monitor, orchidectomy can be done through insufflator and light source were positioned inguinotomies, but as most such patients at the foot of the patient. The surgical have impalpable testes, a laparoscopic PATIENTS AND METHODS technique included the classical steps for exploration and gonadectomy is indicated laparoscopic surgery, i.e. peritoneal [6,7]. When the patient is assigned to or From March 1994 to April 2004, 50 patients insufflation with a Veress needle inserted assumes a male role, laparoscopic with intersex disorders (mean age 18.3 infraumbilically, insertion of a 5–10 mm gonadectomy is still necessary when the years, range 0.5–46) were treated at our umbilical trocar for laparoscopic evaluation, gonads are dysgenetic or tumoral, but when institution. The disorders included male and two or three additional pelvic trocars for the testes are normal, orchidopexy is pseudohermaphroditism (MPH) in 34 patients, therapeutic procedures. The patient was then indicated. In cases of MPH with male gender, female pseudohermaphroditism (FPH) in two, placed in a Trendelenburg position. The resection of Müllerian duct derivatives is mixed gonadal dysgenesis (GD) in nine, true gonadal structures were evaluated initially, always necessary [8]. In the rare cases of FPH hermaphroditism (TH) in four and complex and when necessary, the bowel retracted. In with a male social sex, laparoscopic hypospadias in one. Laparoscopy was some cases when the gonads are not easily gonadectomy with resection of Müllerian indicated for evaluation, but mainly to seen, the gonadal vessels may be identified duct derivatives is also always necessary. In remove unwanted gonads and ductal and followed downwards. Most often, the patients with TH and female social sex, structures. Whenever necessary, associated gonads are identified near the inguinal region, laparoscopic orchidectomy or resection of genitoplasty was also performed. eventually with normal testicular or ovarian testicular tissue from the ovotestis is appearance, but also with a dysplastic or indicated. In patients with TH and male social The preoperative evaluation included a careful tumoral aspect. In some cases the gonads are sex laparoscopic resection of the Müllerian clinical history and detailed physical not clearly identified because of dysplasia, duct derivatives, ovary or the ovarian tissue examination, particularly of the external sometimes leading to confusion with ductal from ovotestis is indicated, as well as genitals and perineal orifices, with palpation structures. Once identified, the gonads are orchidopexy in selected cases. In patients with

LAPAROSCOPIC MANAGEMENT OF INTERSEX PATIENTS

TABLE 2 Clinical and histopathological information of patients with gonadal tumours; the incidence was seven in 75 gonads (9%) and ﬁve of 50 patients (10%)

Age, years Social sex Karyotype Clinical diagnosis Histological ﬁnding, right/left 13 Male 46,XY TH Ovotestis with gonadoblastoma/gonad absent 14 Female 46,XYq+/45X GD Hypoplastic ovary/gonadoblastoma 20 Female 46,XY MPH Gonadoblastoma/dysgerminoma 20 Female 45,X/46,XY GD Dysgerminoma + gonadoblastoma both sides 23 Male 46,XY GD Leydig cell hyperplasia/gonadoblastoma + mixed germinative cell tumour

FIG. 1. A 22-year-old with TH (XX, SrY+) with a male social sex: Left, genitography showing the bladder, Fallopian tubes to vestigial structures urogenital sinus, uterine cavity and tubes. Right, the result of laparoscopic hysterosalpingectomy with associated or not with normal or hypoplastic unilateral gonadectomy (ovary) and urogenital sinus resection (surgery also included open orchidopexy for uteri. Differences were also noted between palpable right testes and masculinizing genitoplasty). sides in the same patient. In all, 17 uteri and 12 urogenital sinuses were conﬁrmed laparoscopically.

After laparoscopic evaluation there were 38 bilateral and seven unilateral procedures intended to removed gonads and ductal structures, as well as 12 resections of the vaginal component of the urogenital sinus, six hysterosalpingectomies and ﬁve hysterectomies, one unilateral orchidopexy, and one resection of an ovarian segment of ovotestis associated with orchidopexy (Fig. 1). One bilateral herniorrhaphy and one cholecystectomy were also performed.

FIG. 2. A 14-year-old with GD (46,XY/45,X; female findings, are summarized in Table 1. When Only 75 gonads were confirmed histologically, social sex). A laparoscopic view of the increased left necessary, associated genitoplasty is also including five that were not identified gonad; the diagnosis was gonadoblastoma. performed, according to the sexual role of during surgery, but were resected each patient. incidentally together with the ductal structures. These gonads were either We evaluated the efficacy of laparoscopy in normal but contrary to the social sex, identifying the gonads, the success of dysgenetic or tumoral. gonadal and ductal resection, the relationship between surgical findings and gonadal Three of the 12 patients with a urogenital histology, the need for conversion to an open sinus who had its vaginal component procedure, the incidence of complications removed laparoscopically required a during or after surgery, and the need for blood combined perineal approach to complete transfusion. the removal, which was accomplished together with masculinizing genitoplasty. RESULTS Associated genital masculinization was done in 12 patients and feminization in seven. One All 50 patients had a laparoscopic evaluation ovotestis was replaced without laparoscopy in GD, particularly those with a Y chromosome, that identified the pelvic structures. Ten the scrotum after removing the ovarian gonadectomy is essential, while resection of gonads in six patients were absent on segment. Müllerian duct derivatives is indicated in laparoscopic evaluation. Two patients had patients with male social sex [8]. bilateral ‘vanishing testes’ identified by Five patients had seven neoplastic gonads blind-ending gonadal vessels. We defined (represented mainly by gonadoblastoma, a Because of social and geographical laparoscopically 86 structures as gonads; tumour of low malignant potential, and conditions, most of the present patients were some of these were not confirmed dysgerminoma, a malignant tumour), but only first evaluated as adults, and their treatment histologically, as described below. three of these gonads were enlarged (as seen adjusted to the already defined sexual role. before surgery on imaging, and during The laparoscopic procedures, according to The ductal structures were also very variable, laparoscopy), suggesting tumoral clinical diagnosis, social sex and laparoscopic ranging from normal epididymis and involvement (Fig. 2) (Table 2).

DÉNES ET AL.

All procedures were completed with minimal In most cases identifying these structures is resection of the inferior vaginal segment blood loss, except in one patient who had easy and their removal straightforward. of the urogenital sinus may be required. significant bleeding during genitoplasty, However, the accuracy of identifying the Genitoplasty, according to social sex, can receiving one unit of blood. The duration of gonads is not total. As documented here, be performed simultaneously with the procedures was 55–270 min, including there are cases where structures identified as laparoscopy. associated genitoplasty. There were no gonads and removed were not confirmed complications during surgery nor conversion histologically as such. On the other hand, to laparotomy, but in one patient with TH the some dysgenetic gonads were not identified, CONFLICT OF INTEREST resection of the ovarian portion of the being removed incidentally as ductal ovotestis and subsequent orchidopexy was structures. This reinforces the need to remove None declared. done through an inguinal incision, after all ductal structures when the gonads are not laparoscopic removal of the uterus and clearly identified, as most unseen dysplastic urogenital sinus, and the contralateral gonad. and potentially malignant gonads will be thus REFERENCES Only two patients had complications after removed. surgery, one with an umbilical port infection 1 Denes FT, Mendonca BB, Arap S. and another with a pelvic abscess, both The relative risk for testicular germ-cell Laparoscopic management of intersexual successfully treated with antibiotics. When tumours associated with intersex syndromes states. Urol Clin North Am 2001; 28: 31– there was only a laparoscopic procedure the is increased more than 100 times, justifying 42 hospital stay was 1–3 days, and with prophylactic gonadectomy as soon as is 2 Yu TJ, Shu K, Kung FT, Eng HL, associated genitoplasty the stay was feasible after the diagnosis is established [14]. Chen HY. Use of laparoscopy in 6–11 days. The risk of gonadal neoplasia is not confined intersex patients. J Urol 1995; 154: to patients with a 46,XY karyotype, but 1193–6 extends to patients with GD and any mosaic 3 Kriplani A, Abbi M, Ammini AC, DISCUSSION karyotype containing a Y chromosome or the Kriplani AK, Kucheria K, Takkar D. SRY antigen [15]. In the present patients Laparoscopic gonadectomy in male The first laparoscopic bilateral gonadectomy 9.3% of the gonads in 10% of the patients pseudohermaphrodites. Eur J Obstet in an intersex patient was reported in had tumours, but only three of them had Gynecol Reprod Biol 1998; 81: 37–41 1992 and since then this procedure has macroscopic abnormalities suggesting 4 Bardeguez AD, De Ziegler D, Weiss gradually become the standard for evaluating tumour. G. Multifetal pregnancy in a gonadal and treating the internal genital organs dysgenesis mosaic. Obstet Gynecol 1990; in these patients [9,10]. The classical We treated all patients by laparoscopy, with 76: 502–4 advantages of laparoscopy include the no conversion to laparotomy, or significant 5 Sauer MV, Lobo RA, Paulson RJ. elimination of a sizeable laparotomy bleeding or intraoperative complications. The Successful twin pregnancy after embryo incision, resulting in less discomfort after most difficult procedures are those associated donation to a patient with XY gonadal surgery, less need for analgesia, and a shorter with resecting the vaginal portion of the dysgenesis. Am J Obstet Gynecol 1989; hospital stay, convalescence and return to urogenital sinus, particularly in those whose 161: 380–1 normal activities [10]. Other advantages distal end extends beyond the urogenital 6 McDougall EM, Clayman RV, include magnification, excellent visibility diaphragm. The complication rate after Anderson K, Andriole GL, Coffin CM. and illumination, and less venous oozing surgery was 4%, including two localized Laparoscopic gonadectomy in a case of because of the pressure effect of the infections treated successfully with testicular feminization. Urology 1993; 42: pneumoperitoneum. One of the main conservative measures. 201–4 advantages of this method is the lack of scars, 7 Cadeddu JA, Watumull L, Corwin TS, a very important issue for these patients, who In conclusion, laparoscopy allows easy McConnell JD. Laparoscopic need reaffirmation of their body image and visualization of impalpable gonads, ductal gonadectomy and excision of mullerian self-esteem [1]. remnants and urogenital sinus in intersex remnant in an adult intersex patient. patients. All procedures necessary for Urology 2001, 554–7 The intersexual states for which laparoscopy adequately treating intersex disorders can 8 Grumbach M. Disorders of sex is more frequently used are MHP, FHP, TH and be done with few complications and all differentiation. In Wilson KH ed. GD [1]. It is helpful for gonadal evaluation, the advantages of the laparoscopic Endocrinology. Philadelphia: WB resection or biopsy, and for identifying procedures, even in small children. All Saunders Co., 1998: 853–951 internal ductal derivatives [3,11]. It is also dysgenetic, nonfunctioning and neoplastic 9 Wilson EE, Vuitch F, Carr BR. used for removing all normal structures gonads, and contradictory ductal structures, Laparoscopic removal of dysgenetic contrary to the assigned social sex, as can be resected. In cases where the gonad is gonads containing a gonadoblastoma in well as gonads that are either dysgenetic, not clearly identified, ipsilateral ductal a patient with Swyer syndrome. Obstet nonfunctional or malignant or of increased derivatives must be resected, as some Gynecol 1992; 79: 842–4 malignant potential [12,13]. specimens may include undetected 10 Gomel V. From microsurgery to dysgenetic gonads. Laparoscopic resection laparoscopic surgery: a progress. Fertil Laparoscopy gives an excellent view of the of urogenital sinus, with or without the Steril 1995; 63: 464–8 pelvic structures, including the genital organs. uterus, is feasible. Complementary perineal 11 Major T, Borsos A, Csiszar P.

LAPAROSCOPIC MANAGEMENT OF INTERSEX PATIENTS

Laparoscopic removal of gonads in N Jr. Laparoscopy in the management Correspondence: Francisco T. Dénes, Division gonadal dysgenesis. Int J Gynaecol Obstet of nonpalpable testes and intersex states. of Urology, University of São Paulo School of 1995; 49: 53–4 Arch Esp Urol 1993; 46: 638–41 Medicine Hospital, Caixa Postal 11273–9, CEP 12 Martin TV, Anderson KR, Weiss 14 Ulbright TM. Testis risk and prognostic 05422–970, São Paulo, SP, Brazil. RM. Laparoscopic evaluation and factors. The pathologist’s perspective. Urol e-mail: [email protected] management of a child with ambiguous Clin North Am 1999; 26: 611–26 genitalia, ectopic spleen, and Meckel’s 15 MacMahon RA, Cussen LJ, Walters WA. Abbreviations: MPH, male diverticulum. Tech Urol 1997; 3: 49–50 Importance of early diagnosis and pseudohermaphroditism; FPH, female 13 Ferreira U, Cassiano Esteves S, gonadectomy in 46,XY females. J Pediatr pseudohermaphroditism; GD, mixed gonadal Nogueira Castilho L, Rodrigues Netto Surg 1980; 15: 642–5 dysgenesis; TH, true hermaphroditism.

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Original Article PREDICTING THE INVOLUTION OF PRENATALLY DETECTED MCDK RABELO et al.

Predictive factors of ultrasonographic involution of prenatally detected multicystic dysplastic kidney

ELI ARMANDO S. RABELO*‡, EDUARDO A. OLIVEIRA*†, GUILHERME SOUZA SILVA*, ISABELA LEITE PEZZUTI* and EDSON SAMESINA TATSUO‡ *Paediatric Nephrourology Unit, †Department of Paediatrics, and ‡Department of Surgery, Hospital das Clínicas, Federal University of Minas Gerais – Belo Horizonte, MG, Brazil Accepted for publication 15 November 2004

OBJECTIVE method to evaluate the involution of the admission using two thresholds, 62 and MCDK, with differences between subgroups 78 mm). After adjusting by Cox’s model To evaluate possible predictive factors of assessed using the two-sided log-rank test. only a renal length at diagnosis of <62 mm involution on ultrasonography (US) or Cox’s regression model was applied for the remained associated with complete involution disappearance of a prenatally detected multivariate analysis. (relative risk 8, 95% confidence interval multicystic dysplastic kidney (MCDK). 0.98–68; P = 0.05). RESULTS PATIENTS AND METHODS CONCLUSION The mean (range) follow-up was 50 (12–167) Forty-five children with unilateral MCDK months; in all, 279 ultrasonograms were These results suggest that only a renal length detected by prenatal ultrasonography taken, the mean (range) number per patient of 62 mm on initial US was predictive of between 1989 and 2002 were analysed. All being 6 (3–10). US showed partial involution < complete involution of the MCDK during the patients except one had 99mTc isotopic of the MCDK in 30 (67%) cases and complete follow-up. scintigraphy to confirm the absence of renal involution in nine (20%). The absolute MCDK function in the MCDK. All children were length remained almost unchanged in six managed conservatively with follow-up visits children (13%). Univariate analysis showed KEYWORDS every 6 months, with US 6-monthly during that four variables were possibly associated the first 2 years of life and yearly thereafter. with complete involution of the MCDK multicystic kidney, prenatal diagnosis, Survival was analysed using the Kaplan-Meier (gender, impalpable kidney, renal length at management, ultrasonography

INTRODUCTION controversies persist about the best approach (ii) at least three ultrasonograms; (iii) ≥1 year [10,11]. of follow-up; (iv) the presence of a unilateral The management of the multicystic dysplastic MCDK; and (v) no chromosome alterations kidney (MCDK) has changed over the past In the present study, we analysed the or associated multiple malformations. Six 20 years; the surgical approach has been outcome of children with prenatally detected children were excluded from the study, replaced by conservative management MCDK managed conservatively, the purpose two because they were lost to follow-up through a conjunction of factors [1]. After being to identify variables that are and four because they had only two US the spread of antenatal ultrasonography independent predictors of the rate of studies up to the date of analysis. All (US) a better understanding of the natural involution of MCDK. patients except one had a 99mTc-DMSA history of renal disorders has allowed a isotope scan to confirm the absence of more conservative approach to many of renal function in the MCDK. A voiding these conditions [2]. There has been a cysto-urethrogram was taken in 44 patients substantial increase in cases detected in PATIENTS AND METHODS (98%). Prophylactic antibiotics were used asymptomatic neonates as a consequence only until the voiding cysto-urethrogram of prenatal US [3]. Advances in modern Forty-five children (23 boys) with unilateral was taken or, if VUR was detected, until it US combined with DMSA renal scintigraphy MCDK detected by prenatal US between 1989 resolved. have permitted diagnoses with a high degree and 2002 and who fulfilled the criteria of of certainty [4]. In addition, most MCDK the study were included in the analysis. Patients were investigated according to a undergo spontaneous involution during The following criteria were adopted for systematic protocol described in detail follow-up, as shown by serial US studies [5,6]. inclusion in the study: (i) diagnosis of MCKD elsewhere [13]. Briefly, patients had US, a Nevertheless, the rate of involution can raise according to the variables described by Stuck clinical examination (including growth and concern about the malignant potential of et al. [12], including the presence of multiple blood pressure measurements), and MCDK. Although this is a rare complication, a noncommunicating cysts of various sizes and laboratory assessments at 6-month intervals few cases have been reported [7–9], and thus no evidence of identifiable renal parenchyma; during the first 2 years of life and yearly

PREDICTING THE INVOLUTION OF PRENATALLY DETECTED MCDK

FIG. 1. A admission, serum renal function was The effect of time from diagnosis 100 within the normal limits for age; the and MCDK length at diagnosis mean (range) serum creatinine level was (>62 mm, green line; <62 mm, 80 0.45 (0.2–0.9) mg/dL and the estimated GFR red line) on involution, as 60 65.8 (25.5–145.6) mL/min. At the end of the detected on US. The crosses follow-up the mean serum creatinine was represent censored values. 40 0.5 (0.3–0.9) mg/dL and the estimated GFR 121 (65–188) mL/min. Two children (4.5%) 20 developed hypertension during the follow-up. Cumulative percentage 0 The mean follow-up was 50 (12–167) B months; in all, 279 ultrasonograms were 100 taken in the 45 patients, the mean number per 80 patient being 6 (3–10). US showed partial involution of the MCDK in 30 (67%) cases and 60 complete involution in nine (20%). The absolute MCDK length remained almost 40 unchanged in six children (13%). 20

Cumulative percentage Of the 45 MCDK, 22 (49%) reduced by half the 0 6162626465666768696 maximum longitudinal renal length at Time from diagnosis, months diagnosis. The estimated mean (95% CI) time for the MCDK to attain half the initial renal length was 76 (62–92) months. From the thereafter. Plasma creatinine was determined patient subgroups assessed by the two- Kaplan-Meier analysis it was estimated that at the postnatal examination and yearly sided log-rank test. A Cox regression model 23% of the MCKD had this reduction at thereafter. The GFR was estimated by the was then applied to identify variables that ª2 years and 40% by 5 years (Fig. 1a). method of Schwartz et al. [14]. were independently associated with the involution of the MCDK [17]. Only those Nine of 43 MCDK became undetectable on US, For US, a scanner (Sonoline Prima SLC, variables that were associated with an of which five disappeared after 24 (9–122) Siemens, Germany) and a 5-MHz probe were adverse outcome by univariate analysis months of follow-up. The estimated mean used, with the patients prone and supine. The (P < 0.25) were included in the Cox regression (95% CI) time to complete involution of kidneys were measured on US to obtain the model [18]; using a backward elimination the MCDK was 121 (99–142) months. The maximum longitudinal and transverse kidney strategy, those variables that retained a Kaplan-Meier estimate of complete MCDK sections; the maximum length, width and significant independent association with involution showed that 20% were anteroposterior dimension of both kidneys adverse outcome (P < 0.05) were included in undetectable on US at ª36 months and half were measured, and renal volume calculated the final model. Two end-points were at ª10 years of age. according to the formula of Han and Babcock considered for these analyses: (i) the time [15]. when MCDK decreased to half the size of the The univariate analysis showed that no maximum longitudinal length at diagnosis; variables were significantly associated with The predictive indices used were based and (ii) the time when the MCKD became partial MCDK involution (Table 1). According on patient data at the time of entry into undetectable on US. All children showing to our methods, three variables were suitable the study. The following variables were complete involution had had at least two US for inclusion in the multivariate analysis, i.e. included in the analysis: gender, affected studies, both of which confirmed the absence gender, palpable kidney and MCDK length side (left or right), flank palpation (MCDK of the MCDK. Informed consent was obtained (75th percentile). After adjusting by the Cox palpable or impalpable on first physical from the parents and the study was approved model, no variable was associated with a examination), MCDK length at first US, by the Ethics Committee of the authors’ decrease in the MCDK to half the size of the and contralateral kidney length and institution. maximum longitudinal length at diagnosis. volume on first US. Continuous variables (renal length) were dichotomised using the According to our criteria, four variables were mean and the 75th percentile of each RESULTS suitable for inclusion in the multivariate measurement. analysis, i.e. gender, palpable kidney and Postnatal US confirmed the diagnosis of MCDK length (at two thresholds, 62 and The statistical analysis was conducted in unilateral MCDK and suggested mild 72 mm). As an example, the mean time two steps. In the first, a univariate analysis hydronephrosis in five contralateral units; estimated for involution of MCDK of <62 mm was used to identify variables that were renal scintigraphy showed exclusion of the long was 100 months (95% CI 70–130). significantly associated with the involution affected kidney in all cases. VUR into the Conversely, the estimated probability for an of the MCDK, using the Kaplan-Meier contralateral ureter was found in only three MCDK of ≥62 mm on initial US was method [16], with differences between patients (6%). On laboratory evaluation at 123 months (95% CI 10–243). The effect of

RABELO ET AL.

TABLE 1 Predictive factors of the partial and complete involution of MCDK (univariate analysis)

Factor Partial (+)Partial (-) log-rank P Complete (+) Complete (-) log-rank P N2223936 Gender, male/female 13/9 10/13 2.76 0.09 6/3 17/19 1.35 0.24 Side, right/left 8/14 13/10 0.12 0.73 3/6 18/18 0.06 0.80 MCDK: palpable, present/absent 14/8 10/13 2.46 0.11 8/1 16/20 6.41 0.01 mean length, >62/£62 mm 13/9 11/12 0.44 0.50 8/1 16/20 5.28 0.02 >78/£78 mm 4/18 8/15 1.48 0.22 9/0 24/12 3.90 0.05 Contralateral kidney (mean) >55/£55 mm 7/15 10/13 0.90 0.34 7/2 21/15 1.16 0.28 >60/£60 mm 5/17 4/19 0.02 0.89 8/1 28/8 0.02 0.89

MCDK length at diagnosis on involution on US well-documented cases of Wilms’ tumour in initial US (at a threshold of 62 mm) remained is shown in Fig. 1b; there was a significant children with MCDK [8,9]. associated with complete involution of difference between the survival curves (log- MCKD. An impalpable kidney was strongly rank 5.28, P = 0.02). On the multivariate In the present study we estimated the rate of associated with the disappearance of the analysis, only MCDK length remained partial or complete involution of the MCDK by MCDK on univariate analysis, but this variable marginally significant after backward the Kaplan-Meier method; the mean (95% CI) did not remain significantly associated with adjustment by the regression model (hazard time for each endpoint was 76 (62–92) and complete involution in the multivariate ratio 8, 95% CI 0.98–68; P = 0.05). 121 (99–142) months, respectively. On the analysis. This was probably because a palpable basis of survival analyses, we estimated that kidney and a longer MCDK are normally highly after 3 years of follow-up, 20% of MCDK correlated, and this may account for the DISCUSSION would become undetectable on US and after insignificant finding on multivariate analysis. 10 years half would show complete We found only one study that related renal We report here an homogeneous series of involution. Several studies have examined the size and the rate of involution of the MCDK; asymptomatic infants with prenatally development of MCDK by US [1,4,5,21–27]; Rottenberg et al. [5] evaluated 55 children detected MCDK. The management was notably, the time for involution estimated by over 32 months and showed that only four of conservative and serial US showed total the present Kaplan-Meier analysis is 15 MCDK of ≥60 mm became undetectable on involution in 20% and partial involution comparable to those reported in multicentre US. Moreover, they found that the involution in 67% of the MCDK. The strength of the registries with a prolonged follow-up. The rate was inversely correlated with the age present study is based on characteristics of its preliminary report of the North American of the children. The involution rate was design. All children underwent a systematic MCDK registry showed data from 49 centres -0.5 mm/week for those examined in the protocol and were prospectively followed in USA and Canada. Of 260 patients enrolled first 3 months of life, -0.2 mm/week at 3–12 long-term by the same medical team. In at the registry, 29 were followed for >5 years months and -0.02 mm/week after the first addition, the patients had serial US by the and seven (24%) MCKD became undetectable year. same examiner, with 279 scans in all for by US [1]. Interestingly, the report of a analysis. However, we recognize that the collaborative project from the UK showed Taken together, these data show a clear relatively few patients limits our conclusion similar findings [25]; in that registry, 11 of 46 tendency of spontaneous involution of MCDK about the predictive factors of MCDK (24%) MCDK showed complete involution at on US, but the slow rate of involution can involution. 2 years of follow-up, three of 21 (14%) at cause concern about the increased risk of 5 years and two of five at 10 years. complications associated with MCDK, notably In this series, there were no cases of malignant transformation and hypertension. malignant transformation over a median To our knowledge, the present is the first study Some authors have advocated surgical follow-up of 50 months. Only two children to evaluate predictive factors associated with removal based on cost-effectiveness and on developed asymptomatic hypertension (one the involution of MCDK. In this context, the advances in surgical technique [28–30]. was associated with obesity and the other had identifying the variables associated with the Nevertheless, we think that thus far there is spontaneous normalization of blood pressure rate of involution may contribute to no strong evidence for the best management levels at ª12 months) [13,19]. This low rate of establishing a more rational, efficient and of MCDK. Only long-term prospective studies complications agrees with most series cost-effective management of MCDK. from the neonatal period to adult life can reported [1,20]. In a computer survey of Univariate analysis showed that only two define the natural history of MCDK. published work, covering a period of 20 years, variables were significantly associated with Gordon et al. [7] found only six reports of complete involution, i.e. a palpable kidney and In conclusion, we report the natural history of malignancy associated with the MCDK. In a MCDK length (Table 1). After adjustment by prenatally detected and clinically managed more recent review, we found three other multivariate analysis, only renal length at the MCDK. The disappearance rate was slower

PREDICTING THE INVOLUTION OF PRENATALLY DETECTED MCDK

than those reported in previous studies, 8 Homsy YL, Anderson JH, Oudjhane K, by prenatal ultrasonography. Natural according to the survival analysis used here. Russo P. Wilms tumor and multicystic history and results of conservative Only a renal length of <62 mm on initial US dysplastic kidney disease. J Urol 1997; management. Br J Urol 1992; 69: was associated with a faster involution of the 158: 2256–9 538–40 MCDK during the follow-up. 9 de Oliveira-Filho AG, Carvalho MH, 22 Strife JL, Souza AS, Kirks DR, Strife CF, Sbragia-Neto L, Miranda ML, Bustorff- Gelfand MJ, Wacksman J. Multicystic ACKNOWLEDGEMENTS Silva JM, de Oliveira ER. Wilms tumor in dysplastic kidney in children. US follow- a prenatally diagnosed multicystic kidney. up. Radiology 1993; 186: 785–8 This study was partially supported by J Urol 1997; 158: 1926–7 23 Heymans C, Breysem L, Proesmans W. Fundação de Amparo à Pesquisa do Estado de 10 Gough DC, Postlethwaite RJ, Lewis MA, Multicystic kidney dysplasia. a prospective Minas Gerais (FAPEMIG), Conselho de Bruce J. Multicystic renal dysplasia study on the natural history of the Desenvolvimento Científico e Tecnológico diagnosed in the antenatal period. a note affected and the contralateral kidney. Eur (CNPq) and Pró-Reitoria de Pesquisa-UFMG. of caution. Br J Urol 1995; 76: 244–8 J Pediatr 1998; 157: 673–5 11 Webb NJ, Lewis MA, Bruce J et al. 24 Rudnik-Schoneborn S, John U, Deget F, CONFLICT OF INTEREST Unilateral multicystic dysplastic kidney: Ehrich JH, Misselwitz J, Zerres K. the case for nephrectomy. Arch Dis Child Clinical features of unilateral multicystic None declared. 1997; 76: 31–4 renal dysplasia in children. Eur J Pediatr 12 Stuck KJ, Koff SA, Silver TM. Ultrasonic 1998; 157: 666–72 REFERENCES features of multicystic dysplastic kidney: 25 Sukthankar S, Watson AR. Unilateral expanded diagnostic criteria. Radiology multicystic dysplastic kidney disease: 1 Wacksman J, Phipps L. Report of 1982; 143: 217–21 defining the natural history. Acta Paediatr the Multicystic Kidney Registry: 13 Rabelo EA, Oliveira EA, Diniz JS et al. 2000; 89: 811–3 preliminary findings. J Urol 1993; Natural history of multicystic kidney 26 Okada T, Yoshida H, Matsunaga T et al. 150: 1870–2 conservatively managed: a prospective Multicystic dysplastic kidney detected by 2 James CA, Watson AR, Twining P, study. Pediatr Nephrol 2004; 19: 1102–7 prenatal ultrasonography. natural history Rance CH. Antenatally detected urinary 14 Schwartz GJ, Haycock GB, Edelmann and conservative management. Pediatr tract abnormalities. changing incidence CM Jr, Spitzer A. A simple estimate of Surg Int 2003; 19: 207–10 and management. Eur J Pediatr 1998; glomerular filtration rate in children 27 Eckoldt F, Woderich R, Wolke S, Heling 157: 508–11 derived from body length and plasma KS, Stover B, Tennstedt C. Follow-up of 3 Eckoldt F, Woderich R, Smith RD, creatinine. Pediatrics 1976; 58: 259–63 unilateral multicystic kidney dysplasia Heling KS. Antenatal diagnostic aspects 15 Han BK, Babcock DS. Sonographic after prenatal diagnosis. J Matern Fetal of unilateral multicystic kidney dysplasia measurements and appearance of normal Neonatal Medical 2003; 14: 177–86 – sensitivity, specificity, predictive values, kidneys in children. Am J Roentgenol 28 Elder JS, Hladky D, Selzman AA. differential diagnoses, associated 1985; 145: 611–6 Outpatient nephrectomy for malformations and consequences. Fetal 16 Kaplan EL, Meier P. Nonparametric nonfunctioning kidneys. J Urol 1995; 154: Diagn Ther 2004; 19: 163–9 estimation from incomplete observation. 712–4 4 Kuwertz-Broeking E, Brinkmann OA, J Am Statis Ass 1958; 53: 457–81 29 Perez LM, Naidu SI, Joseph DB. Von Lengerke HJ et al. Unilateral 17 Cox DR. Regression models and life- Outcome and cost analysis of operative multicystic dysplastic kidney: experience tables (with discussion). J R Stat Soc B versus nonoperative management of in children. BJU Int 2004; 93: 388–92 1972; 74: 187–220 neonatal multicystic dysplastic kidneys. 5 Rottenberg GT, Gordon I, De Bruyn R. 18 Greenland S. Modeling and variable J Urol 1998; 160: 1207–11 The natural history of the multicystic selection in epidemiologic analysis. Am J 30 Kaneko K, Kun W, Yamataka A, Ohtomo dysplastic kidney in children. Br J Radiol Public Health 1989; 79: 340–9 Y, Yamashiro Y, Miyano T. Is 1997; 70: 347–50 19 Oliveira EA, Silva AC, Rabelo EA, nephrectomy for neonatal multicystic 6 Oliveira EA, Diniz JS, Vilasboas AS, Filgueiras FF, Pereira AK, Mesquita FM. dysplastic kidneys still inappropriate? Rabelo EA, Silva JM, Filgueiras MT. Spontaneous improvement of Nephron 2000; 86: 376–7 Multicystic dysplastic kidney detected hypertension in multicystic dysplastic by fetal sonography. Conservative kidney: a case report. Pediatr Nephrol Correspondence: Eduardo Araújo de Oliveira, management and follow-up. Pediatr Surg 2002; 17: 954–8 Rua Patagonia 515/701, Belo Horizonte, Minas Int 2001; 17: 54–7 20 Cochat P. La dysplasie rénale Gerais, Brazil. 7 Gordon AC, Thomas DF, Arthur RJ, multikystique: Etude multicentrique. Ann e-mail: [email protected] Irving HC. Multicystic dysplastic kidney: Pédiatr 1994; 41: 24–31 is nephrectomy still appropriate? J Urol 21 Rickwood AM, Anderson PA, Williams Abbreviations: MCDK, multicystic dysplastic 1988; 140: 1231–4 MP. Multicystic renal dysplasia detected kidney; US, ultrasonography.

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

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Mini Rev Article GENE-EXPRESSION ANALYSIS IN BLADDER CANCER SMITH et al.

The promise of gene-expression analysis in bladder cancer: a clinician’s guide

STEVEN C. SMITH, GARY OXFORD and DAN THEODORESCU Departments of Urology and Molecular Physiology, The University of Virginia, Charlottesville, VA, USA Accepted for publication 20 December 2004

INTRODUCTION start to address important clinical questions genes of interest are all represented in a grid in bladder cancer. Two such pressing of barely more than a square centimetre. Several years since the advent of genomics, questions are how bladder cancer progresses, the promise of investment in the human and what markers for prognosis can be Oligonucleotide arrays, like those genome project has begun to be repaid in gleaned from the study of how progression manufactured by the company Affymetrix full across many areas of science. The occurs. (www.affymetrix.com), represent a popular most immediate result is the availability of standardized approach. These microarrays extensive public databases of sequences (e.g. are grids of thousands of 20–25 bp NCBI, Ensembl and ExPASy), from proteins to A PRIMER ON MICROARRAY TECHNOLOGY oligonucleotides selected from known entire genomes. These resources, coupled with sequences based on design algorithms modern advances in robotics and A DNA microarray is a highly miniaturized formulated to choose probes that hybridize miniaturization, have resulted in the grid of hundreds to tens of thousands of to their complements with high affinity and development of many new ‘high throughput’ nucleic acid probes, representative of many specificity [2,8]. Each fluorescently labelled technologies based roughly on two differing known biological sequences, affixed to a solid sample of mixed nucleic acids is hybridized to concepts: either assaying one sample for framework. Because nucleic acids have the array individually, and results represent many different constituent molecules or the property of hybridizing to their measures of absolute gene expression assaying many samples for one molecule of complementary sequences, such a framework levels (Fig. 2A). cDNA microarrays, by interest. may be used to assay for the presence of contrast, function through simultaneous particular sequences in the complex mix of cohybridization of fluorescently labelled Gene-expression analysis of bladder cancer endogenous RNA species that may be isolated nucleic acids isolated from a test sample, e.g. using DNA microarrays represents the former from biological samples like bladder cancer bladder cancer tissue, and differently labelled concept, where a single sample of cell line or tissue or cell lines. The assay begins with nucleic acids from a reference sample, e.g. tissue (Fig. 1) is assayed for the level of isolation and stabilization of total RNA or normal bladder tissue [1,9]. The results expression of a significant number of RNA mRNA from the sample. This sample can be therefore represent a ratio of gene expression transcripts, in parallel and under the same derived from bulk normal or tumour tissue, or from the test sample to the reference sample experimental conditions [1,2]. Expression of microdissected tumour or normal tissue (Fig. 2B). cDNA arrays are commercially specific genes of interest can be subsequently (Fig. 1). Microdissection has allowed a more available or may be fabricated specifically to validated by means of the latter experimental discrete evaluation of tumour gene assay the experimental system in question concept: assaying protein expression in expression profiles by effectively excluding [10]. parallel across many tissue samples on a most stromal tissues [7]. This step is followed human tissue microarray (TMA) via by generation of labelled nucleic acids from The analysis of microarray data was reviewed immunohistochemistry (IHC) [3]. The this RNA, and hybridization of the mixture to recently [11]; the essence of analysing array preponderance of published evidence shows the microarray of probes. Finally, a detector, data is the comparison of gene expression that the biological dysregulation that usually a type of scanner, images the pattern between hybridizations, i.e. the ratio of characterises cancer is complex and diverse. of hybridization and signal intensity of the expression of a gene in one sample to the As such, high-throughput technologies labelled RNA at probe positions on the grid. same gene in another. This concept holds true like microarrays seem an appropriate Roughly speaking, the presence of a despite differences in DNA microarray experimental platform to begin to dissect the hybridization signal identifies the expression platform, as the comparison can be made of pathways that contribute to the development of a particular gene, while the signal intensity either fluorescence signals of each of the two and progression of bladder cancer. is proportional to the level of expression. Two differentially labelled samples at a probe popular platforms of DNA microarrays (Fig. 1) in one cohybridization cDNA assay, or While experimental designs using microarrays are oligonucleotide microarrays, where short between fluorescence at a probe on one devised to identify molecular targets in DNA probes of ª20 bp are synthesized oligonucleotide array run with each sample bladder cancer have been reviewed recently directly on a glass chip [8] and cDNA [12]. Often, the ratio of expression between [4,5], as well as array-based advances in the microarrays, where cDNA probes experimental and reference samples of classification of bladder cancer and other complementary to known genes are spotted sequences probed on the arrays are ‘log

neoplasms [6], we seek to both provide an on specially prepared microscope slides [9]. In transformed’, to log2 values, to give an easier accessible explanation of the technology and either platform, probes for the expression scale to use in further analysis. For example, a review developments from array studies that level of hundreds to tens of thousands of ratio of experiment to reference sample gene

GENE-EXPRESSION ANALYSIS IN BLADDER CANCER

FIG. 1. Experimental design. Samples may be derived from bulk normal or tumour tissue or microdissected tumour or normal tissue. Illustrated here, microdissection allows a more discrete evaluation of tumour gene expression proﬁles by effectively excluding most stromal tissues [8] before isolating RNA and generating labelled nucleic acids for microarray analysis.

Patient Samples

Biopsy

Isolate RNA, generate labelled nucleic acids

Microdissection

Oligonucleotide microarrarys

cDNA microarrays

expression of 4 : 1, indicating relative up- amount of starting RNA, or numerous other such as superﬁcial or invasive cancer. Either regulation, would be transformed to factors [12]. way, similarity is graphically displayed by log2 4 = 2, and a ratio of 1 : 4, indicating proximity on a cluster tree, or dendrogram relative down-regulation, would be Microarray studies use a variety of algorithms (Fig. 3). Cluster-analysis images often show transformed to log2 (1/4) = -2. to manipulate extensive expression data into clusters of samples and genes in two meaningful patterns [12,13]. Two types of dimensions, with a graphical representation Array data also must be ‘normalized’, approaches to analysis are unsupervised and of relative up-regulation as red and relative so that data may be compared between supervised. Unsupervised approaches are down-regulation as green (Fig. 4) [15]. oligonucleotide arrays or between designed to identify similarity between differentially labelled nucleic acid samples samples based on expression data, with no a On the other hand, supervised analysis is hybridized to the same cDNA array. This priori grouping of the samples. Commonly, designed to identify different expression process often involves adjusting or scaling all studies use hierarchical clustering algorithms patterns that correlate with a known the expression values so that the total signal to group samples based on similarity of their characteristic of the samples, e.g. histological from each array or from each different gene expression [14]. Alternatively, genes can grade, prognosis, recurrence, etc. Often ﬂuorescent nucleic acid sample cohybridized be clustered based on similarity of their bladder cancer studies use supervised is the same, accounting for differences in the expression across different classes of samples, analyses to determine an optimal ‘gene

SMITH ET AL.

FIG. 2. Differing approaches. (A) Oligonucleotide microarrays. Labelled nucleic acids derived from RNA isolated from two tissue samples are hybridized to arrays individually. Expression results for genes are compared between the assays. (B) cDNA microarrays. Nucleic acids derived from RNA isolated from two tissue samples are labelled with different dyes and then co-hybridized to the same cDNA microarray. Gene expression results are then compared between the samples on the same array.

Oligonucleotide A microarrays B cDNA microarrays

Sample 1 Sample 2 Sample 1 Sample 2

Isolate RNA, generate labelled nucleic acids

Isolate RNA, generate differentially labelled nucleic acids Comparison of

gene expression between samples

Co-hybridizationi and analysis of expression ratios from same assay

FIG. 3. Hierarchical clustering. In this representative cluster tree, or dendrogram, similarity is illustrated by proximity on branches of the cluster. In this case, superficial UC samples are shown to cluster together on the left main branch and separately from invasive UC samples on the right main branch. The higher-grade superficial UC sample clusters separately from the two lower-grade superficial UC samples, but it is still on the same main superficial UC branch.

Low GradeLow Grade High Grade

Superficial urothelial Invasive urothelial carcinoma carcinoma

GENE-EXPRESSION ANALYSIS IN BLADDER CANCER

FIG. 4. Cluster analysis. In this representative cluster analysis, horizontally across the top, two main types of known clinical follow-up for correlating the tissue samples, e.g. superﬁcial UC and invasive UC, shown blue or yellow, are clustered based on similarity of candidate gene expression pattern to the gene expression [15]. Vertically, genes are clustered by similarity of expression pattern across all the samples. patient’s course, therapy response, and By convention, red indicates relative up-regulation and green relative down-regulation. outcome. Tumour samples USING MICROARRAY TECHNOLOGY TO UNDERSTAND BLADDER CANCER PROGRESSION

HUMAN TISSUE STUDIES

One of the most compelling potential uses of gene expression analysis via microarray technology is to identify molecular markers that correlate with clinical outcome. In one early study, Sanchez-Carbayo et al. [18] used cDNA microarrays to study bladder cancer cell lines to identify differentially expressed genes between distinct histopathological tumour

Genes types and stages of disease. Then, they used TMAs to validate the potential clinical significance of markers identified in the array studies. Expression of the genes keratin 10 and caveolin-1 was associated with both the presence of squamous differentiation, stage and tumour grade. Further, the expression levels of zyxin, E-cadherin, and moesin were significantly associated with urothelial carcinoma (UC) stage and grade. Membrane moesin expression was significantly associated with overall survival in a subset of 69 patients where the clinical follow-up was available.

More recently, using a larger cDNA microarray Superficial urothelial carcinoma platform, the same group analysed gene expression in early-stage and advanced Invasive urothelial carcinoma bladder tumours, again with TMA validation for potential markers [19]. Using hierarchical clustering, early-stage tumours clustered expression signature’ for tumour immunoblotting can verify translation of together and separately from invasive UC. classification. These expression signatures mRNA into protein, and IHC can show the Gene expression profiling separated may be evaluated either by using an pattern of expression on histological sections carcinoma in situ (CIS) from superficial independent test set of tumour samples, or by of tissue. However, one technology that has papillary lesions, and two subgroups with cross-validation, where each sample is in turn been useful for validating array data and different clinical outcomes within early-stage excluded, the remaining samples used to studies with markers of clinical interest is the and invasive tumour clusters were identified. generate an expression signature classifier, TMA [3,16]. Hundreds of cylindrical, ª1 mm Moreover, expression analysis identified a and the classifier used to group the excluded tissue cores from paraffin-embedded tissue subgroup of early-stage tumours that gave sample [15]. An error rate can then be blocks are inserted in a grid into a new expression profiles similar to organ-confined calculated for the classifier, using only the paraffin block (Fig. 5) [4,18]. These TMA blocks invasive lesions, hinting that expression samples tested, when an independent test set can then be sectioned and manipulated just profiling may eventually provide predictive of tumour data is unavailable. as any tissue section. Using this technology, information for patients with early-stage parallel studies of DNA by fluorescence in situ bladder cancer. In analyses targeted to Finally, various techniques are used to hybridization (FISH), RNA in situ hybridization, identify genes differentially expressed validate gene expression data garnered from or most commonly, protein IHC, may be between early-stage and invasive bladder microarrays. Traditional molecular biological undertaken on hundreds of tissue samples on cancer, the genes, cytokeratin-20, neuropilin- techniques such as real-time RT-PCR can a single glass slide. Often, the tissue samples 2, p21 and p33ING1, were analysed using verify gene expression at the level of mRNA, chosen to produce the array have significant TMAs. While expression of all these genes was

SMITH ET AL.

FIG. 5. Construction and use of a TMA. (A) Cylindrical, ª1 mm tissue cores are taken from representative areas of parafﬁn-embedded tissue blocks, guided by pathological examination of previous sections. Tissue cores are then inserted in a grid into a new parafﬁn block. The resultant TMA block can be sectioned many times for analysis of all the tissue samples in parallel by a variety of techniques [4,18]. (B) Example of TMA application for IHC of RhoGDI2, a gene associated with bladder cancer metastasis [17].

A Tumour core removed Tissue microarray and inserted into new block sectioned and paraffin tissue block stained as desired

RhoGDI2 IHC

Normal Positive Negative

significantly correlated with tumour stage test set of 68 samples that had been analysed surrounding CIS, UCs with no surrounding and grade, only p33ING1 was associated with separately using different oligonucleotide CIS, and muscle-invasive UCs [22]. When overall survival. Patients with higher levels of array technology, and resulted in a correct comparing only a total of 28 superficial UCs p33ING1 expression had a shorter survival classification of 84% of stage Ta, 50% of with CIS (13 samples) and with no CIS (15 than those with lower expression. The same stage T1 and 74% of stage T2+ tumours. samples), hierarchical cluster analysis group also recently reported the use of array Moreover, the Ta tumours that were separated tumours by presence or absence of technology to identify the tumour suppressor misclassified as stage T1 or T2 had a CIS, with only one exception. To examine the gene, KiSS-1 [20]. significantly higher likelihood of progression expression profiles of these two groups, they or solid-tumour growth. Additionally, for the selected the 50 most up-regulated genes in Dyrskjot et al. [21] used oligonucleotide Ta samples, an outcome predictor was each group, either UCs with or with no microarray analysis of 40 bladder tumours to formulated and tested to ascertain if array surrounding CIS. The expression profile identify distinct, clinically relevant subclasses data alone could predict the likelihood of characterizing the CIS group was present in of bladder carcinoma. Hierarchical cluster recurrence. In cross-validation studies, the nearly all of the muscle-invasive UC samples, analysis separated the tumours into clusters outcome predictor correctly classified 75% of and was absent in all of the normal bladder representing three major stages, Ta, T1 and the samples as recurrent or not recurrent. The biopsies. Surprisingly, the CIS expression T2–4, with few outliers. Because of the group is currently conducting a 3-year profile was even shown by histologically potential clinical utility of a means to prospective study to explore the potential normal biopsies taken from areas adjacent to objectively classify tumour samples, they first clinical application for their classifiers. CIS. Because the presence of CIS is a useful developed a classifier model using 32 genes to prognostic marker in bladder cancer, a gene obtain a correlation with pathological staging. Most recently, the group used oligonucleotide expression signature in UCs or in bladder This classifier was applied to an independent microarrays to compare superficial UCs with biopsies that identified the presence of CIS

GENE-EXPRESSION ANALYSIS IN BLADDER CANCER

FIG. 6. Association between RhoGDI2 status and disease-free survival time. Comparison of Kaplan-Meier between chromosomal abundance and gene estimates of disease-free survival between patients with RhoGDI2 positive tumours (red) and those with expression. The group also used microarray reduced or absent protein expression (green) (P < 0.001) [24]. Typical IHC results are shown in Fig. 5B. technology to analyse a cell-line progression series of increasing metastatic potential, 1.0 generated through repetitive cycles of passage of T24T through lung metastases and 0.9 culture of resultant metastases [25]. These results, when combined with microarray 0.8 analysis of human bladder cancer, identiﬁed genes associated with bladder cancer lung 0.7 metastasis that may eventually prove to be 0.6 targets for future therapy. Clearly, DNA microarray technology will continue to be an 0.5 important tool for studying models of bladder cancer progression. 0.4

0.3

Cumulative proportion surviving DISCUSSION 0.2 Often, when considering developments like 0.1 these, the question becomes a matter of how or when technologies based on or derived 0.0 020406080100120 140 from the results of expression analysis might become generally available or relevant in Time, months patient care. It is very attractive to consider that, with time and prospective validation, prognostic markers for recurrence might be would be clinically useful. To that end, they expression of which (also assayed by one day used to provide increased vigilance of used cross-validation strategies to generate a microarrays) was inversely correlated to stage follow-up in subsets of patients with CIS, or 16-gene CIS classifier to identify the CIS gene and grade in 105 human primary carcinomas. trigger the use of adjuvant chemotherapy in expression profile, which might be of future Re-expression of the gene in T24T cells patients at high risk of metastasis after use for patients with bladder cancer. suppressed the invasive and metastatic cystectomy [24]. Unfortunately, such phenotype, but did not affect in vitro growth, prospective trials have been difficult but were EXPERIMENTAL PROGRESSION MODELS colony formation, or in vivo tumorigenicity, recently facilitated by the establishment of the requirements for a metastasis suppressor. organizations such as the National Cancer There are several limitations associated with More recently, RhoGDI2 was shown to be an Institutes’ Early Detection Research Network human tissue studies. One of them is the lack independent predictor for developing in the USA (http://www3.cancer.gov/ of tissues from metastatic deposits, making metastasis and death from bladder cancer prevention/cbrg/edrn/index.html). the study of the genes associated with the after radical cystectomy, further reinforcing metastatic process difficult. Therefore, to its role as a metastasis suppressor (Fig. 6) [24]. Most likely, new tests based on technologies address this deficiency, investigators have that have proven to be of some clinical utility derived animal models of bladder cancer Also, we reported an analysis of the in the past will be the first to be validated metastasis and used these to study the expression profile changes in T24 and T24T prospectively and become available for process. For example, several recent using a novel ‘positional expression profiling’ clinical use. One example of this is the publications have shed light on the utility technique that analysed gene expression data international validation effort for p53 IHC as a of microarray studies in expanding from oligonucleotide microarrays based on prognostic factor for bladder cancer invasion understanding of the biological mechanisms chromosomal position [17]. Spectral [26]. In this model, gene expression analysis of bladder cancer progression. Our group karyotyping and comparative genomic using microarray technology can serve as a recently published the identification of hybridization were used to fully characterize ‘high-throughput’ means to discover markers RhoGDI2, an invasion and metastasis the cytogenetic abnormalities in these cell that distinguish between clinically relevant suppressor gene in human cancer, based on lines, and then the functional consequences classes of tumour. As growing databases of oligonucleotide microarray analysis of the of the chromosomal rearrangements were tumour data become available for analysis, differences between the noninvasive, assayed by comparing gene expression there is great hope that interventions tailored minimally metastatic UC cell line T24 and its differences between T24 and T24T based on to an individual’s tumour phenotype, based invasive, aggressively metastatic isogenic chromosomal position. In some cases, e.g. the on a panel of initial tests, may become a variant, T24T [23]. Comparing the most X chromosome, there was a good correlation reality. Such an approach is called differentially expressed genes between the between higher chromosomal dosage and ‘pharmacogenomics’, where the drugs used lines showed that one gene, RhoGDI2, was higher expression in T24 than T24T; however, are personalized to the genetic constitution of down-regulated in invasive T24T, and the in many cases there is a less direct correlation a particular patient and tumour.

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In the long term the use of gene-expression 7 Elkahloun AG, Gaudet J, Robinson biological phenotypes. Cancer Res 2002; analysis techniques will lead to an GS, Sgroi DC. In situ gene expression 62: 6973–80 understanding of tumour biology. As analysis of cancer using laser capture 19 Sanchez-Carbayo M, Socci ND, Lozano teleologically, a cancer cell is the product of microdissection, microarrays and real JJ et al. Gene discovery in bladder cancer the genes it expresses, analysing these time quantitative PCR. Cancer Biol Ther progression using cDNA microarrays. Am J through technologies like microarrays will 2002; 1: 354–8 Pathol 2003; 163: 505–16 provide the insight required into what 8 Lockhart DJ, Dong H, Byrne MC et al. 20 Sanchez-Carbayo M, Capodieci P, molecules and processes contribute to the Expression monitoring by hybridization to Cordon-Cardo C. Tumor suppressor phenomenon of bladder cancer and high-density oligonucleotide arrays. Nat role of KiSS-1 in bladder cancer: loss progression. In the end, these are the insights Biotechnol 1996; 14: 1675–80 of KiSS-1 expression is associated with that will undoubtedly engender the greatest 9 Schena M, Shalon D, Davis RW, bladder cancer progression and clinical difference in the diagnostic and therapeutic Brown PO. Quantitative monitoring outcome. Am J Pathol 2003; 162: 609– approach to bladder cancer. of gene expression patterns with a 17 complementary DNA microarray. Science 21 Dyrskjot L, Thykjaer T, Kruhoffer M et al. 1995; 270: 467–70 Identifying distinct classes of bladder ACKNOWLEDGEMENTS 10 Cheung VG, Morley M, Aguilar F, carcinoma using microarrays. Nat Genet Massimi A, Kucherlapati R, Childs G. 2003; 33: 90–6 The authors thank Dr Christopher Moskaluk Making and reading microarrays. Nat 22 Dyrskjot L, Kruhoffer M, Thykjaer T et al. and Mr Alex Baras for their helpful Genet 1999; 21 (Suppl. 1): 15–9 Gene expression in the urinary bladder: suggestions. 11 Butte A. The use and analysis of a common carcinoma in situ gene microarray data. Nat Rev Drug Discov expression signature exists disregarding 2002; 1: 951–60 histopathological classification. Cancer CONFLICT OF INTEREST 12 Quackenbush J. Microarray data Res 2004; 64: 4040–8 normalization and transformation. Nat 23 Gildea JJ, Seraj MJ, Oxford G et al. None declared. Genet 2002; 32 (Suppl.): 496–501 RhoGDI2 is an invasion and metastasis 13 Wu TD. Analysing gene expression data suppressor gene in human cancer. Cancer from DNA microarrays to identify Res 2002; 62: 6418–23 REFERENCES candidate genes. J Pathol 2001; 195: 53– 24 Theodorescu D, Sapinoso LM, Conaway 65 MR, Oxford G, Hampton GM, Frierson 1 Duggan DJ, Bittner M, Chen Y, Meltzer 14 Eisen MB, Spellman PT, Brown PO, HF Jr. Reduced expression of metastasis P, Trent JM. Expression profiling using Botstein D. Cluster analysis and display suppressor RhoGDI2 is associated with cDNA microarrays. Nat Genet 1999; 21 of genome-wide expression patterns. Proc decreased survival for patients with (Suppl. 1): 10–4 Natl Acad Sci USA 1998; 95: 14863–8 bladder cancer. Clin Cancer Res 2004; 10: 2 Lipshutz RJ, Fodor SP, Gingeras TR, 15 Golub TR, Slonim DK, Tamayo P et al. 3800–6 Lockhart DJ. High density synthetic Molecular classification of cancer: class 25 Nicholson BE, Frierson HF, Conaway oligonucleotide arrays. Nat Genet 1999; discovery and class prediction by gene MR et al. Profiling the evolution of human 21 (Suppl. 1): 20–4 expression monitoring. Science 1999; metastatic bladder cancer. Cancer Res 3 Shergill IS, Shergill NK, Arya M, Patel 286: 531–7 2004; 64: 7813–21 HR. Tissue microarrays: a current medical 16 Kononen J, Bubendorf L, Kallioniemi A 26 McShane LM, Aamodt R, Cordon-Cardo research tool. Curr Med Res Opin 2004; et al. Tissue microarrays for high- C et al. Reproducibility of p53 20: 707–12 throughput molecular profiling of tumor immunohistochemistry in bladder tumors. 4 Sanchez-Carbayo M. Use of high- specimens. Nat Med 1998; 4: 844–7 National Cancer Institute Bladder Tumor throughput DNA microarrays to identify 17 Harding MA, Arden KC, Gildea JW et al. Marker Network. Clin Cancer Res 2000; 6: biomarkers for bladder cancer. Clin Chem Functional genomic comparison of 1854–64 2003; 49: 23–31 lineage-related human bladder cancer cell 5 Sanchez-Carbayo M, Cordon-Cardo C. lines with differing tumorigenic and Correspondence: Dan Theodorescu, Applications of array technology: metastatic potentials by spectral Department of Urology, Box422, University identification of molecular targets in karyotyping, comparative genomic of Virginia Health Sciences Center, bladder cancer. Br J Cancer 2003; 89: hybridization, and a novel method of Charlottesville, Virginia, 22908, USA. 2172–7 positional expression profiling. Cancer Res e-mail: [email protected] 6 Dyrskjot L. Classification of bladder 2002; 62: 6981–9 cancer by microarray expression profiling: 18 Sanchez-Carbayo M, Socci ND, Abbreviations: FISH, fluorescence in situ towards a general clinical use of Charytonowicz E et al. Molecular hybridization; IHC, immunohistochemistry; microarrays in cancer diagnostics. Expert profiling of bladder cancer using cDNA UC, urothelial carcinoma; CIS, carcinoma Rev Mol Diagn 2003; 3: 635–47 microarrays: defining histogenesis and in situ; TMA, tissue microarray.

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956

Original Article SYNERGISTIC INHIBITION WITH HIFU and CHEMOTHERAPY PAPAREL et al.

Synergistic inhibitory effect of high-intensity focused ultrasound combined with chemotherapy on Dunning adenocarcinoma

PHILIPPE PAPAREL, LAURA CURIEL*, SABRINA CHESNAIS*, RENE ECOCHARD† JEAN-YVES CHAPELON* and ALBERT GELET Urology, Edouard Herriot Hospital, *INSERM, and †Biostatistics, Hospices Civils de Lyon, Lyon, France Accepted for publication 21 November 2004

OBJECTIVE chemotherapy + HIFU (the last three treated chemotherapy + HIFU and the control for 1 week). The growth in tumour volume group. The tumour doubling times were To evaluate the therapeutic effect of was recorded for 3 weeks, the point at which 13.2 days for HIFU-only, 31.2 days for high-intensity focused ultrasound (HIFU) tumour volume was considered to have chemotherapy + HIFU and 7.7 days for the combined with chemotherapy (paclitaxel doubled (doubling time). The growth curves of controls. + estramustine) on AT2 Dunning each group were plotted and evaluated adenocarcinoma, as no satisfactory treatment statistically. CONCLUSION for localized prostate cancer is available for patients with a poor prognosis, e.g. stage T3, a RESULTS These results suggest that this combined high Gleason score, or a prostate-specific therapy could be useful for treating patients antigen level of 15 ng/mL. At 30 days of follow-up the distributions of > with high-risk prostate cancer. tumour volume with treatment group were MATERIALS AND METHODS significantly different (P < 0.001); volumes were significantly greater in the control KEYWORDS Forty-one Dunning AT2 tumour-bearing than in the chemotherapy-only or in the Copenhagen rats were divided into four HIFU-only group (both P = 0.006). The prostate cancer, paclitaxel, estramustine groups, i.e. control, chemotherapy, HIFU, and greatest difference was between the phosphate, Dunning model, HIFU

INTRODUCTION alone. The use of microtubular poisons with liquid nitrogen. For experiments, cellular estramustine to enhance the response was samples of the same pool were warmed and Patients presenting with nonmetastatic recently reported with taxane (paclitaxel) in cultured under standard conditions. A rat was prostate cancer have a high probability of combination [8,9]. Several experimental given an abdominal subcutaneous injection relapse if they are treated simply by surgery studies also show the potential of with 107 cells and after 15 days the solid [1], radiation [2] or high-intensity focused chemotherapy associated with HIFU [10–14]. tumour formed was excised and minced; ultrasound (HIFU) alone [3] when there are 20-mg pieces were then implanted in the factors indicating a poor prognosis, e.g. Thus the objective of the present study was to experimental animals. Under these conditions, clinical stage (≥T2B), Gleason score (≥4 + 3), assess in vivo the synergistic effect of with no treatment, death from tumour or a high PSA level (>15 ng/mL), i.e. those combining taxane (paclitaxel) with normally occurs within 7–8 weeks after factors most significantly related to estramustine and HIFU in a model of prostatic implantation with the AT2 subline. treatment failure. The synergistic effect of adenocarcinoma (Dunning R3327AT2) chemical castration (androgenic suppression) implanted in Fischer Copenhagen rats. This The prototype HIFU device used for treatment and radiotherapy has been confirmed in vitro therapeutic combination, for which efficacy consisted of three integrated components: an [4] and in vivo [5]. By contrast, it was reported was reported in humans [15], could be used to ultrasound treatment system consisting of a that neoadjuvant hormone therapy does not improve the results of HIFU in patients spherical transducer with a geometrical focus modify the survival rate for patients treated presenting with a high risk of relapse. at 45 mm, an active diameter aperture of by radical surgery [6]. 50 mm and a central frequency of 3 MHz; an imaging system consisting of an ultrasound Several studies support the view that MATERIALS AND METHODS scanner (Combison 311, Kretz, Austria); and a chemotherapy can contribute significantly to computer-controlled excitation system that treating human prostate adenocarcinoma. Fischer Copenhagen rats (Harlan, USA), were commands the firing sequence (power, Tannock et al. [7] showed that the time to housed in a laboratory and only male rats duration, waiting-time between shots) and symptomatic progression was prolonged by (10–12 weeks old) used in all experiments. The controls the movements of the firing head adding mitoxantrone (anthracyclines) to R3327 Dunning prostatic adenocarcinoma through a three-dimensional positioning prednisolone, compared with prednisolone subline AT2 was used, the cells being stored in system (Microcontrôle, France).

PAPAREL ET AL.

TABLE 1 Days and administration protocols for HIFU treatments and chemotherapy. Dosage was 15 mg/kg for EMP and 4 mg/kg for paclitaxel, the distribution of tumour volumes at 30 days and the percentage growth/day

Chemotherapy Protocol or variable HIFU + chemotherapy HIFU alone alone Control 15 days EMP – EMP – 16 paclitaxel – paclitaxel – 17 HIFU HIFU – – 18 paclitaxel – paclitaxel – 19 EMP – EMP – Tumour volume, mL Median (interquartile range) [range] 6.47 26.40 26.95 74.72 (0.25–13.00) (20.83–29.04) (21.25–29.61) (73.50–104.75) [0.25–57.42], 6 [9.25–42.22], 10 [3.86–44.95], 10 [61.36–115.36], 6 Mean (95% CI) % increase/day 2.2 (-0.5 to 5.0) 6.6 (4.1–9.2) 5.4 (2.8–7.9) 9.4 (6.4–12.4) P >0.05 <0.001 <0.001 <0.001 Tumour doubling time, days 31.2 10.8 13.2 7.7

To treat the tumour several pulses were implanting the tumour, when the tumour FIG. 1. Pulse position and order during HIFU applied following the model shown in Fig. 1, was ª10 mL, the rats were separated into treatment. each with an acoustical power of 13 W for 5 s four groups; controls (six), HIFU-only with a 5-s waiting-time between them, and (11), chemotherapy-only (12) and separated by a step of 1.6 mm. Under general HIFU + chemotherapy (12). The treatment anaesthesia, the animal was placed on a lasted 5 days and followed the treatment specially designed Plexiglas gantry with an protocol given in Table 1. opening below the abdominal area for the penetration of ultrasound. The tumour was The rats were weighed and the tumour immobilized with a silicone ring fastened to volume measured weekly; over the course of the gantry. This gantry was then mounted on tumour growth in the weeks after treatment, the three-axis positioning system to roughly the rats were killed if the tumour was position the animal over the firing arm at the >60 mm in diameter or if the tumour approximate focal distance. The tank was then volume was such that the rats were no filled with warm (35 ∞C) degassed and longer able to move. The tumours were deionized water. The ultrasonographic probe photographed in two dimensions each week was then used to make an image before the with a scale allowing a precise measurement; pulses, to define the treatment zone. The tumour volume was then calculated as coordinates of the target volume were sent to length ¥ width ¥ height ¥ 0.5236 [17]. the instrument computer which controlled the movements of the HIFU transducer. The distributions of tumour volume at 30 days increase per day and as tumour doubling Programming by the computer software of follow-up were compared overall using a times in days. produces several pulses according to the nonparametric ANOVA (Kruskal–Wallis test) target volume, the dimension of which and then more specifically, each group was corresponds to 75% of the tumour volume. A compared with the others (Mann–Whitney RESULTS HIFU-lesion model [16] was used to predict U-test) with a Bonferroni correction to the lesion volume under the actual conditions keep the overall significance level of the Some of the animals did not survive the and then the number of pulses calculated to comparison tests at P < 0.05. complete follow-up because they died before cover 75% of the tumour volume. the threshold dates (Table 1). The distributions The effects of chemotherapy, HIFU and of tumour volume according to the treatment Two chemotherapy agents were used: their interaction on tumour volumes group were significantly different (P < 0.001; paclitaxel (Taxane, Bristol-Myers-Squibb, USA) were analysed using linear regression Table 1). The volumes were significantly as a subcutaneous injection at 4 mg/kg; for repeated measurements after a greater in the control group than in the and estramustine phosphate (EMP, Estracyt, logarithmic transformation of the volumes. chemotherapy-only group (P = 0.006) or Pharmacia & Upjohn, SA) by intraperitoneal The results of this regression analysis were in the HIFU-only group (P = 0.006). The injection at 15 mg/kg. Fifteen days after expressed as percentages of volume greatest difference was between the

SYNERGISTIC INHIBITION WITH HIFU AND CHEMOTHERAPY

FIG. 2. 100 and act as a mirror for the ultrasound, The mean tumour volume with 90 preventing the energy from reaching the time for the four groups (red 80 tissue underneath this boiling region [18]. dotted line, HIFU + chemotherapy; 70 green solid line, chemotherapy 60 In clinical practice, the efficacy of HIFU for only; light red dash/dot, HIFU only; 50 localized cancers is high, but all authors light green dashed, control) from 40 report the appearance of residual cancerous 8 days after HIFU treatment 30 tissue in 6–17% of treated patients [21–23]. (at 24 days). Tumour volume, mL 20 The persistence of malignant cells within 10 prostatic tumours treated by HIFU is probably 0 explained by the presence in the target zone 20 25 30 35 40 45 50 55 of macrobubbles of several millimetres in Days diameter, provoked by the intracellular boiling of the water. These macrobubbles form a screen for the HIFU beam. Zones insufficiently HIFU + chemotherapy and the control group, causes direct changes in the biological treated persist beneath the boiling zones; this but that difference was not significant system. The thermal effect is associated with phenomenon could be amplified when tissues because there were too few rats. the absorption of ultrasound energy in the are highly vascularized, in particular within tissue, which is then converted into heat. The tumours that are very undifferentiated. For In all 41 rats at 15 days of follow-up the mean biological changes induced by this heating are large tumours (clinical stage T2b–T3), the (SD) tumour volume was 9.4 (3.3) mL; this determined by the temperature reached and persistence of malignant cells is explained by volume increased rapidly in the controls, the duration of the exposure. The lesion the frequent capsular extension (the tumour HIFU-only and the chemotherapy-only extension is determined where a dose invades the periprostatic fat). As HIFU is groups, but in the HIFU + chemotherapy threshold is reached. For thermal doses limited to the gland, cells situated in the group the mean increase in tumour volume above the threshold, irreversible damage is periprostatic fat (outside the capsule) are not was 2.2%/day (and not significantly different induced in the tissue as coagulation necrosis. in the field of the ultrasound beam. from zero; Table 1 and Fig. 2). The increase in For thermal doses below the threshold, the tumour volume can also be expressed as the effect depends on the tissue sensitivity to The objective of the present study was to tumour doubling time, also shown in Table 1. heat [19]. reproduce the clinical situation, to assess whether some malignant cells escape The effects of chemotherapy alone and At high intensities the biological effects destruction by HIFU, either within the HIFU alone on tumour volume were associated with the activity of cavitation tumour or at its periphery. Hence we used both statistically significant, as was the bubbles appear. Much living tissue contains a partial treatment limited to 75% of interaction between them. The difference sites at which microbubbles will form in the tumour volume; the results show that in tumour growth rates between the response to pressure variations. Bubbles of the response was supra-additive when HIFU + chemotherapy and the combined a certain diameter will resonate depending chemotherapy and HIFU were administered chemotherapy-only and HIFU-only groups on the frequency of the wave. Indeed, even simultaneously. was 3.8% (P = 0.002, 95% CI 1.5–6.1). bubbles that are not large enough to resonate Therefore, the HIFU + chemotherapy increase their diameter by a phenomenon Others have reported animal models in which treatment was more effective in preventing termed ‘rectified diffusion’ and the cavitation HIFU associated with chemotherapy gave tumour growth than HIFU or chemotherapy is enhanced. At higher intensities the bubble better results than treatment with HIFU alone. alone, which indicates synergy between these increases in size and suddenly collapses, Fry and Johnson [14] reported an additive treatments. producing shock waves with enormous effect of HIFU + carmustine on the pressure, up to 2–3 GPa, thus causing meduloblastome of the hamster; the rate of mechanical stress and temperatures that can healing after HIFU only was 29%, vs 40% with DISCUSSION reach several thousand degrees Kelvin. This HIFU + carmustine. Yang et al. [13] reported results in the formation of free radicals which better survival in a hepatome model (Moris The mechanism of tissue destruction by HIFU are chemically active. However, despite the 3924 A implanted in the rat) when combining is complex. Ultrasound energy applied to force of this reaction, the phenomenon HIFU and doxorubicin or HIFU and adriamycin. tissues results in mechanical stress of the remains localized at the level of the cavitation However, in these studies, the difference cells, causing changes in the biological bubble and spreads for only a few between the chemotherapy and HIFU group system. Three effects can be distinguished micrometres [20]. and the HIFU-only group was not significant. during ultrasound exposure, i.e. mechanical, Moore et al. [11] reported a similar result in thermal and cavitation-induced; the presence In addition to the mechanical, thermal and the same animal model (hepatome 3924 A) by of each depends on the field intensity and cavitation effects, another can be present using cyclophosphamide. The interaction they are frequently interdependent [18]. when during HIFU; because of heat mechanism of HIFU and chemotherapy is not accumulation from thermal effects, the yet known. Yang et al. [12] suggested it could The mechanical interaction includes radiation temperature increase can cause boiling. be related to a better intracellular diffusion of force, radiation torque and streaming, and Bubbles of steam can then form at the focus the chemotherapy agent after concomitant

PAPAREL ET AL.

increases in permeability of the cell CONFLICT OF INTEREST vivo effects of cavitation alone or in membrane and from high intratumoral blood combination with chemotherapy in a flow. In the present study assessing partially None declared. Source of funding: INSERM. peritoneal carcinomatosis in the rat. Br J treated tumours and chemotherapy before Cancer 1993; 68: 13–7 and after HIFU, two explanations for the 11 Moore WE, Lopez RM, Matthews DE. synergistic effect are possible. The first would REFERENCES Evaluation of high-intensity therapeutic be that chemotherapy before HIFU degrades ultrasound irradiation in the treatment of the cells by a cytotoxic effect and thus 1 Aleman M, Karakiewicz PI, Kupelian P experimental hepatoma. J Pediatr Surg favours their destruction during HIFU. The et al. Age and PSA predict likelihood of 1989; 24: 30–3 second hypothesis is that the cells at the organ-confined disease in men presenting 12 Yang R, Reilly CR, Rescorla FJ et al. periphery of the tumour and outside the zone with PSA less than 10 ng/mL: implications Effects of high intensity focused treated by HIFU are degraded by the diffusion for screening. Urology 2003; 62: 70–4 ultrasound in the treatment of of the ultrasound beam. This diffusion is 2 Shipley WU, Thames HD, Sandler HM experimental neuroblastoma. J Pediatr increased by the presence of cavitation et al. Radiation therapy for clinically Surg 1992; 27: 246–50 bubbles within the target zone. The cells localized prostate cancer: a multi- 13 Yang R, Reilly CR, Rescorla FJ et al. High- affected by this diffused ultrasound beam institutional pooled analysis. JAMA 1999; intensity focused ultrasound in the consequently become more sensitive to the 281: 1598–604 treatment of experimental liver cancer. action of chemotherapy. A weak acoustic 3 Gelet A, Chapelon JY, Bouvier R, Arch Surg 1991; 126: 1002–9 intensity would be sufficient to produce this Rouviere O, Lyonnet D, Dubernard JM. 14 Fry FJ, Johnson LK. Tumor irradiation effect. Saad and Hahn [24] showed in vitro Transrectal high intensity focused with intense ultrasound. Ultrasound Med that exposure to ultrasound with an intensity ultrasound: factors influencing the out Biol 1978; 4: 337–41 of 1 W/cm2 increased the action of come. Eur Urol 2001; 40: 124–9 15 Haas N, Roth B, Garay C et al. Phase I doxorubicin. Yumita and Umemura [25] 4 Zietman AL, Prince EA, Nakfoor BM, trial of weekly paclitaxel plus oral obtained a similar result on a colon cancer Park JJ. Androgen deprivation and estramustine phosphate in patients with model by using chloroaluminium radiation therapy: sequencing studies hormone-refractory prostate cancer. phthalocyanine and an acoustic intensity of using the Shionogi in vivo tumor system. Urology 2001; 58: 59–64 3 W/cm2. Finally, Yu et al. [26] also showed a Int J Radiat Oncol Biol Phys 1997; 38: 16 Chavrier F, Chapelon JY, Gelet A, synergistic effect on an ovarian cancer model 1067–70 Cathignol D. Modeling of high-intensity by using adriamycin and an acoustic intensity 5 Bolla M, Collette L, Blank L et al. Long- focused ultrasound-induced lesions in the of 7.84 W/cm2. term results with immediate androgen presence of cavitation bubbles. J Acoust suppression and external irradiation in Soc Am 2000; 108: 432–40 In clinical practice, the association of HIFU patients with locally advanced prostate 17 Lokeshwar L, Ferell SM, Block NL. and chemotherapy could be used for cancer (an EORTC study): a phase III Enhancement of radiation response of patients with prostate cancer who are at randomised trial. Lancet 2002; 360: 103– prostatic carcinoma by taxol: therapeutic high risk of recurrence, either because of 6 potential for late-stage malignancy. an aggressive tumour (undifferentiated 6 Klotz LH, Goldenberg SL, Jewett MA Anticancer Res 1995; 15: 93–8 Gleason 4 + 3 and higher) or regional et al. Long-term followup of a randomized 18 Chapelon JY, Margonari J, Vernier F, extension of the tumour (stage T2b–T3). trial of 0 versus 3 months of neoadjuvant Gorry F, Ecochard R, Gelet A. In vivo Indeed, the efficacy of the taxane-EMP androgen ablation before radical effects of high-intensity ultrasound on combination was reported in humans; Oudart prostatectomy. J Urol 2003; 170: 791–4 prostatic adenocarcinoma Dunning et al. [27] showed in a randomized study that 7 Tannock IF, Osoba D, Stockler MR et al. R3327. Cancer Res 1992; 52: 6353–7 combined docetaxel and EMP was more Chemotherapy with mitoxantrone plus 19 Sapareto SA, Dewey WC. Thermal dose effective than mitoxantrone or prednisolone prednisone or prednisone alone for determination in cancer therapy. Int J combined. The biological response was a symptomatic hormone-resistant prostate Radiat Oncol Biol Phys 1984; 10: 787–800 reduction in the PSA level of more than half, cancer: a Canadian randomized trial with 20 Fry WJ, Tucker D, Fry FJ, Wulff VJ. 67% and 18%, respectively (P < 0.001) and an palliative end points. J Clin Oncol 1996; Physical factors involved in ultrasonically overall survival rate 18.6 vs 11.6 months 14: 1756–64 induced changes in living systems. II. (P = 0.08). The feasibility of neoadjuvant 8 Petrylak DP. Chemotherapy for advanced Amplitude duration relations and the chemotherapy by taxane has already been hormone refractory prostate cancer. effect of hydrostatic pressure for nerve tested before radical prostatectomy in Urology 1999; 54 (Suppl. 6A): 30–5 tissue. In Dunn F, O’Brien WD. Ultrasonic high-risk patients [28]. 9 Savarese DM, Halabi S, Hars V et al. Biophysics. Stroudsburg: Dowden, Phase II study of docetaxel, estramustine, Hutchinson & Ross, Inc, 1976: 249–58 In conclusion, the present results indicate that and low-dose hydrocortisone in men with 21 Gelet A, Chapelon JY, Bouvier R et al. combined treatment using chemotherapy and hormone-refractory prostate cancer: a Transrectal high-intensity focused HIFU has a synergistic effect on prostate final report of CALGB 9780. Cancer and ultrasound. minimally invasive therapy of cancer progression through a prolonged Leukemia Group B. J Clin Oncol 2001; 19: localized prostate cancer. J Endourol slowing of tumour growth, suggesting that 2509–16 2000; 14: 519–28 such combined therapy could be useful for 10 Prat F, Chapelon JY, El Fadil FA, 22 Gelet A, Chapelon JY, Bouvier R, treating high-risk prostate cancer. Theillere Y, Ponchon T, Cathignol D. In Pangaud C, Lasne Y. Local control of

prostate cancer by transrectal high phthalocyanine tetrasulfonate on murine 28 Konety BR, Eastham JA, Reuter VE et al. intensity focused ultrasound therapy: solid tumour. J Pharm Pharmacol 2004; Feasibility of radical prostatectomy preliminary results. J Urol 1999; 161: 56: 85–90 after neoadjuvant chemohormonal 156–62 26 Yu T, Huang X, Hu K, Bai J, Wang Z. therapy for patients with high risk or 23 Blana A, Walter B, Rogenhofer S, Treatment of transplanted adriamycin- locally advanced prostate cancer: results Wieland WF. High-intensity focused resistant ovarian cancers in mice by of a phase I/II study. J Urol 2004; 171: ultrasound for the treatment of localized combination of adriamycin and 709–13 prostate cancer: 5-year experience. ultrasound exposure. Ultrason Sonochem Urology 2004; 63: 297–300 2004; 11: 287–91 Correspondence: Philippe Paparel, 24 Saad A, Hahn GM. Ultrasound enhanced 27 Oudard S, Legrier ME, Boye K et al. Department of Urology, Edouard Herriot drug toxicity on Chinese hamster ovary Activity of docetaxel with or without Hospital, Lyon, France. cells in vitro. Cancer Res 1989; 49: 5931– estramustine phosphate versus e-mail: [email protected] 4 mitoxantrone in androgen dependent and 25 Yumita N, Umemura S. Sonodynamic independent human prostate cancer Abbreviations: HIFU, high-intensity focused antitumour effect of chloroaluminum xenografts. J Urol 2003; 169: 1729–34 ultrasound; EMP, estramustine phosphate

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Original Article THE PONTINE MICTURITION CENTRE DALMOSE et al.

Stereotactic electrical stimulation of the pontine micturition centre in the pig

ASGER L. DALMOSE, CARSTEN R. BJARKAM* and JENS CHRISTIAN DJURHUUS† Department of Urology, Hospital of Aalborg, Aalborg, *Institute of Anatomy and †Institute of Experimental Clinical Research, University of Aarhus, Århus, Denmark Accepted for publication 21 November 2004

OBJECTIVE visualized by fluoroscopy, magnetic resonance stereotactic procedure followed by imaging (MRI) or histologically. subsequent MRI (one animal), and by To apply stereotactic electrical stimulation of histological analysis, verifying it to be in the the pig brainstem and thus identify a pontine RESULTS dorsolateral pontine region. micturition centre. The stimulation evoked responses similar to CONCLUSIONS MATERIALS AND METHODS voiding, i.e. a urethral pressure decrease followed by a bladder pressure increase; or These results show that a pontine micturition In 10 anaesthetized female Vietnamese similar to a continence manoeuvre, i.e. centre exists in pigs similar to that described minipigs a needle-electrode was positioned urethral pressure increase and no change in in rats, cats, dogs and humans. in the pontine region. Pressure responses bladder pressure. In a few cases a continence in the lower urinary tract identified the response was evoked by stimulating a site KEYWORDS micturition centre functionally during 1 mm away from the site where a voiding electrical stimulation. Stereotactic response was evoked. The electrode position central nervous system, pons, micturition, Sus coordinates were recorded, and the needle was detected by the fluoroscopy-based scrofa, stereotactic technique

INTRODUCTION ventilation with 1–3.5% isoﬂurane in a 33% retracted to the bladder base to stabilize it and

O2 and 67% N2O mixture, with continuous serve as a watertight seal between bladder and One of the early stereotactic studies on monitoring of heart rate, blood-oxygen urethra. One lumen of the bladder catheter micturition was in cats, showing a pontine saturation and temperature. was used for continuous adjustment, to keep micturition centre (PMC) crucial for the the bladder volume at 50–100 mL. The other control of urine storage and voiding [1]. A Cadaver studies had established the location lumen and the attached catheter was perfused PMC has also been detected by stereotactic of the arteriolar formation ‘rete mirabilis’ with saline and connected to pressure procedures in rats and dogs, and in humans 1–2 cm anterior and 1–2 cm rostral to the transducers (Truflow, Baxter, Santa Ana, by positron-emission tomography and in anterior surface of the pons. California). The pressures and the stimulations clinical cases of brainstem disease [2–5]. were recorded on a computer (Dantec Menuet, The pigs were placed prone and an arterial Medtronic, Skovlunde, Denmark). Pigs have been used increasingly in research catheter (Cordis, Johnson and Johnson, on the regulation of voiding function because Miami, Florida) was inserted, during repeated The head of the pig was fixed in a stereotactic of their anatomical and physiological infusion with contrast medium (Visipaque, frame (Stoelting, Wood Dale, Illinois, USA) resemblance to humans [6–9]. The aim of the Amersham Health, Princeton, New Jersey) and by bilateral bone-screws inserted into the present study was to identify and locate a fluoroscopy guidance (Exposcop CB 7-D, zygomatic arc directly below the lateral PMC by transurethral recording of lower Ziehm, Kraus GmbH, Germany), into the margin of the eye (Fig. 1). The skin was urinary tract pressures during stereotactic internal carotid artery just proximal to the removed from the vertex and the pig’s head electrical stimulation of the pontine region. rete mirabilis. position locked with a bar placed over the snout, so that the skull surface 3 cm anterior MATERIALS AND METHODS A transurethral separation catheter made of a to the bregma was 7 mm lower than the 16 F silicon double-lumen bladder catheter bregma, thus defining the horizontal plane. A Ten female Vietnamese minipigs (Sus scrofa, (Rüsch, Kernen, Germany) was used to record 3 ¥ 5 cm hole was made in the skull giving 30–70 kg) were used in accordance with a lower urinary tract pressures. It had a 5 F access to the frontal sinus, which in adult pigs protocol approved by the Danish Board on silicone catheter (Vygon, Ecouen, France) stretches almost to the line where the Research Animals. The animals were sedated attached with a side-opening 1 cm proximal trapezoid muscle inserts. A 2 ¥ 3 cm hole was with ketaminol 10 mg/kg, midazolam to the balloon of the bladder catheter, for made in the floor of the frontal sinus, the 0.5 mg/kg and etomidatum 0.5 mg/kg, and urethral pressure recording [10]. The 10 mL underlying dura cut open, and the brain then intubated and kept on assisted balloon of the separation catheter was exposed.

THE PONTINE MICTURITION CENTRE

A tungsten-needle electrode (WPI, Sarasota, region of the first three animals, guided were established (Fig. 2), enabling positioning Florida) was inserted through a lumbar by repeated fluoroscopic visualization of of the needle electrode in the remaining puncture cannula (Sensi Touch, Kendahl, the needle electrode relative to the rete seven pigs based on the obtained stereotactic Mansfield, Massachusetts) into the pontine mirabilis, until stereotactic coordinates coordinates. The electrode was connected to a custom-made battery-driven unit enabling stimulation with the following FIG. 1. parameters: pulse width 100 ms; frequency The stereotactic apparatus with a 30 pulses/s; amplitude 10–40 mA. The mounted pig skull. stereotactic mapping was then performed in 1-mm steps in all three planes during subsequent transurethral pressure recording, until an electrode position that elicited transurethral bladder responses was identified.

For histological specimens the brain was perfused with 4% formaldehyde injected under high pressure into one common carotid artery. The brain was then removed and dehydrated before parafﬁn embedding and coronal microtome sectioning into 10 mm thick sections. The sections were Nissl-stained with 0.1% toluidine blue in citrate buffer (pH 4.0) at room temperature for 4 min, followed by a rinse in distilled water, differentiation through 99% alcohol, clearing in xylol and mounting (DePex, Laboratory Supplies, Poole, England).

One of the pigs with a voiding response was assessed by MRI in a 1.5 T scanner (Signa, General Electric, Milwaukee, Wisconsin) with the needle electrode left in place.

RESULTS

The stimulation evoked responses similar to voiding, i.e. a urethral pressure decrease followed by a bladder pressure increase

FIG. 2. Internal carotid angiography; arrows mark FIG. 3. the rete mirabilis, which was used as a landmark. Plots of relative pressure (scale,

every 5 cmH2O) with time (min) Anterior during stimulation. Top tracing, each box (height in arbitrary units) denotes applied EMGave stimulation; middle tracing, 200 mV bladder pressure; bottom tracing, Pves urethral pressure. The needle is 5 cmH2O moved 1 mm in the vertical plane between stimulations. Abortive Pura stimulations are followed by ﬁve 5 cmH2O responses from the lower urinary Posterior tract, four of which are distinctly like voiding. 0:00 10:00 20:00 30:00 40:00 cc

DALMOSE ET AL.

(Fig. 3); or similar to a continence manoeuvre, FIG. 4. i.e. a urethral pressure increase and no A similar plot to Fig. 3, showing change in bladder pressure (Fig. 4). three weak responses from the lower urinary tract, followed by The responses were evoked from oval zones in six strong continence-like EMGave the pontine region with a longitudinal rostro- responses during which the 200 mV caudal axis and measuring 1–3 ¥1–7 mm. needle was unmoved. Pves Voiding responses were elicited from sites 5 cmH2O with coordinates in the three planes of Pura (relative to the bregma); posterior 0–8 mm, 5 cmH2O lateral 3–10 mm, and depth 51–69 mm. Continence responses were elicited from sites with coordinates in the three planes of 0:00 6:00 12:00 18:00 24:00 30:00 (relative to the bregma); posterior 0–5 mm, cc lateral 5–10 mm, and depth 43–60 mm. In a few cases a site responsible for, e.g. a voiding response, had a site responsible for a FIG. 5. continence response directly next to it, so that A similar plot to Fig. 3; the needle a 1-mm change in needle tip location would is moved 1 mm in the vertical evoke reciprocal results (Fig. 5). plane between stimulations. Four abortive stimulations are The range of pressures in the voiding response EMGave followed by two responses from was a bladder pressure increase of 3–7 cmH2O 200 mV the lower urinary tract. The ﬁrst of and a urethral pressure decrease of these is a voiding-like response Pves 10–35 cmH2O (Fig. 3). The range of pressure and the last is a continence-like increase of the continence response was up to 5 cmH2O response. 45 cmH O (Fig. 4). The delay from onset of 2 Pura stimulation to the pressure response was 5 cmH2O 11–21 s in the voiding responses and 7–13 s in the continence responses.

MRI immediately after the experiment in one of the pigs with a voiding response, and 0:00 2:00 4:00 6:00 cc histological analysis in the others, showed that the stimulation sites were in the pons (Fig. 6). FIG. 6. A, Coronal MRI of the pig brain; the thin arrows mark the needle electrode tip in the pons and wide arrows the rete mirabilis. B, A microphotograph of a Nissl-stained coronal section through the rostral pons at the transition to mesencephalon. Arrows mark a cleavage artefact corresponding to the electrode DISCUSSION stimulation sites in the dorsolateral pontine tegmentum. 4 V, fourth ventricle; CI, colliculus inferior; FLM, fasciculus longitudinalis medialis; LC, locus coeruleus; NRM, nucleus raphe magnus; PCM, pedunculus Pontine areas capable of evoking either cerebellaris medius. voiding or continence responses in the lower urinary tract were detected reproducibly. In A B other species related areas have been reported and the term PMC is now established both in human studies and animal research [1,2,4,11].

In pigs, most urodynamic studies so far have focused on the lower urinary tract and only a few anatomical studies of the role of the CNS in regulating voiding and continence have been published [7,12]. The value of having identiﬁed a porcine PMC is considerable, as pigs have well-established functional and anatomical similarities with humans [6,8,9]. The large pig brain (6 ¥ 5 ¥ 4 cm) is advantageous as it enables complicated surgical procedures and the use of neural

THE PONTINE MICTURITION CENTRE

stimulation devices intended for human use. CONFLICT OF INTEREST 9 Mills IW, Noble JG, Brading AF. The size of the pig brain also enables the use Radiotelemetered cystometry in pigs. of fluoroscopy and MRI equipment for clinical None declared. validation and comparison of natural use, which makes in vivo monitoring of filling versus diuresis cystometry. J Urol stereotactic procedures and the position of 2000; 164: 1745–50 implants, and thus chronic studies, possible REFERENCES 10 Dalmose AL, Rijkhoff NJ, Andersen IS, [7]. Stefania D, Jorgensen TM, Djurhuus JC. 1 Barrington FJF. The effect of lesions of Bladder and urethral responses to pelvic In the voiding responses the urethral the hind- and mid-brain on micturition nerve stimulation in the pig. Scand J Urol relaxation preceded the bladder response by in the cat. Q J Exp Physiol 1924; 15: 81– Nephrol Suppl 2002; 210: 34–45 <1 s; not only was the urethral response 102 11 Nishizawa O, Sugaya K, Noto H, Harada earlier than the bladder response in these 2 Noto H, Roppolo JR, Steers WD, de T, Tsuchida S. Pontine micturition center pigs, it was also much larger (Fig. 3). The Groat WC. Excitatory and inhibitory in the dog. J Urol 1988; 140: 872–4 sequential activation of the two structures influences on bladder activity elicited by 12 Mills IW, Drake MJ, Greenland JE, and the difference in pressure patterns was electrical stimulation in the pontine Noble JG, Brading AF. The contribution similar to that of normal female humans [13] micturition center in the rat. Brain Res of cholinergic detrusor excitation in a pig and female pigs [14], but it is unclear whether 1989; 492: 99–115 model of bladder hypocompliance. BJU Int these exact patterns are present in voiding in 3 Nishizawa O, Sugaya K, Noto H, Harada 2000; 86: 538–43 cats [15], rats [2] and dogs [11]. This is a T, Tsuchida S. Pontine urine storage 13 Tanagho EA, Miller ER. Initiation of clinically important aspect, as some lower center in the dog. Tohoku J Exp Med 1987; voiding. Br J Urol 1970; 42: 175–83 urinary tract disorders are characterized by 153: 77–8 14 Bridgewater M, MacNeil HF, Brading premature [16] or isolated [17] urethral 4 Blok BF, Willemsen AT, Holstege G. A AF. Regulation of tone in pig urethral relaxation, and therefore the pig seems to be PET study on brain control of micturition smooth muscle. J Urol 1993; 150: 223–8 highly relevant as a research animal for in humans. Brain 1997; 120: 111–21 15 Holstege G, Griffiths D, de Wall H, investigating diseases of urinary storage 5 Athwal BS, Berkley KJ, Hussain I et al. Dalm E. Anatomical and physiological function. Brain responses to changes in bladder observations on supraspinal control of volume and urge to void in healthy men. bladder and urethral sphincter muscles in In conclusion, the present results show that a Brain 2001; 124: 369–77 the cat. J Comp Neurol 1986; 250: 449–61 PMC exists in pigs, similar to that described in 6 Dalmose AL, Hvistendahl JJ, Olsen LH, 16 Papa Petros PE, Ulmsten U. Bladder rats, cats, dogs and humans. This allows very Eskild-Jensen A, Djurhuus JC, Swindle instability in women. a premature relevant experiments, as the pig is MM. Surgically induced urologic models activation of the micturition reflex. urodynamically similar to humans, and the in swine. J Invest Surg 2000; 13: 133–45 Neurourol Urodyn 1993; 12: 235–9 large pig brain permits good anatomical 7 Dalmose AL, Bjarkam CR, Sorensen JC, 17 Sorensen S, Norgaard JP, Djurhuus JC. accuracy. Djurhuus JC, Jorgensen TM. Effects of Continuous urethral pressure high frequency deep brain stimulation on measurement in women with unstable urine storage and voiding function in detrusor. Neurourol Urodyn 1986; 5: 525– conscious minipigs. Neurourol Urodyn 34 ACKNOWLEDGEMENTS 2004; 23: 265–72 8 Brading AF, Teramoto N, Dass N, Correspondence: Asger L. Dalmose, Christian This study was supported by The Danish McCoy R. Morphological and Winthers Vej 10, DK-8230 Åbyhøj, Denmark. Health Research Council, the University of physiological characteristics of urethral e-mail: [email protected] Aarhus Research Foundation, The Sahva circular and longitudinal smooth muscle. Foundation, and The Mads Clausen Scand. J Urol Nephrol Suppl 2001; 207: Abbreviations: PMC, pontine micturition Foundation. 12–8 centre.

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Original Article GENE TRANSFER OF VIP INTO PENILE CORPUS CAVERNOSUM SHEN et al.

Gene transfer of vasoactive intestinal polypeptide into the penis improves erectile response in the diabetic rat

ZHOU-JUN SHEN, HUA WANG, YING-LI LU*, XIE-LAI ZHOU, SHAN-WEN CHEN and ZHAO-DIAN CHEN Department of Urology, 1st Afﬁliated Hospital and *Department of Endocrinology, Sir Run Run Shao Hospital, Medical School of Zhejiang University, Hangzhou, PR China Accepted for publication 8 November 2004

OBJECTIVES 1.5 ms, 20 V, 1 min) were measured in abdominal aorta samples after injection subsamples of rats at 1, 3, 7 and 14 days after (P > 0.05). To determine the feasibility of transfecting injection; after measuring the ICP the animals penile corpora cavernosa with pcDNA3/ were killed, and penile, hepatic, renal artery CONCLUSIONS vasoactive intestinal polypeptide (VIP) cDNA, and abdominal aorta tissue samples were which encodes for VIP in streptozotocin (STZ)- frozen in liquid nitrogen and stored at -80∞ C. VIP cDNA is easily incorporated into corpus diabetic rats, to clarify whether transfection The gene expression of VIP in all samples, cavernosum, and the expression is sustained of VIP cDNA into the cavernosum affects the assessed as the expression of VIP mRNA, for ≥2 weeks in the penis in vivo. The physiological response to cavernosal nerve was estimated using a semiquantitative transfer of VIP is capable of altering the stimulation, and whether this process would reverse-transcription polymerase chain physiologically relevant erectile response, as affect other organs in the diabetic rat model reaction. measured by an increase in the ICP after in vivo. stimulating the cavernosal nerve. The RESULTS intracorporal micro-injection of pcDNA3/VIP MATERIALS AND METHODS cDNA had little effect on the expression of VIP The mean amplitude of ICP and expression of mRNA in other important organs. pcDNA3/VIP cDNA was injected into the VIP mRNA in the cavernosa of the VIP-treated corpus cavernosum of STZ-induced diabetic rats was greater at 1, 3, 7 and 14 days after KEYWORDS Sprague-Dawley rats. The intracavernosal injection (P < 0.05) than in the control pressure (ICP) and response to electrical animals. There were no changes in the vasoactive intestinal polypeptide, gene stimulation of the cavernosal nerve (15 Hz, expression of VIP mRNA in hepatic, renal and transfer, penis, diabetes mellitus, rat

INTRODUCTION as neural co-mediators of penile erection gradient is particularly steep in men with [5,6]. Differing from NO, VIP requires a diabetes. In one cohort study [11], ED affected Penile erection depends on the integration of receptor. After release into the corpus >47% of men with type 1 diabetes aged vascular, endocrine and neurological cavernosum, VIP first binds to its receptors £43 years, compared with 1.1% of those aged mechanisms. Neurally mediated vascular and then stimulates the activity of the 21–30 years. According to one estimate [12] dilatation and relaxation of penile smooth enzyme adenylate cyclase. The increased more than half of men will develop ED within muscle leads to increased blood flow and cAMP activates protein kinase A, and this then 10 years of the onset of diabetes. Not only erection of the cavernosal tissue [1]. Nitric closes Ca2+ channels and opens K+ channels, does diabetes nearly double the risk of ED, but oxide (NO), produced by NO synthase (NOS), is thereby inducing smooth muscle cell ED may also be the first symptom of diabetes, one of the main neurotransmitters for penile relaxation with subsequent penile and was significantly predictive of erection. The NO-cGMP signalling pathway is vasodilatation [7,8]. neuropathic symptoms and poor glycaemic the major biochemical mechanism for control in a 5-year prospective study [13]. ED regulating erection [2]. NO is released from Erectile dysfunction (ED) is a common and diabetes each affect >150 million people nerve terminals within the corpora after comorbidity in patients with diabetes; up to worldwide, and this value is projected to sexual stimulation; it is a fairly unique 75% of diabetic men will be confronted at double by the year 2025 [14]. signalling molecule, as it does not require a some time in their lives with a consistent or receptor (e.g. a hormone or protein receptor) recurrent inability to achieve and maintain an The mechanisms responsible for diabetes- to act [3]. Vasoactive intestinal polypeptide erection adequate for sexual performance induced ED are controversial. There has been (VIP), which is a 28-residue polypeptide [9], typically when younger than their no agreement about VIP as a neural co- originally isolated from porcine duodenum, is counterparts with normal glycaemic control mediator of penile erection with NO and its a potent vasodilator and smooth muscle [10]. effects on diabetes-induced ED, as some relaxant, and fulfils several of the criteria for a studies reported less VIP and fewer VIP nerve neurotransmitter mediating penile erection Whereas the incidence of ED increases as a fibres [5,15], but others found increased VIP in [4]. Some studies suggest that NO and VIP act function of age in the general population, the the major pelvic ganglion and penis in

GENE TRANSFER OF VIP INTO PENILE CORPUS CAVERNOSUM

diabetic rats [16]. Various additional but with 100 mg pcDNA3 vector) and 3 (as 1, Monophasic rectangular pulses were mechanisms, including central neuropathy with gene therapy with the pcDNA3/VIP delivered by a single generator (custom-made and decreased levels of circulating androgens, cDNA). Before injection, animals were and with built-in constant current amplifier). have also been proposed to explain the anaesthetized with pentobarbital sodium The stimulation parameters were: 15 Hz, pulse erectile disorders found in diabetic rats. (35 mg/kg). A midline incision was made to width 0.22 ms, 20 V for 1 min. The changes expose the penis, and blood flow to the penis in ICP were recorded at this level of Thus if smooth muscle relaxation is impaired, occluded by securely tying a length of rubber neurostimulation. either by an inadequate release of NO and VIP, band at the base of the organ. Injections were or by penile fibrosis, ED may ensue. delivered into the corpus cavernosum with a The methods used for RT-PCR and analysis of Inadequate smooth muscle relaxation is 1-mL insulin syringe. The ligature was expression were reported previously in detail estimated to be the primary cause of ED in removed after 30 min and the incision closed. [19]. All experimental values are expressed as 66–75% of patients [15]. In men with Basal and nerve-stimulated ICP was measured the mean (SD) and difference assessed using inadequate smooth muscle relaxation, at 1, 3, 7 and 14 days after injection, ANOVA or Dunnett’s t-test, with differences sildenafil inhibits the activity of respectively. considered significant at P < 0.05. phosphodiesterase type 5, an enzyme that normally degrades cGMP within the penile Finally, tissues (penile, liver, kidney and corpora. Patients maintain an adequate abdominal aorta) for VIP mRNA RESULTS concentration of cGMP, allowing sufficient determination were harvested after and continued rigidity after sexual measuring ICP, immediately frozen in liquid The mean basal ICP for subgroups 1, 2 stimulation. However, this therapy is not nitrogen and stored at -80∞C. The VIP cDNA and 3 were 6.1 (1.9), 6.8 (2.5) and 8.3 (2.1) effective for all patients with ED, including (ª 500 nucleotides; i.e. 0.5 kb) was inserted cmH2O, respectively; these values were not diabetic men, and there remains a need for into the pcDNA3 vector, where expression is significantly different (P > 0.05). The effects other forms of therapy. induced using the cytomegalovirus promoter. of electrostimulation of the cavernosal nerve on the ICP in vivo was used to evaluate the The present study was devised to determine The methods used to surgically prepare and potential physiological relevance of any whether transfection of VIP cDNA into the place the pressure-monitoring cannula was change in expression of VIP in the different corpus cavernosum of the penis can correct reported elsewhere [17,18]. Briefly, the rats groups; the results are shown in Table 1. There ED without affecting other important organs were anaesthetized by an intraperitoneal was a significant difference in the mean ICP in diabetic rats. As VIP is one of the main injection with pentobarbital sodium between the controls (i.e. sham-operated with neurotransmitters for penile erection, (35 mg/kg), placed supine, and the bladder PBS or vector only, subgroup 1 and 2) and introducing it into the penis may improve and prostate exposed through a midline VIP-treated rats (P < 0.05) at all times after erectile function. abdominal incision. The inferior hypogastric treatment. plexus (i.e. the pelvic plexus or major pelvic ganglia), pelvic nerves, and the cavernosal The expression of VIP mRNA in the corpus MATERIALS AND METHODS nerve were identified posterolateral to the cavernosum, liver, kidney and abdominal prostate on both sides, and stainless-steel aorta of all groups is also shown in Table 1. Diabetes was induced in male Sprague- bipolar wire electrodes placed around these There was a significant difference between Dawley rats (200–300 g at onset) by one structures for electrical stimulation. The penis the corpus cavernosum of the control and the intraperitoneal injection with streptozotocin was denuded of skin, and the right corpus VIP-treated rats (P < 0.05) at 1, 3, 7 and (STZ, 65 mg/kg). Controls received the citrate cavernosum exposed. To monitor ICP, a 23 G 14 days after treatment, but no significant buffer carrier alone. Rats were accepted as cannula filled with 250 U/mL of heparin difference in hepatic, renal and abdominal diabetic if the whole-blood glucose level solution was connected to polyethylene-50 aorta VIP mRNA among the three subgroups was ≥16.0 mmol/L, as measured with a tubing and inserted into the right corpus (P > 0.05) at any time after treatment. glucometer (Advantage, Roche, USA) in cavernosum. The tubing was then fixed to the whole blood taken from the proximal ventral tunica with a 7–0 nylon suture to ensure tail vein. These rats were maintained in stability during measurement of ICP. The ICP DISCUSSION alternating cycles of darkness (18.00 to 06.00 line was connected to a pressure transducer, hours) and light (06.00 to 18.00 hours). Food in turn connected via a transducer amplifier Various mechanisms have been suggested for and water were freely available. Finally, 61 rats to a data acquisition board. The pressure the erectile disorders associated with were accepted as diabetic and used in the values were displayed in real-time and diabetes. Vascular disease and neuropathies study at 10 weeks after treatment. recorded on a computer. The pressure resulting from diabetes are frequently transducers and analogue-to-digital board underlying causes of impotence in younger

The 61 diabetic rats were randomly divided were calibrated in cmH2O. men. Autonomic neuropathy can account for into groups A–D of 15 rats each (16 in D), with decreased function of erectogenic nerves or the ICP measured after injection, then at 3, 7 The cavernosal nerve was electrostimulated an altered balance of the pro-erectile and and 14 days after injection, respectively. Each directly with a delicate stainless-steel bipolar anti-erectile transmitters reaching the group was subdivided into subgroup 1 (sham- hook electrode attached to a multi-jointed cavernosal smooth muscle. The vascular operated, and an intracorporal injection with clamp. Each probe was 0.2 mm in diameter supply of the penis is highly sensitive to 200 mL PBS containing 20% sucrose), 2 (as 1, and the two poles were separated by 1 mm. atherosclerotic changes, which are

SHEN ET AL.

accelerated in diabetic men. In the human, TABLE 1 The groups and subgroups (1, PBS; 2, pcDNA3; and 3, pcDNA3/VIP), with the mean (SD) psychological factors often add to these neurostimulation-induced ICP and VIP mRNA level of the penis, liver, kidney and abdominal aorta, after organic disturbances. treatment The pathophysiology of diabetic ED has yet to Mean (SD) Mean (SD) VIP expression in arteries of be completely elucidated, but in vitro work Group/subgroup ICP, cmH O penis liver kidney aorta showed that corporal smooth muscle from 2 men with diabetes had less autonomically A (1 day) mediated or endothelium-dependent 1 50.2 (8.4) 0.42 (0.09) 0.72 (0.45) 1.16 (0.10) 0.86 (0.39) relaxation than tissues from non-diabetic 2 55.4 (9.3) 0.55 (0.15) 1.01 (0.36) 1.25 (0.06) 0.74 (0.45) counterparts [20]. A more recent 3 86.0 (17.4)* 1.19 (0.31)† 0.89 (0.28) 1.36 (0.45) 0.95 (0.72) immunohistochemical study suggested that B (3 days) advanced glycation end products in diabetic 1 59.6 (14.4) 0.52 (0.35) 1.17 (0.27) 1.54 (0.82) 0.47 (0.23) men, when deposited within the penile tunica 2 59.4 (17.2) 0.47 (0.24) 1.35 (0.08) 0.89 (0.38) 0.66 (0.27) and corporal collagen, might result in down- 3 85.8 (15.5)* 1.47 (0.48)† 1.24 (0.44) 1.18 (0.90) 0.82 (0.34) regulation of NOS through modulation of C (7 days) endothelial NOS and/or inducible NOS 1 49.0 (9.0) 0.46 (0.23) 1.05 (0.29) 0.90 (0.48) 0.90 (0.48) enzymatic activity [21]. Although NO is 2 59.6 (25.6) 0.51 (0.20) 0.90 (0.16) 0.74 (0.28) 0.57 (0.35) considered the neurotransmitter responsible 3 94.8 (11.6)* 1.07 (0.31)† 1.16 (0.31) 0.89 (0.27) 0.89 (0.27) for mediating the relaxation of the corpora D (14 days) cavernosa, it is may not be the only factor 1 53.2 (26.6) 0.54 (0.13) 0.84 (0.51) 1.06 (0.41) 1.01 (0.52) involved, because mice lacking neuronal NOS 2 53.8 (16.6) 0.49 (0.22) 1.04 (0.34) 1.01(0.37) 0.74 (0.46) mate successfully [22]. VIP, which is found at 3 82.8 (13.9)* 1.03 (0.44)† 0.95 (0.53) 1.04 (0.52) 0.87 (0.40) high concentrations in the terminals of the major pelvic ganglia [23] and deep arteries of *P < 0.05 for control vs VIP-treated rats; †Dunnett’s t-test, P < 0.05 between controls and VIP-treated the penis, and in nonvascular smooth muscle groups. tissue of the corpus cavernosum and corpus spongiosum [24], may also have a role in the ED associated with diabetes. There are fewer VIP- immunoreactive fibres in penile tissue the concomitant release of NO from the option for ED requires planning before from impotent men with diabetes [25] cavernosal nerve terminals. However, this intercourse. Gene therapy could restore and from STZ-diabetic rats [26]. VIP-like release may diminish with diabetes, ageing, or ‘physiological’ erection to the normal immunoreactivity was detected in the some other disease states. In addition, the endogenous signals, with no need for any pudendal vein effluent after pelvic nerve number of vascular smooth muscle cells may other form of therapy. stimulation [27], showing that the VIP- be diminished by the ageing and/or diabetic containing secretory vesicles found within process, such that sildenafil is insufficient to Gene therapy treats a specific disease by cholinergic nerve endings in the penis produce a clinical effect. Indeed, many introducing genes engineered to correct the undergo exocytosis when these endings are diabetic men with ED do not respond well to dysfunction leading to the disease. It can be invaded by action potentials, as is also found this medication [36]. Likewise, the injection of designed to replace a specific ‘mutant’ gene during erection [28,29]. VIP can stimulate exogenous VIP can induce erection in several with a good copy, or to introduce a gene sexual behaviour and enhance the penile animal species, including man. There are two to overcome a specific pathophysiological reflex [30,31]. In addition, VIP antibodies block recent reports of direct intracavernosal VIP disorder. In the case of ED, where the the penile erection evoked by electrical treatment for ED; Dinsmore et al. [37] and dysfunction is multifactorial, current and stimulation of the pelvic nerve in the dog [32]. Elkabir et al. [38] both reported that future strategies are primarily focused on The VIP-induced vasodilatation, which results intracavernosal injection with VIP combined neurotransmitters and smooth muscle. To in tumescence, is mediated by a cAMP with phentolamine mesylate is a safe and date, various gene therapies have been mechanism, after its activation by adenylate effective means of treating male ED of investigated for treating ED, including cyclase [7,8]. primarily non-psychogenic cause. There was a inducible NOS [39,40], endothelial NOS response rate of 85% in diabetic men with ED [41,42], penile-expressed neuronal NOS [43], Therefore, treatment that potentiates the [37]. human smooth muscle maxi-K+ channel effects of NO/VIP is a rational therapeutic protein [18], calcitonin gene-related peptide alternative if there is potentially attenuated There is no doubt that despite the advent of [44], and brain-derived neurotrophic factor NO/VIP output. Sildenafil improves erectile oral therapies and injection with exogenous [45] gene therapy. function in men with ED [33–35] because it VIP, there is room for improvement in the facilitates relaxation of smooth muscle cells treatment of ED. Such opportunities exist on In the present study, we chose VIP that have become dysfunctional during the at least two levels. First, there is a need for because: (i) although it is one of the main ageing and/or diabetic process. However, not more effective treatments for patients with neurotransmitters and neural co-mediators every man with ED responds to sildenafil, moderate to severe ED, and second, every with NO of penile erection [5], there are no mainly because its effect depends directly on currently approved non-surgical treatment reports of its use in gene therapy for ED; and

GENE TRANSFER OF VIP INTO PENILE CORPUS CAVERNOSUM

(ii), as VIP levels are lower in patients with greater ICP response to electrostimulation of helospectin, and vasoactive intestinal diabetes- and ageing-related ED, the study the cavernosal nerve, and without changing polypeptide in human corpus was designed to introduce the VIP gene to the expression of VIP in the liver, kidney and cavernosum. Br J Pharmacol 1995; 116: overcome ED, and thus explore a potential abdominal aorta wall. It seems reasonable to 2258–66 effective and long-lasting therapy for ED by assume that transfection with VIP cDNA is a 8 Miller MA, Morgan RJ, Thompson CS. addressing the physiology underlying potentially promising and physiologically Effects of papaverine and vasointestinal erection, with no frequent injections. Briefly, relevant strategy for treating diabetic ED, if polypeptide on penile and vascular cAMP the rationale of VIP for gene therapy is that necessary, combined with NOS gene therapy. and cGMP in control and diabetic animals: over-expression of this important an in vitro study. Int J Impot Res 1995; 7: endogenous smooth muscle relaxant and 91–100 vasodilator will assist in ameliorating the ACKNOWLEDGEMENTS 9 Metro MJ, Broderick GA. Diabetes and diminished erectile response characteristic of vascular impotence: does insulin ED in many patients. This study was supported by grants from The dependence increase the relative severity? National Nature Science Foundation of China Int J Impot Res 1999; 11: 87–9 The preliminary results indicate that pcDNA3/ (No. 30240034). 10 Lehman TP, Jacobs JA. Etiology of VIP cDNA is easily incorporated and its diabetic impotence. J Urol 1983; 129: expression sustained in diabetic rat corpus 291–4 cavernosum in vivo; moreover, this prolonged CONFLICT OF INTEREST 11 Klein R, Klein BE, Lee KE, Moss SE, up-regulation of VIP is capable of altering the Cruickshanks KJ. Prevalence of self- physiologically relevant erectile response, as None declared. Source of funding: National reported erectile dysfunction in people measured by a significant increase in the ICP Nature Science Foundation of China with long-term IDDM. Diabetes Care after stimulation of the cavernosal nerve. (No. 30240034). 1996; 19: 135–41 12 Buvat J, Lemaire A, Buvat-Herbaut M, The penis is an ideal organ for gene therapy Fourlinnie JC, Racadot A, Fossati P. because it is an appendage and therefore easy REFERENCES Hyperprolactinemia and sexual function to access. In addition, while it communicates in men. Horm Res 1985; 22: 196–203 with the peripheral vascular system, drugs 1 Andersson KE, Wagner G. Physiology of 13 McCulloch DK, Young RJ, Prescott RJ, (and by inference, gene-therapy vectors) penile erection. Physiol Rev 1995; 75: Campbell IW, Clarke BF. The natural rarely escape into the systemic circulation. 191–236 history of impotence in diabetic men. However, as the corpus cavernosum is highly 2 Ignarro LJ, Bush PA, Buga GM, Wood Diabetologia 1984; 26: 437–40 perfused, as are the liver, kidney and other KS, Fukuto JM, Rajfer J. Nitric oxide and 14 Aytac IA, McKinlay JB, Krane RJ. The organs, materials injected into the corpora cyclic GMP formation upon electrical field likely worldwide increase in erectile may still rapidly enter the venous circulation. stimulation cause relaxation of corpus dysfunction between 1995 and 2025 and So that other organs were unaffected, we cavernosum smooth muscle. Biochem some possible policy consequences. BJU occluded blood flow to the rat penis by Biophys Res Commun 1990; 170: 843–50 Int 1999; 84: 50–6 ligating the base of the organ for 30 min. The 3 Bush PA, Aronson WJ, Buga GM, Rajfer 15 Jevtich MJ, Khawand NY, Vidic B. present results show that the expression of J, Ignarro LJ. Nitric oxide is a potent Clinical significance of ultrastructural VIP mRNA in the liver, kidney and abdominal relaxant of human and rabbit corpus findings in the corpora cavernosa of aorta was not changed significantly after VIP cavernosum. J Urol 1992; 147: 1650–5 normal and impotence men. J Urol 1990; gene therapy; VIP gene transfer to the penis 4 Andersson PO, Bloom SR, Mellander S. 143: 289–93 may have no effects on these other organs. Hemodynamics of pelvic nerve induced 16 Maher E, Bachoo M, Elabbady AA, penile erection in dog possible mediation Polosa C, Begin LR, Collier B. Vasoactive As with all other in vivo gene-therapy by vasoactive intestinal peptide. J Physiol intestinal peptide and impotence in approaches, the basic objectives of gene 1984; 350: 209–24 experimental diabetes mellitus. Br J Urol therapy for organic ED should include: (i) 5 Ehmke H, Junemann KP, Mayer B, 1996; 77: 271–8 efficient delivery of a gene into the penis; (ii) Kummer W. Nitric oxide synthase and 17 Rehman J, Chenven E, Brink P et al. strong expression of the protein without vasoactive intestinal polypeptide Diminished neurogenic but not altering its site of expression, and activated colocalization in neurons innervating the pharmacological erections in the 2- to only during sexual stimulation; (iii) no serious human penile circulation. Int J Impot Res 3-month experimentally diabetic F-344 side-effects; and (iv) a long-term effect. The 1995; 7: 147–56 rat. Am J Physiol 1997; 272: H1960– present results suggest that VIP cDNA is 6 Ding YQ, Takada M, Kaneko T, Mizuno H1971 efficiently incorporated into corpus N. Colocalization of vasoactive intestinal 18 Christ GJ, Rehman J, Day N et al. cavernosum, and that its expression is polypeptide and nitric oxide in penis- Intracorporal injection of hSlo cDNA in sustained for at least 2 weeks in the penis, innervating neurons in the major pelvic rats produces physiologically relevant and activated only during nerve-stimulation ganglion of the rat. Neuroscience Res alterations in penile function. Am J Physiol in vivo. 1995; 22: 129–31 1998; 275: H600–H608 7 Hedlund P, Alm P, Ekstrom P, 19 Shen ZJ, Lu YL, Chen ZD, Chen F, Chen In conclusion, VIP gene transfer to the Andersson KE. Pituitary adenylate Z. Effects of androgen and ageing on diabetic rat penis was successful, with a cyclase-activating polypeptide, gene expression of vasoactive intestinal

polypeptide in rat corpus cavernosum. 29 Dixson AF, Kendrick KM, Blank MA, intestinal polypeptide and phentolamine BJU Int 2000; 86: 133–7 Bloom SR. Effects of tactile and electrical mesylate. BJU Int 1999; 83: S51 20 Saenz de Tejada I, Goldstein I, Azadzoi stimuli upon the release of vasoactive 39 Garban H, Marquez D, Magee T K, Krane RJ, Cohen RA. Impaired intestinal polypeptide in the mammalian et al. Cloning of rat and human neurogenic and endothelium-mediated penis. J Endocrinol 1984; 100: 249–52 inducible penile nitric oxide synthase. relaxation of penile smooth muscle from 30 Gozes I, Meltzer E, Rubinrout S, Application for gene therapy of erectile diabetic men with impotence. N Engl J Brenneman DE, Fridkin M. Vasoactive dysfunction. Biol Reprod 1997; 56: 954– Med 1989; 320: 1025–30 intestinal peptide potentiate sexual 63 21 Seftel AD, Vaziri ND, Ni Z et al. behavior, inhibition by novel antagonist. 40 Chancellor MB, Tirney S, Mattes CE Advanced glycation end products in Endocrinology 1989; 125: 2945–9 et al. Nitric oxide synthase gene transfer human penis. elevation in diabetic tissue, 31 Gozes I, Fridkin M. A fatty neuropeptide: for erectile dysfunction in rat model. BJU site of deposition, and possible effect potential drug for noninvasive impotence Int 2003; 91: 691–6 through iNOS or eNOS. Urology 1997; 50: treatment in a rat model. J Clin Invest 41 Champion HC, Bivalacqua TJ, Hyman 1016–26 1992; 90: 810–4 AL et al. Gene therapy of endothelial nitric 22 Huang PL, Dawson TM, Bredt DS, 32 Aoki M, Matsuzaka J, Yeh KH. oxide synthase to the penis augments Snyder SH, Fishman MC. Targeted Involvement of vasoactive intestinal erectile response in the aged rat. Proc Natl disruption of the neuronal nitric oxide peptide VIP; as a humoral mediator of Acad Sci USA 1999; 96: 11648–52 synthase gene. Cell 1993; 75: 1273–86 penile erectile function in the dog. 42 Bivalacqua TJ, Champion HC, Mehta YS 23 Dail WA, Minorsky N, Moll MA, J Androl 1994; 15: 174–82 et al. Adenoviral gene transfer of Manzanares K. The hypogastric nerve 33 Goldstein I, Lue TF, Padma-Nathan endothelial nitric oxide synthase (eNOS) pathway to penile erectile tissue: H, Rosen RC, Steers WD, Wicker to the penis improves age-related erectile histochemical evidence supporting a PA. Oral sildenafil in the treatment of dysfunction in the rat. Int J Impot Res vasodilator role. J Auton Nerv Syst 1986; erectile dysfunction. The Sildenafil Study 2000; 12: S8–S17 15: 341–9 Group. N Engl J Med 1998; 338: 1397– 43 Magee TR, Ferrini M, Garban HJ et al. 24 Polak JM, Gu J, Mina S, Bloom SR. 404 Gene therapy of erectile dysfunction VIPergic nerves in the penis. Lancet 1981; 34 Goldenberg MM. Safety and efficacy of in the rat with penile neuronal nitric 2: 217–9 sildenafil citrate in the treatment of male oxide synthase. Biol Reprod 2002; 67: 25 Lincoln J, Crowe R, Blacklay PF, Pryor erectile dysfunction. Clin Ther 1998; 20: 20–8 JP, Lumley JS, Burnstock G. Changes in 1033–48 44 Bivalacqua TJ, Champion HC, Abdel- the VIP-, cholinergic and adrenergic 35 Marks LS, Duda C, Dorey FJ, Macairan Mageed AB, Kadowitz PJ, Hellstrom innervation of human penile tissue in ML, Santos PB. Treatment of erectile WJG. Gene therapy of prepro-calcitonin diabetic and non-diabetic impotent dysfunction with sildenafil. Urology 1999; gene-related peptide restores erectile males. J Urol 1987; 137: 1053–9 53: 19–24 function in the aged rat. Biol Reprod 26 Crowe R, Lincoln J, Blacklay PF, 36 Rendell MS, Rajfer J, Wicker PA, Smith 2001; 65: 1371–7 Pryor JP, Lumley JS, Burnstock G. MD. Sildenafil for treatment of erectile 45 Bakircioglu ME, Lin CS, Fan P, Sievert Vasoactive intestinal polypeptide-like dysfunction in men with diabetes: a KD, Kan YW, Lue T. The effect of adeno- immunoreactive nerves in diabetic penis. randomized controlled trial. The Sildenafil associated virus mediated brain derived A comparison between streptozocin- and Diabetes Study Group. JAMA 1999; neurotrophic factor in an animal model of treated rats and man. Diabetes 1983; 32: 281: 421–6 neurogenic impotence. J Urol 2001; 165: 1075–7 37 Dinsmore WW, Gingell C, Hackett G 2103–9 27 Anderson PO, Bjornberg J, Bloom SR, et al. Treating men with predominantly Mellander S. Vasoactive intestinal nonpsychogenic erectile dysfunction Correspondence: Zhou-Jun Shen, Department polypeptide in relation to penile erection with intracavernosal vasoactive intestinal of Urology, 1st Affiliated Hospital, Medical in the cat evoked by pelvic and by polypeptide and phentolamine mesylate College of Zhejiang University, Hangzhou hypogactric nerve stimulation. J Urol in a novel auto-injector system: a 310003, PR China. 1987; 138: 419–22 multicentre double-blind placebo- e-mail: [email protected] 28 Ottesen B, Wagener G, Virag R, controlled study. BJU Int 1999; 83: Fahrenkrug J. Penile erection: possible 274–9 Abbreviations: ED, erectile dysfunction; role for vasoactive intestinal polypeptide 38 Elkabir JJ, Walker RMH, Williams G. NO(S), nitric oxide (synthase); STZ, as a neurotransmitter. Br Med J 1984; Successful treatment of venogenic streptozotocin; VIP, vasoactive intestinal 288: 9–11 erectile dysfunction with vasoactive polypeptide; ICP, intracavernosal pressure.

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Original Article MICROHETEROGENEITY OF BLOOD FLOW IN RAT URINARY BLADDER KIMURA et al.

Assessment of microheterogeneity of blood ﬂow in the rat urinary bladder by high-resolution digital radiography

TAKAHIRO KIMURA, TOKUNORI YAMAMOTO, ATSUSHI SONE, ATSUSHI TAKENAKA and MASATO FUJISAWA Department of Urology, Kawasaki Medical School, Kurashiki, Japan Accepted for publication 24 November 2004

OBJECTIVES radiography combined with the deposition of 0.16 (0.019), respectively (P < 0.001) at the 3H-labelled desmethylimipramine. The spatial capillary level. To assess high-resolution digital radiography pattern of blood flow was quantified by the for measuring blood flow and thus examine coefficient of variation of the regional flow CONCLUSION the microheterogeneity of bladder (CV = SD/mean). microcirculation in a rat model. There was a heterogeneous distribution of blood flow in the microcirculation to capillary RESULTS vessels in the muscular layer, possibly MATERIALS AND METHODS reflecting a difference in dynamic blood flow Muscle blood flow was less than mucous of regional perfusion of the emptied bladder. Microheterogeneity of blood flow in both blood flow (muscle : mucosa, 2.9 : 5) in the mucosa and detrusor muscle of eight empty bladder. In the muscle layer the blood KEYWORDS anaesthetized rats was investigated using an flow distribution was more heterogeneous imaging technique with very high spatial than that in the mucosa, with a mean (SD) CV bladder, radioactive molecular flow tracer, resolution (0.1 ¥ 0.1 mm2) using digital in muscle and mucosa of 0.33 (0.033) and microcirculation, flow heterogeneity

INTRODUCTION MATERIALS AND METHODS plate, TR2040, Fuji Co., Tokyo, Japan). This plate has a >100-fold higher sensitivity for There are several studies of the relationship Eight male Wistar rats (8 weeks old) were detecting radiation than conventional X-ray between bladder dysfunction and blood intra-abdominally administered 30 mg/kg film, and detects and visualizes radioactivity flow [1,2], with a heterogeneous distribution pentobarbital, artificially ventilated after over a wide dynamic range, with good of blood flow in the bladder, and large tracheotomy, the bladder exposed by a linearity, high resolution and accuracy within differences in blood flow between the median incision of the lower abdomen, and a short time (Fig. 1). To minimize the effects of muscular and mucosal layers reported [3–6]. then emptied by cannulation from the top of environmental radiation the bladder sections The relationship between bladder dysfunction the bladder. The heart was exposed by a were placed in contact with the imaging plate and blood flow has also been recognised. median incision of the breast bone; a cannula for 3 days in a lead-shielded box. Analogue Blood flow patterns in the bladder have was inserted for sampling arterial blood and images of the distribution of activity of a- conventionally been examined at a spatial measuring blood pressure. After the stability radiation released from the plate were resolution of several millimetres, but the of cardiac function was confirmed by converted into digital signals at a resolution microcirculation cannot be measured at such monitoring blood pressure, 2.2 MBq of blood of 0.1 ¥ 0.1 mm2/pixel by linear resolution. Thus the distribution of local blood flow tracer (3H-DMI) was injected into the left transformation using a bioimaging analyser flow in each of the muscular and mucosal ventricle. One minute after the injection the (HGE, Fuji; Fig. 2B). As the intensity of a- layers has not yet been clarified. heart was stopped by administering KCl to the radiation activity was linearly transformed left ventricle, and the bladder excised and into a grey scale, and as the concentration In the present study we used a method stored in a freezer at -80 ∞C. Serial coronal corresponded to the distribution of blood for imaging the microcirculation in sections (10 mm) of the bladder from the neck flow, the region of interest (ROI) of each cardiac muscles and applied it to imaging to the top were cut at -25 ∞C using a muscular and mucosal layer was traced the blood flow in the bladder wall [7], cryostat, spread on a glass slide and dried. (Fig. 2B) based on the submacro images obtaining the distribution at a much higher corresponding to each image, and analysed spatial resolution (0.1 ¥ 0.1 mm) than As 3H-DMI administered to the left ventricle is (Fig. 2A). The variable for assessing the previously reported, using H3-labelled taken up in the bladder wall and binds to a2- heterogeneity of the distribution of blood desmethylimipramine (3H-DMI), as a receptors in endothelial cells in capillary flow was the coefficient determined by blood flow tracer. Using this method we vessels, a-radiation activity increases with dividing the SD of the grey scale values in the evaluated the heterogeneity of blood flow high densities of blood flow. The a-radiation traced ROI by the mean, i.e. the coefficient of (microcirculation) in the muscular and activity was detected using an ultra-high variation (CV) of local blood flow. The intensity mucosal layers of bladder separately. sensitivity radiation energy sensor (imaging of a-radiation activity and the CV of local

KIMURA ET AL.

FIG. 1. The sensitivity of the imaging plate (red) FIG. 2. (A) A submacro image of the bladder wall, and (B), a digital radiogram of blood ﬂow distribution in the compared with conventional X-ray ﬁlm (green). bladder wall.

AB 105 High flow 2 serosa mucosa

103 Radioactivity, dpm/mm 101 10-1 101 103 Response, AU/mm2 blood ﬂow between the muscular and muscle mucosal layers, and between the serial top and neck sections of the bladder wall were Low flow 0.1 mm ¥ 0.1 mm/pixel analysed using Student’s t-test. 6 mm

RESULTS 600 FIG. 3. The change in blood flow from In all eight rats examined the mean (SD) 500 the dome to the neck of the intensity of a-radiation activity was 497 (21) bladder for the mucosal (red) and 400 in the mucosal and 282 (17) in the muscular muscle (green) layers. layer, giving a ratio of 5 : 2.9. Direct 300 comparison of the blood flow showed that the intensity of a-radiation activity was Grey scale 200 significantly higher (1.8-fold) in the mucosal 100 than in the muscular layer (P < 0.001). The blood flow in the bladder was slightly higher 0 in the neck region than in the top region Dome Neck (Fig. 3), with the serial sections of the top and neck regions of the bladder wall indicating significantly higher flow in the neck region of both muscular and mucosal layers than in the resolution of this method is limited to same difference in blood flow, with a ratio of top region, at 275 (22) vs 301 (22) (P = 0.007) 3–8 mm because smaller blood vessels 2 : 1 to 13 : 12 [8,9]. This may have been and 476 (18) vs 492 (9) (P = 0.010), become obstructed, evaluating the caused by microcirculation disorders induced respectively. microcirculation is impossible in this way. In by vascular obstruction, which is a the present study, blood flow in the bladder disadvantage of the conventional The heterogeneity of the distribution of was imaged at ª60 times higher resolution microsphere method. As >98% of the 3H-DMI blood flow in the muscular and mucosal (100 mm) than with the conventional method, used in the present study binds to a2- layers, expressed as the mean (SD) CV, and the heterogeneity of the distribution of receptors in endothelial cells in capillary was 0.33 (0.033) in the muscular and blood flow in the mucosal and muscular layer vessels, the results are stable, with no 0.16 (0.019) in the mucosal layer, being evaluated for the first time. The blood flow artefacts caused by vascular obstruction significantly higher (about twice) in the tracer (3H-DMI) mostly binds to a2-receptors and reduced resolution by diffusion to other former than in the latter, indicating greater in endothelial cells in capillary vessels, and its tissues, as occurs with other molecular flow heterogeneity of blood flow in the muscular usefulness for analysing microcirculation tracers. The evaluation of blood flow in serial layer (P < 0.001). has been confirmed in cardiac muscles [7]. sections prepared from the neck to the top of We applied this method to evaluate the bladder indicated that it was significantly microcirculation in the bladder, which is a higher in the former than in the latter. This DISCUSSION luminal organ with contractile function, like was considered to be caused by differences in the heart. the density of blood microvessels within the Since the first report by Nemeth et al. [8] in vascular network in the bladder. 1977, the distribution of blood flow in the The results indicate that blood flow in the bladder has been measured using the mucosal was significantly higher than in the We confirmed the heterogeneity of the microsphere method, but as the spatial muscular layer. Previous studies reported the distribution of blood flow in the mucosal and

MICROHETEROGENEITY OF BLOOD FLOW IN RAT URINARY BLADDER

muscular layer, using the higher resolution of Hohlbrugger et al. [11] reported on the 5 Gosling JA, Kung LS, Dixon JS et al. the present method, with a significantly autoregulation of vesical circulation in the Correlation between the structure and higher CV of blood flow in the muscular human full bladder, using Doppler function of the rabbit urinary bladder than in the mucosal layer, i.e. greater ultrasonography. In future work we will clarify following partial outlet obstruction. J Urol heterogeneity. The heterogeneity is affected the heterogeneity of blood flow in the full 2000; 163: 1349–56 by blood-flow regulation of the network bladder at the microvascular level using the 6 Schroder A, Chichester P, Kogan BA structure of blood vessels, mechanical present method. et al. Effect of chronic bladder outlet stimulation by expansion and contraction obstruction on blood flow of the rabbit of the bladder wall, and changes in the In conclusion, we examined blood flow bladder. J Urol 2001; 165: 640–6 arterial tonus corresponding to local patterns at a much higher resolution than 7 Matsumoto T, Ebata J, Tachibana H metabolism. Schroder et al. [6] produced conventional methods allow, using a et al. Transmural microcirculatory blood chronic BOO in rabbits, measured the blood molecular flow tracer that is selectively flow distribution in right and left flow in the bladder, and reported that in accumulated by endothelial cells in capillary ventricular free walls of rabbits. Am J the mucosa it was increased through vessels of the bladder wall. The distribution of Physiol 1999; 277: 183–91 loading on the bladder by BOO, up to a blood flow in the microcirculation to capillary 8 Nemeth CJ, Khan RM, Kirchner P et al. certain level, but continuously decreased vessels was more heterogeneous in the Changes in canine bladder perfusion with in the muscular layer. This suggested that muscular than in the mucosal layer. This distention. Invest Urol (Berl) 1977; 15: the difference in the heterogeneity of blood technique will be helpful to clarify 149–50 flow between the mucosal and muscular physiological changes in the blood supply of 9 Azadzoi KM, Pontari M, Vlachiotis J layers in the present study might be caused the bladder in various disease states. et al. Canine bladder blood flow and by mechanical stimulation and changes in oxygenation: changes induced by filling, the arterial tonus. Stress on the bladder CONFLICT OF INTEREST contraction and outlet obstruction. J Urol wall probably induced the proliferation 1996; 155: 1459–65 of fibres in the interstitial tissues, which None declared. 10 Levin RM, Leggett R, Whitbeck C, excluded blood vessels, and consequently Horan P. Effect of calcium and calcium caused local ischaemia. This induced micro- REFERENCES chelators on the response of the bladder ischaemia-enhanced fibrogenesis of the to in vitro ischaemia. Br J Urol 1998; 82: muscular layer, resulting in reduced bladder 1 Brading AF, Greenland JE, Mills IW et al. 882–7 compliance. However, as fibres do not exist Blood supply to the bladder during filling. 11 Hohlbrugger G, Frauscher F, Strasser H, in the mucosal layer, ischaemia is unlikely Scand J Urol Nephrol Suppl 1999; 201: Stenzl A, Bartsch G. Evidence for the to create the same stress as in the muscular 25–31 autoregulation of vesical circulation by layer. Levin et al. [10] reported that the 2 Greenland JE, Brading AF. The effect of intravesical potassium chloride and in vitro reactivity to ischaemia was higher bladder outflow obstruction on detrusor distension in the normal human bladder. in the mucosal than in the muscular layer. blood flow changes during the voiding BJU Int 2000; 85: 412–5 Furthermore, as blood flow is lower in the cycle in conscious pigs. J Urol 2001; 165: muscular than in the mucosal layer, the 245–8 Correspondence: Masato Fujisawa, inhibition of blood flow in capillary vessels by 3 Azadzoi KM, Tarcan T, Kozlowski R et al. Department of Urology, Kawasaki Medical haemocytes may be higher in the former than Overactivity and structural changes in the School, 577 Matsushima, Kurashiki, the latter, suggesting that the distribution chronically ischemic bladder. J Urol 1999; 701–0192, Japan. of blood flow is more heterogeneous, as a 162: 1768–78 e-mail: [email protected] result of the reduced density of functional 4 Miodonski AJ, Litwin JA. Microvascular capillary vessels. There is a significant architecture of the human urinary bladder Abbreviations: 3H-DMI, H3-labelled difference in bladder microcirculation wall: a corrosion casting study. Anat Rec desmethylimipramine; CV, coefficient of between the empty and full bladder. 1999; 254: 375–81 variation.

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Pharm review Article WYLLIE

Back to the future for urological drug development?

Over the last few years several long-term More recently, several long-term studies have studies, by design or accident, have had a led to a loss of confidence in the safety of at potentially negative impact on the future of least one statin (cerivistatin) and several urological and andrological drug research and cyclooxygenase (COX) inhibitors, to an extent development. The more positive of these have where stock prices have been substantially included the Medical Treatment Of Prostatic reduced as products have been withdrawn, Symptoms, which ultimately showed that and warnings in product labels have been either 5a-reductase inhibitor (finasteride) or strengthened. The impact of such post- a-blocker (doxazosin) therapy was good marketing studies is already going beyond the as monotherapy but also offered advantages primary therapeutic indication of the affected (apart from cost perhaps) when used in drugs. combination. It is not known whether this has any actual impact on the extent of the co- In the context of urological and andrological administration of these drugs in the real drug development, the consequence of post- world. Initially, the results with finasteride marketing long-term follow-up is already well from the Prostate Cancer Prevention Trial documented. The clinical data resulting in were more equivocal, showing a lower contraindications and warnings for incidence of prostate carcinoma but phosphodiesterase inhibitors with a-blockers apparently a higher grade when manifest. only became apparent almost 5 years after However, it now appears that the latter is the prototype (sildenafil) reached the market artefactual and the data augers well for the place. There is good evidence that FDA are use of finasteride, at least in preventing increasingly interested in the safety aspects of prostate cancer. It remains to be seen what novel chemical entities (NCEs). The re-filed the outcome of a similar study involving NDA for Uprima by TAP was rejected as much GSK’s dutasteride will be in terms of both for cardiovascular safety concerns as for any efficacy and artefact. other reasons. It is likewise assumed that the Proctor and Gamble testosterone patch for Unfortunately, perceptions can be difficult to women with hypoactive sexual desire disorder dislodge. At the turn of the millennium the was rejected on a similar basis. The recent Antihypertensive and Lipid-Lowering events in the COX-2 field can only have Treatment to Prevent Heart Attack Trial had a made the FDA even more conservative. substantial impact on the considerable Will this have any impact on the future of cardiovascular sales of doxazosin, it was urological drug discovery and development? subsequently realised that the change in Unfortunately the answer is almost certainly perception arose from the trial design, yes. however, the damage to patient and physician confidence was remarkably difficult to In general urology deals with diseases that are reverse. Although, it should have resulted in not life-threatening (apart from cancers), and little change in the management of patients sexual medicine is associated with ‘lifestyle with BPH, there was a considerable decrease drugs’, at least in the eyes of the regulators in prescriptions for this indication for over and pricing authorities. As Lilly have found 2 years. with duloxetine, which is under review both

WYLLIE

as an antidepressant and for treating stress ‘antidepressant’ SSRIs, which have been prototype, oxybutynin. The problem is that the incontinence, the regulators can require designed to give 24-h cover with much longer overactive bladder and BPH markets are different benefit-risk ratios for approval in half-lives, would not have the advantage already reasonably well served, and the each indication. of such rapid clearance. Statistically, the commercial returns for NCEs may be average man has sex 49 times per year and questionable. It is possible that the regulatory authorities on this basis, the requirement for long-term could mandate more extensive (i.e. longer safety testing of an on-demand agent So where does this leave urological/ term) safety data before approval, rather than such as dapoxetine might be considerably andrological drug discovery and the existing post-marketing follow-up. For relaxed. development? Any chronic-use NCE for most chronic-use drugs this would not be any field is going to be subject to ever- commercially viable. It has been calculated Another way of reducing the possibility of an increasing regulatory hurdles, if it is for that an additional 1 year to the whole phase unexpected long-term side-effect is to an indication that is ‘lifestyle’ or not life- III programme would increase the cost to the develop only mechanistically similar or threatening. On this basis, areas where a company by almost 75%. In this era of pricing chemically similar NCEs. The latter option is short-term risk-benefit ratio, e.g. urological restriction and competition from generics seldom available as a tactic for a competitor cancers, would be particularly attractive. at an early stage, several poorly served these days because of the more effective and Equally, any situation where drugs could be urological diseases, e.g. stress incontinence wider structuring of patent claims. However, used on demand or strategically, e.g. and ejaculatory function, would become terazosin and doxazosin are both structurally ejaculatory disorders or stress incontinence, borderline viable, and interstitial cystitis and similar quinazolines, yet developed by would be viable. Perhaps in other areas, e.g. prostatitis would be excluded completely. different companies. The more viable strategy BPH and urinary urge incontinence, the only is the development of agents that are advances may be made by using combinations The picture for on-demand drugs is more mechanistically similar, e.g. antimuscarinics of existing agents. optimistic, where the scale of long-term and a-blockers. In addition, being slow to safety testing, e.g. for J&Js selective serotonin market is not necessarily a handicap; Next month I will examine what the re-uptake inhibitor (SSRI) dapoxetine for tamsulosin was the fifth a-blocker in most pharmaceutical industry is doing to identify premature ejaculation may be less exacting markets, yet gained and still retains >45% new urological targets. but no less meaningful from the safety of the $2 billion BPH market, mainly perspective. Dapoxetine appears to have a because of an effective marketing strategy. MICHAEL G. WYLLIE, nearly ideal profile in this respect, as it is Equally the second, third and fourth Urodoc Ltd, Maryland, Ridgeway Road, effective within an hour and has a short (but antimuscarinics to be marketed are likely to Herne, Kent, CT6 7LN, UK clinically useful) half-life of ª6 h. The provide a better commercial return than the e-mail: [email protected]

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Original Article MODIFIED SKIN FLAP REPAIR FOR PROXIMAL HYPOSPADIAS PATEL et al.

Modiﬁed tubularized transverse preputial island ﬂap repair for severe proximal hypospadias

RAKESH P. PATEL, ASEEM R. SHUKLA, J. CHRISTOPHER AUSTIN and DOUGLAS A. CANNING Division of Paediatric Urology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Accepted for publication 15 November 2004

INDICATIONS meatal opening or penis was small, or when the chordee was severe. Recently, we The best surgical approach for repairing developed a modification of the Duckett TPIF proximal hypospadias with chordee remains that uses one side of the island flap to controversial among urologists. Based on recreate a urethral plate, with the remainder various considerations, from age and of the flap being tailored and rolled to anatomy to surgeon preference, techniques recreate a neourethra. This modification have been described that might be broadly makes it easier to tailor the urethroplasty classified as single- or multiple-stage appropriately to create a more consistent procedures. Numerous alternatives have been neourethra with less risk of diverticulum and described for single-stage neourethral stenosis. We consider that reducing the reconstruction for proximal hypospadias, likelihood of leaving redundant tissue in situ including prepuce-based flaps, incised-plate minimizes the risk of diverticulum formation, urethroplasty, and free grafts, with varying turbulent voiding and urethrocutaneous results [1–4]. Surgical innovation has enabled fistula. The purpose of this report is to share most variants of hypospadias to be repaired our technique and results. with preservation of the urethral plate, but proximal hypospadias with severe chordee METHODS might still require transection of the urethral plate. Since Duckett [5] first described the The TPIF is created as follows. A glans-holding transverse preputial island flap (TPIF) repair in suture is placed and a circumcising incision is 1980, we have continued to prefer to outlined with a marker and extended on the incorporate vascularized preputial flaps for midline to the penoscrotal junction. We think these difficult cases. that proximal extension of the ventral incision facilitates subsequent harvesting of the onlay The traditional TPIF creates the neourethra by flap by allowing the penile shaft skin to tubularizing the dorsal preputial tissue into a flatten, resulting in better visibility of the neourethra and then transferring the tube to pedicle of the flap, and better separation of the native urethra proximally, and to the glans the pedicle and the dorsal penile shaft skin. To distally. This repair has a complication rate of ensure haemostasis, we infiltrate a solution of 32–42% in some reports [6–8]. In our 1 : 100 000 noradrenaline and 1% lidocaine experience there were complications after along the marked line. The skin is then incised repair, especially urethral diverticula and and the penis degloved superficial to Buck’s meatal stenosis, in a few boys when the fascia, beginning the dissection ventrally,

PATEL ET AL.

FIG. 1. The modified tubularized TPIF repair. A. An inner preputial skin flap is harvested dorsally, beginning at the middle of the penile shaft where the vascular pedicle to the inner prepuce is better defined. The dissection then proceeds proximal to the penopubic junction and distal, completely separating the preputial flap from the distal penile shaft skin. We create a ‘button hole’ through the vascular pedicle at the penopubic junction, which reduces the extent of the pedicle dissection while minimizing risk of penile torque after the flap is transferred to the ventrum in preparation for the urethral reconstruction. The arrow indicates the site of the ‘button hole’. B. The medial margin of the flap is anchored longitudinally to the ventral surface of the corpora cavernosa just to the right or left of the midline, using a series of interrupted 7–0 polyglactin sutures. These subcuticular sutures do not pass through the epithelium of the flap. The arrow indicates the location of the urethral meatus, and the vertical solid line represents the proposed plane for placing the second parallel suture line that completes the tubularization of the neourethra. C. The opposite margin of the flap is stretched to accurately match the flap to the desired size of the neourethra (the marked area indicates the portion of flap to be discarded while preserving underlying vascular supply). The narrowed proximal flap is sutured to the spatulated native urethral meatus. D. The neourethra is constructed over an 8 F feeding tube that is replaced with a 6 F urethral stent before applying the dressing. E. The dorsal preputial skin is split in the midline and rotated ventrally to allow adequate circumferential skin coverage with a series of subcuticular sutures.

AB C

from the urethral meatus to the penoscrotal away from the corporal tissue until the are made off the midline and closed junction, and then dorsally to the penopubic tethering effect of the spongiosal tissue is horizontally to correct chordee. The artificial junction. The urethral meatus is incised released. The ventral dissection of the urethral erection is then repeated. proximally until vascularized corpora plate sometimes results in a relatively spongiosum of normal appearance is distal urethra displaced to the penoscrotoal When the penis is straight, a segment of inner encountered, and normal bleeding from the junction or even to the perineum. The glans is preputial tissue is harvested from the native urethra is noted. An artificial erection is deeply incised in the midline and excess redundant dorsal prepuce, and the mesentery induced, and if the chordee is severe, the epithelium trimmed. If required, dorsal of the flap is buttonholed and ventrally urethral plate is transected and dissected longitudinal incisions of appropriate length transposed (Fig. 1a). The native urethral

MODIFIED SKIN FLAP REPAIR FOR PROXIMAL HYPOSPADIAS

meatus, which is now relocated more Between 1997 and 2001, we performed 12 DIFFICULTIES AND COMPLICATIONS proximally, is fixed to the corpora cavernosa modified TPIF repairs on boys with with fine absorbable monofilament sutures. penoscrotal or scrotal hypospadias with Two of the 12 boys undergoing a TPIF repair severe chordee. All of these repairs required developed a complication requiring surgical Previously we constructed the urethra from transection of the urethral plate to resolve the intervention; one developed a fistula and one the island flap by rolling the tissue over a tube penile curvature, and the mean (median, was treated for meatal stenosis that caused and then suturing the proximal end to the range) follow-up is now 24.5 (24, 20– proximal urethral ballooning. Excellent native urethral meatus at the penoscrotal 33) months. results, with a straight penis and voiding from junction or at the perineum [5]. We currently a distal glanular meatus, were obtained in 11 construct the urethra by first anchoring one boys. The final slit-like meatus was properly side of the flap longitudinally to the ventral ADVANTAGES AND DISADVANTAGES placed, with no fistulae, urethral diverticula, surface of the corpora cavernosa just to the stenosis or persistent chordee in these boys. right or left of the midline using 7–0 The ideal surgical correction for penoscrotal Separation of the glans wings in one boy will polyglactin sutures (Fig. 1b). The anchoring or perineoscrotal hypospadias with severe require an additional procedure for definitive begins at the posterior wall of the native chordee remains elusive. In addition to repair. urethra and proceeds distally to the proposed allowing a single-stage repair with the location of the neomeatus in the glans. This attendant benefits to the patient, the primary This relatively simple modification of creates a new urethral plate of inner preputial advantage of the modified TPIF over free graft Duckett’s original description has resulted skin, which no longer binds the ventral repairs is the incorporation of vascularized in a considerable reduction in our corpora. The anchored medial edge of the preputial flaps. We recently reported a 20- complication rate after these procedures. tube allows the opposite end of the flap to year review of outcomes using vascularized Although there were few patients, which be stretched to mark the redundant flap preputial flaps for severe hypospadias at our reflects the few that we think require skin that can be discarded to construct an institution, that confirmed the long-term transection of the urethral plate with release appropriately sized neourethra (Fig. 1c). The viability of these flaps [9]. Our preference of ventral tethering tissue, we consider that tube must be narrowed substantially at the continues to be to use preputial flaps as an this modification will help others who have proximal anastomosis between the new and island onlay when the urethral plate is had similar difficulties with the traditional spatulated native urethra to align the preserved, or as an island tube when it is not TPIF repair. anastomosis properly, and to construct a tube [10]. of ideal calibre with no diverticulum at the CONFLICT OF INTEREST distal extent of the native urethra. For most Essentially, the modified TPIF converts a boys reconstructed in their first year, we use difficult procedure (the original TPIF) into a None declared. an 8 F feeding tube as a template to gauge the more commonly used and consistent island urethral lumen as the closure proceeds. onlay repair, by recreating a urethral plate REFERENCES with one side of the ventrally transposed To construct the neourethra, a second inner preputial skin that is anchored to the 1 Snodgrass WT, Lorenzo A. Tubularized interrupted subcuticular suture line is placed, medial margin of the corpora. By anchoring incised-plate urethroplasty for proximal adjacent to the first suture line, longitudinally the medial edge of the flap to the corpora, the hypospadias. BJU Int 2002; 89: 90–3 along the ventral penile shaft (Fig. 1d). The opposite end of the flap can be stretched to 2 Powell CR, Mcaleer I, Alagiri M, Kaplan urethral reconstruction continues proximally match the neourethra accurately to the size of GW. Comparison of flaps versus grafts in to the glans penis. A glansplasty is completed the native urethra. This minimizes formation proximal hypospadias surgery. J Urol over an 8 F urethral stent with 6–0 absorbable of a urethral diverticulum where the native 2000; 163: 1286–9 monofilament horizontal mattress sutures urethra meets the neourethra, and reduces 3 Kolon TF, Gonzales ET. The dorsal inlay placed parallel to the cut edge of the glans, to the risk of turbulent voiding that might graft for hypospadias repair. J Urol 2000; cover the distal edge of the tube and to contribute to the formation of urethral 163: 1941–3 provide an anatomically accurate appearance. diverticula. Furthermore, the adjacent suture 4 Kocvara R, Dvoracek J. Inlay-onlay The 8 F stent is exchanged for a 6 F stent that lines are dorsal, which we think also flap urethroplasty for hypospadias and is left indwelling for 2–2.5 weeks, and dorsal minimizes the risk of fistula. urethral stricture repair. J Urol 1997; 158: preputial skin is fashioned to provide 2142–5 adequate skin coverage, as in all hypospadias The primary limitation of this initial 5 Duckett JW. Transverse preputial repairs (Fig. 1e). experience remains the relatively short island flap technique for repair of severe follow-up compared to our institutional hypospadias. Urol Clin North Am 1980; 7: The repair is covered with a dressing that experience with the original Duckett TPIF, that 423–30 compresses the penis against the lower now exceeds two decades. However, with a 6 Wiener JS, Sutherland RW, Roth DR, abdominal wall by placing a thin follow-up of at least 2 years for these 12 Gonzales ET Jr. Comparison of onlay nonabsorbent pad and a folded gauze sponge patients after the modified TPIF, we would and tubularized island flaps of inner on top of the penis, followed by a bio- have expected to encounter most preputial skin for the repair of proximal occlusive dressing. Trimethoprim- complications by now. Our experience hypospadias. J Urol 1997; 158: 1172–4 sulphamethaxozole is provided as prophylaxis continues to increase with this technique, and 7 Dewan PA, Dinneen MD, Winkle D, while the urethral stent remains in place. we continue to carefully evaluate our results. Duffy PG, Ransley PG. Hypospadias:

PATEL ET AL.

Duckett pedicle tube urethroplasty. Eur 10 Elder JS, Duckett JW, Snyder HM. Boulevard, Philadelphia, PA 19104–4399, Urol 1991; 20: 39–42 Onlay island flap in the repair of USA. 8 Elbakry A. Complications of the preputial mid and distal penile hypospadias e-mail: [email protected] island flap-tube urethroplasty. BJU Intl without chordee. J Urol 1987; 138: 1999; 84: 89–94 376–9 Abbreviations: TPIF, transverse preputial 9 Patel RP, Shukla AR, Snyder HM 3rd. island flap. The island tube and island onlay Correspondence: Douglas A. Canning, hypospadias repairs offer excellent long- Division of Paediatric Urology, Children’s term outcomes: a 14-year follow-up. Hospital of Philadelphia, 3rd Floor Wood J Urol 2004; 172: 1717–19 Building, 34th Street and Civic Center

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PoT Article TUBELESS and STENTLESS PERCUTANEOUS NEPHROLITHOTOMY GUPTA et al.

Tubeless and stentless percutaneous nephrolithotomy

VIKAS GUPTA, TRILOK C. SADASUKHI, KRISHAN K. SHARMA, RAM G. YADAV and RAJEEV MATHUR Department of Urology, SMS Medical College and Hospital, Jaipur, India Accepted for publication 29 November 2004

INDICATIONS ‘moderate’, or ‘severe pain’) was given to the option must be used. The tubeless PCNL patient on the day after the operation to technique was developed in an attempt to In 1955 Goodwin et al. [1] reported the use assess pain. No routine imaging was used to remove renal stones with minimal morbidity, of percutaneous drainage in a patient detect urinoma or haematoma when the with a JJ stent used for urine drainage with an obstructed kidney. Percutaneous recovery was uneventful. Patients were afterward. However, ureteric stenting nephrolithotomy (PCNL), as a primary discharged when the urine was clear, there increases morbidity, stent-related procedure, was subsequently described by was no leaking from the wound site, and no complications and is an additional cost. Fernstrom and Johanson in 1976 [2]. This pain, with subsequent follow-up at 3 weeks technique is applicable to the removal of a and 3 months. In the present study we evaluated 96 patients wide variety of renal stones [3–5]. treated with tubeless PCNL and no JJ stenting. Modifications have been attempted to The mean (range) age of patients was 32 The patients had a shorter hospital stay and decrease the morbidity of the procedure, (17–58) years. The male : female ratio was less morbidity, primarily as a result of minimal including the use of a smaller working sheath, 3 : 2. The mean (range) operative duration instrumentation of the ureter and no ancillary termed the ‘mini-PCNL’ [6–8], and avoiding a was 18 (10–25) min, which included the time procedures such as nephrostogram or stent nephrostomy tube completely with a JJ stent to obtain access to the desired calyx. The removal. The benefits gained in terms of cost left for drainage of the urine after surgery, mean (range) duration of hospitalisation was saving are substantial, as the cost of a termed the ‘tubeless PCNL’ [9,10]. Here we 1.8 (1–5) days. The patients who had tubeless nephrostomy tube, nephrostogram, a stent, describe our experience with PCNL in selected and stentless PCNL required substantially less and stent removal is completely negated. One cases with no use of a nephrostomy tube or JJ analgesia than those who had the standard patient in the present study required JJ stent after PCNL. PCNL procedure. No patient required stenting for substantial leaking from the PCNL morphine. One patient required a transfusion site, which was thought to be caused by an of two units of blood for haematuria after undetected intraoperative perforation of the METHODS surgery although there was no significant collecting system. Ultrasonography was intraoperative bleeding. Haematuria settled unremarkable; JJ stenting was used and the Between August 2002 and July 2004, 1405 by the third day after surgery and JJ stenting patient improved. patients were treated with PCNL; in 96 was used for excessive leaking from the selected patients no nephrostomy tube and puncture site, and this patient improved on The hospitalisation in the present study was no internal stenting was used afterward. conservative treatment. The JJ stent was kept 1.8 days, longer than in some recent studies Indications included a symptomatic stone in in situ for 10 days. The stones were with standard tubeless PCNL. We discharged the lower calyx of £1 cm with resistance to completely cleared in all the patients, the present patients when there was no ESWL. The stone was considered resistant to confirmed with intraoperative nephroscopy leaking from the PCNL site and the urine was ESWL if there was no fragmentation at the and follow-up radiography. No patient clear, which might have added a few extra end of two sessions or no clearance after four. required readmission in the follow-up for hours. The inclusion criteria for the tubeless and pain, obstruction or infection. stentless PCNL included the selected cases, The tubeless and stentless PCNL is safe, where there was one puncture with no offering substantial advantages in morbidity intraoperative complications, e.g. significant COMPARISON WITH OTHER METHODS and cost-effectiveness when compared with perforation of the collecting system and standard tubeless PCNL techniques, and significant bleeding, complete stone clearance Most simple renal calculi can be treated should be considered as an option for and a clear efflux. satisfactorily with ESWL. Several factors are managing renal calculi in selected patients. associated with poor results using ESWL, The stone-bearing calyx was approached including stones within the dependant or CONFLICT OF INTEREST directly under fluoroscopy. No retrograde obstructed portions of the collecting system, catheter or occlusion balloon was used. The stone composition (mostly calcium oxalate None declared. nephrostomy tract was dilated to 24 F if the monohydrate and brushite), obesity or a stone could not be fragmented by ESWL and habitus that inhibits imaging and causes REFERENCES to 16 F if the stone was fragmented by ESWL unsatisfactory targeting of the stone [11]. In but could not be cleared. The stone was 1992, Sampio and Aragao [12] emphasized 1 Goodwin WE, Casey WC, Woolf removed using two-prong forceps. The the importance of lower calyceal anatomy for W. Percutaneous trocar (needle) nephrostomy site was closed using #1 silk clearing stones. For the patient whose stone nephrostomy in hydronephrosis. JAMA suture. A pain questionnaire (‘no pain’, ‘mild’, cannot be cleared by ESWL another treatment 1955; 157: 891–4

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2 Fernstrom I, Johannson B. Percutaneous pediatric percutaneous nephrolithotomy. nephrolithotomy. World J Urol 1998; 16: pyelolithotomy. A new extraction J Endourol 1997; 11 (Suppl. 1): S133 375–7 technique. Scand J Urol Nephrol 1976; 10: 7 Helal M, Black T, Lockhart J, Figueroa 11 Grasso M, Loisides P, Beaghler M, 257–9 TE. The Hickman peel-away sheath: Bagley D. The case for primary 3 Segura JW, Patterson DE, LeRoy AJ et al. alternative for pediatric percutaneous endoscopic management of upper urinary Percutaneous removal of kidney stones: nephrolithotomy. J Endourol 1997; 11: tract calculi: I. A critical review of 121 review of 1,000 cases. J Urol 1985; 134: 171–2 extracorporeal shock-wave lithotripsy 1077–81 8 Jackman SV, Docimo SG, Cadeddu JA, failures. Urology 1995; 45: 363–71 4 Clayman RV, Surya V, Miller RP, Bishoff JT, Kavoussi LR, Jarrett TW. The 12 Sampaio FJ, Aragao AH. Inferior pole Castaneda-Zuniga WR, Amplatz K, ‘mini-PERC’ technique: a less invasive collecting system anatomy: its probable Lange PH. Percutaneous alternative to percutaneous role in extracorporeal shock wave nephrolithotomy. An approach to nephrolithotomy. World J Urol 1998; 16: lithotripsy. J Urol 1992; 147: 322–4 branched and staghorn renal calculi. 371–4 JAMA 1983; 250: 73–5 9 Bellman GC, Davidoff R, Candela J, Correspondence: Vikas Gupta, Department of 5 Elder JS, Gibbons RP, Bush WH. Gerspach J, Kurtz S, Stout L. Tubeless Urology, SMS Hospital, Jaipur, India. Ultrasonic lithotripsy of a large staghorn percutaneous renal surgery. J Urol 1997; e-mail: [email protected] calculus. J Urol 1984; 131: 1152–4 157: 1578–82 6 Jackman SV, Hedican SP, Docimo SG, 10 Delnay KM, Wake RW. Safety and Abbreviations: PCNL, percutaneous Peters CA. Miniaturized access for efﬁcacy of tubeless percutaneous nephrolithotomy.

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Correspondence Article LETTERS

WRITE TO THE EDITOR AT BJU INTERNATIONAL, 47 ECCLES STREET, DUBLIN 7, IRELAND

THE MOLECULAR STAGING OF a useful contribution to the molecular staging alternative ways of verifying the content of PROSTATE CANCER of prostate cancer. such letters. Although I have no desire to become involved in an unedifying or Sir, GEORGE YARDY, STEPHEN McGREGOR personalised correspondence, I feel that I In their review of current and emerging and SIR WALTER BODMER must highlight and redress the factual approaches to extraprostatic prostate cell Cancer & Immunogenetics Laboratory, inaccuracies contained in this letter. detection [1] McIntyre et al. concentrate on Weatherall Institute of Molecular Medicine, RT-PCR. Immunocytochemistry, an alternative John Radcliffe Hospital, Oxford, In our study we concluded that men with which they mention, has been augmented by large prostates on a DRE were more likely to automation and offers rapid processing of 1 McIntyre IG, Hart CA, Brown MD, Ross have recurrent acute urinary retention (AUR) many samples, visualisation of circulating DG, George NJ, Clarke NW. The or require surgery within a 6-year period of tumour cells and interrogation of their molecular staging of prostate cancer. BJU follow-up after a successful trial without genotype. Int 2004; 94: 1217–20 catheter (TWOC) after presenting with a 2 Kilpatrick MW, Tafas T, Evans MI et al. first episode of AUR. We recognise that Automated immunofluorescence microscopy Automated detection of rare fetal cells in assessment by a DRE limited the value of the was initially developed to allow noninvasive maternal blood: eliminating the false- study, as did the relatively few patients prenatal diagnosis [2]; preparations of positive XY signals in XX pregnancies. Am included (34). However, this finding was maternal blood on microscope slides could be J Obstet Gynecol 2004; 190: 1571–8 supported by data from the ALFAUR study, scanned, signals from fluorescently labelled 3 Epenetos AA, Canti G, Taylor- showing that a higher PSA level (measured fetal-specific antibodies identified, fetal Papadimitriou J, Curling M, Bodmer 1 month after a successful TWOC, as a nucleated red blood cells and FISH of WF. Use of two epithelium-specific surrogate of prostate volume) is associated individual cells could be used to detect monoclonal antibodies for diagnosis of with a greater failure rate in the 6 months polysomy. This technique has been adapted malignancy in serous effusions. Lancet after a successful TWOC [3]. for investigating cancer. After enriching blood 1982; 2: 1004–6 samples by density-gradient centrifugation, 4 Makin CA, Bobrow LG, Bodmer WF. I acknowledge that it is entirely reasonable to fluorescently labelled antibodies to antigens Monoclonal antibody to cytokeratin for criticise our study on the basis that, as the overexpressed in epithelial tumours [3,4] or use in routine histopathology. J Clin study was conducted in four centres, several specifically by prostatic cells (e.g. PSA and Pathol 1984; 37: 975–83 observers were assessing the prostate volume PSMA) are used to highlight cells for further 5 Ellis WJ, Pfitzenmaier J, Colli J, Arfman by DRE. However, these observers were only analysis. FISH (where individual chromosomes E, Lange PH, Vessella RL. Detection and asked to state whether the prostate felt small, or DNA sequences are fluorescently labelled) isolation of prostate cancer cells from medium or large. Consequently, the effect of can detect aneuploidy or even the peripheral blood and bone marrow. inter-observer error on our conclusion should amplification of a specific gene within a Urology 2003; 61: 277–81 be minimal, as there is evidence that assessing circulating tumour cell. This technique gives a prostate size by a DRE tends to underestimate better estimate of the number of tumour cells the volume of the prostate compared with a in blood; to obtain such information using RT- PROSTATE SIZE INFLUENCES THE TRUS measurement [4]. It could be reasonably PCR would require an assessment of the OUTCOME AFTER PRESENTING WITH concluded that when a prostate feels large, amount of mRNA per cell and its survival ACUTE URINARY RETENTION then it is. through the isolation process. Sir, In Irwin’s study the prostate volume of 40 Escape of cells into the circulation seems to I was a little surprised to see this letter [1] patients presenting with ‘AUR’ (retention be an early event in the development of published without being given an opportunity volumes 500–2800 mL, six with a history of prostate cancer [5] and its detection is not to respond to the criticism it makes of our TURP) had their prostate volume assessed by a necessarily a surrogate marker of metastatic paper [2]. Perhaps the BJU International policy DRE by one experienced urologist. The finding disease. When genetic changes associated regarding correspondence has changed, but if that those who had a successful TWOC had a with the acquisition of the capacity for letters about papers are to be published mean prostate volume of 15.9 mL, whilst in establishing distant deposits have been without the corresponding author having an those who failed to void it was 27.5 mL, was identified, circulating cell detection will make opportunity to respond, then there must be statistically significant when tested using

LETTERS

the chi-squared test, and resulted in the material for the da Vinci robot system. Most now a general consensus that laparoscopic conclusion that prostate volume influenced readers will draw the conclusion that they too surgery will replace most of the major the outcome of a TWOC. The follow-up was must obtain a surgical robot to stay ‘in the urological procedures traditionally done by continued to 2 years but no data were game’, and that they can safely skip the open surgery. Heads of department presently presented on the factors that may have awkward intermediate step of laparoscopy. undecided about whether to embark on the influenced longer- term outcome [5]. Having done 500 radical prostatectomies in laparoscopic or robotic pathway should the past 6 years using open, laparoscopic and consider two important points. First, the I trust that a careful reader will agree that robotic surgery I feel well placed to indicate purchase and running costs of a da Vinci these two studies are neither identical nor are some of the problems inherent in this robot for a year could be used instead to the conclusions reached the same. Although approach. provide a 1-year laparoscopic Fellowship for the conclusion reached by Kumar et al [5], 18 urologists, who could then use the skills that prostate size influences the outcome of a The dictionary definition of a robot is ‘a acquired to benefit patients for the rest of TWOC, may be proved to be correct, there machine capable of carrying out a series of their professional careers, or 18 000 h of are several reasons why I believe that this complex series of actions automatically’ [5]. training in a ‘wet lab’. Second, those bodies conclusion cannot be substantiated by the Thus the ingenious da Vinci device is not responsible for healthcare reimbursement are data they presented [6]. In view of this, and really a robot, because it does nothing not likely to agree to purchase two procedures the longer-term nature of our study, we did automatically. Rather, it is a computerized for the same condition, with identical benefits not feel that it was necessary, or entirely master-slave interface. Someone still needs to and outcomes but with vastly differing costs appropriate, to cite the paper by Kumar do the operation, and they are heavily reliant [6]. et al [5]. on the enthusiasm, skill and co-operation of the assistant, who stands at the operating The wave of euphoria surrounding ALAN McNEILL, Consultant Urological table several feet distant from the surgeon. robotic surgery, generated more by the Surgeon, Western General Hospital, Needless to say, the surgeon is also totally manufacturers’ marketing than by fact, Edinburgh, UK reliant on the correct functioning of the threatens to overshadow possibly the most complex piece of equipment between he or important non-clinical problem facing 1 Irwin PP. Prostate size influences the she and the patient. If either of these urologists in 2005, i.e. how to address the outcome after presenting with acute components fails the approach needs to be significant imbalance between the supply urinary retention. BJU Int 2005; 95: abandoned and the procedure completed by and demand for training in laparoscopic 190 open surgery. This is because the manual and urology. Caught between the nay-sayers of 2 McNeill SA, Rizvi S, Byrne D. Prostate problem-solving skills needed to perform laparoscopy and the laparoscopic ‘experts’ size influences the outcome after advanced laparoscopic procedures, especially who have a vested interest in limiting the presenting with acute urinary retention. radical prostatectomy, are very different to diffusion of laparoscopic skills, are very many BJU Int 2004; 94: 559–62 the skill set needed to perform the same trainees whose needs are not currently being 3 McNeill SA, Hargreave TB, Roehrborn procedure sitting at a computer console. This met. This problem can only be solved at a CG and he members of the ALFAUR Study is the crucial weakness of robotic surgery; it national level, but there are too few examples Group. Alfuzosin 10mg once daily in the does not allow the operator to learn (Belgium and Scandinavia are exceptions) of management of acute urinary retention: laparoscopic surgery. It therefore needs to be national bodies taking appropriate steps to results of a placebo-controlled study. viewed as a competitor to laparoscopy rather address this issue. This needs to change. Urology 2005; in press than an aid to mastering it. The Australian 4 Roehrborn CG. Accurate determination Safety and Efficacy Register of New CHRISTOPHER G. EDEN, Department of of prostate size via digital rectal Interventional Procedures review of robotic Urology, North Hampshire Hospital, examination and transrectal ultrasound. surgery is the only independent assessment of Basingstoke, Hants, UK Urology 1998; 51: 19–22 the subject, and indicates several other 5 Kumar V, Marr C, Bhuvangiri A, Irwin P. problems which have receive little or no 1 Peters CA. Robotically assisted paediatric A prospective study of conservatively exposure in publications on robotic surgery, pyeloplasty: cutting edge or expensive managed acute urinary retention: i.e. the need to train the whole theatre team, toy? BJU Int 2004; 93: 1214–5 prostate size matters. BJU Int 2000; 86: limited instrumentation, technical 2 Herrell SD, Smith JA Jr. Laparoscopic 816–9 malfunctions and collision of the robotic and robotic radical prostatectomy: what 6 McNeill AS. A prospective study of arms, and a life-expectancy for the system of are the real advantages? BJU Int 2005; 95: conservatively managed acute urinary only 5 years (http://www.surgeons.org/ 3–4 retention: prostate size matters (letter). asernip-s/publications_robotics.htm). 3 Dasgupta P, Jones A, Gill IS. Robotic BJU Int 2001; 87: 904–5 urological surgery: a perspective. BJU Int Many publications show that in expert hands 2005; 95: 20–3 ROBOTICALLY ASSISTED SURGERY oncological and functional outcomes are 4 Sundaram CP, Koch MO, Gardner T, similar after open and laparoscopic urological Bernie JE. Utility of the fourth arm to Sir, surgery. The generic advantages of facilitate robot-assisted laparoscopic The last two editions of the BJU International laparoscopy and reduced bleeding are the radical prostatectomy. BJU International contained four articles on robotic surgery reasons which make this a more appealing 2005, 183–6 [1–4] and a cover figure of advertising choice for both patient and surgeon. There is 5 Swannell J ed. Oxford Modern English

LETTERS

Dictionary. Oxford: Clarendon Press, SACRAL RATIO AND FECAL CONTINENCE the differences in patient assessment for 1992: 936 IN CHILDREN WITH ANORECTAL continence and classification of the ARMs. 6 Lotan Y, Cadeddu JA, Gettman MT. The MALFORMATION new economics of radical prostatectomy: SUZI DEMIRBAG*, EMRE SENEL†, cost comparison of open, laparoscopic Sir, SALIH CETINKURSUN*, and robot assisted techniques. J Urol We read with interest this article [1] about the *Gulhane Military Medical Academy, Pediatric 2004; 172: 1431–5 sacral ratio and fecal continence in children Surgery, Ankara, Turkey, and †SSI Children with anorectal malformation (ARM). In the Hospital, Pediatric Surgery, Ankara, Turkey PROSTATE CANCERS IN THE TRANSITION study, the sacral ratio was reported as being ZONE: PART 2; CLINICAL ASPECTS of no practical value in identifying patients 1 Macedo M, Martins JL, Freites Filho LG. likely to have fecal incontinence. However, Sacral ratio and fecal continence in Sir, some points about the patients are not clear. children with anorectal malformation. We read with interest this article reviewing The type of the ARM and continence criteria BJU Int 2004; 94: 893–4 the clinical behaviour and characteristics of should be defined more detailed. It is known 2 Pena A. Anorectal malformations. Semin transition zone (TZ) prostate cancers [1]. that type of the ARM is an important Pediatr Surg 1995; 4: 35–47 However, in discussing the efficacy of TRUS- prognostic factor for continence in patients 3 Kelly JH. The clinical and radiological guided biopsies in detecting TZ cancers, the with ARM [2]. In routine clinical practice there assessment of anal continence in authors fail to adequately address the use of are scoring systems for assessing fecal childhood. Aust NZ J Surg 1972; 42: 62–3 TURP biopsies in detecting TZ cancers. Whilst continence; the Kelly scoring system (KSS) 4 Kiesewetter WB, Chang JH. Imperforate the authors mention incidentally diagnosed and Kiesewetter-Chang (KCSS) are the most anus: a five to thirty year follow-up TZ cancers, our experience shows that in common and accepted for evaluating the perspective. Prog Pediatr Surg 1977; 10: patients with persistently elevated PSA levels continence level. According to the KSS the 111–20 and who have had many negative systematic results are classified as good (5–6 points), fair biopsies (24–48), transurethral biopsy and/or (3–4) and poor (1–2), considering the resection in symptomatic men is useful in the frequency of bowel movements, stool COMPARATIVE STUDY OF DARTOS FASCIA diagnosis of prostate cancer [2]. Eleven consistency, soiling, sensation, feeling of AND TUNICA VAGINALIS PEDICLE WRAP patients had prostate cancer diagnosed only fullness, the warning period, and the need for FOR THE TUBULARIZED INCISED PLATE IN on TURP after many negative TRUS-guided care. According to KCSS system patients are PRIMARY HYPOSPADIAS REPAIR biopsies. Of these, five had a radical classified as good (continent), fair (socially prostatectomy, which showed confined continent) and poor (incontinent) [3,4]. Sir, anterior prostate cancer. We suggest that I read with interest this paper [1]; the authors anteriorly directed transurethral biopsies and/ We conducted a study for assessing the described a prospective comparison of two or TURP helps in the diagnosis of prostate continence level in intermediate and high techniques of neourethral cover after cancer in patients with many negative level ARM. Between September 1994 and May tubularized incised plate (TIP) urethroplasty, biopsies, in agreement with others [3]. 2001, 17 patients with intermediate and 11 and their results seem to indicate that one Patients with anterior prostate cancer also with a high-level ARM were operated in our technique was better than the other. However, tend to have organ-confined disease, even clinic, all by the same surgeon and the same I make the following comments. with higher PSA values. technique. In this series we investigated the continence status by the KSS and KCSS, the There is no indication in the report that the JOE PHILIP and sacral ratio and by anorectal manometry. two groups were randomized, and there were RAMASWAMY MANIKANDAN, The Pearson correlation test and chi-squared significantly different numbers of patients in Department of Urology, Royal Liverpool test were used to assess the results. There was the two groups. What were the selection or University Hospital, Liverpool, UK a significant correlation between the sacral inclusion criteria in each group and for ratio and continence score (r = 0.548, inclusion into the study as a whole? The 1 Augustin H, Erbersdobler A, Hammerer P < 0.01), and the clinical results were operative procedures seem to have been PG et al. Prostate cancers in the transition supported by anorectal manometry. In the performed by an array of surgeons from zone: Part 2; Clinical aspects. BJU Int good continence group the mean (SD) anal different institutes. It is well known that 2004; 94: 1226–9 resting pressure was significantly higher than appropriate patient selection is a key factor in 2 Philip J, Dutta Roy S, Scally J, Foster in the fair and poor groups, at 57.9 (8.57) and the success of any hypospadias surgery, as are

CS, Javle P. Importance of TURP in 32 (12.8) cmH2O, respectively. the skills of the individual surgeon. There is no diagnosing prostate cancer in men with indication in the report that these areas of multiple negative biopsies. The Prostate Pena [2] reported that the sacral ratio was a potential bias were addressed. For example, 2005; in press prognostic factor for continence in ARM; we poorly formed urethral plates are unsuitable 3 Mian BM, Naya Y, Okihara K, Vakar- agree, and routinely use the sacral ratio, to the TIP technique and can give poor results. Lopez F, Troncoso P, Babaian RJ. KSS, KCSS and anorectal manometry for Predictors of cancer in repeat extended evaluating the prognosis of the continence The authors report a ﬁstula rate of 15–20% multisite prostate biopsy in men with level in patients with ARM. The differences for TIP with a dartos fascia cover. Considering previous negative extended multisite between the results of Macedo et al. and that most of their cases were of anterior or biopsy. Urology 2002; 60: 836–40 those presented here might be attributed to midpenile variety of hypospadias, this ﬁstula

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rate is rather high. Many earlier reports, some In primary TIP urethroplasty, the dorsal 1 Chatterjee US, Mandal MK, Basu S, Das of them multi-institutional studies with many subcutaneous (dartos) fascia is intact, R, Majhi T. Comparative study of dartos patients, reported much lower fistula rates (as abundant, easy to mobilize and can cover fascia and tunica vaginalis pedicle wrap low as 1%) using a TIP repair with dartos the neourethral suture line even down to the for the tubularized incised plate in cover [2,3]. In other reports, when TIP penoscrotal junction. Thus, it should be the primary hypospadias repair. BJU Int 2004; with a dartos flap was used for proximal logical choice for neourethral cover after 94: 1102–4 hypospadias repair, the fistula rates were still primary TIP repair. Another very useful 2 Jayanthi VR. Modified Snodgrass reasonably low [4]. How can the authors of additional cover for the neourethra is corpus hypospadias repair. reducing the risk of the present study explain their poor results in spongiosum. When mobilized on both sides of fistula and meatal stenosis. J Urol 2003; the group having a TIP with dartos fascia? the urethral plate and sutured in the midline, 170: 1603–5 it can provide additional protection for the 3 Cheng EY, Vemulapalli SN, Kropp BP Apart from selection bias, the high fistula rate neourethra. My personal experience with its et al. Snodgrass hypospadias repair with in the present series could be attributable to use as an adjunct for TIP urethroplasty has vascularised dartos flap. the perfect repair ignoring the basic principles of hypospadias been very gratifying, and spongioplasty can for virgin cases of hypospadias? J Urol surgery, e.g. the use of optical magnification be combined with dartos flap cover for 2002; 168: 1723–6 and fine instrumentation, apparently not additional protection. 4 Chen SC, Yang SS, Hsieh CH, Chen YT. adopted by the authors. Do the authors Tubularized incised plate urethroplasty for recommend that hypospadias repairs be Separating the processus vaginalis proximal hypospadias. BJU Int 2000; 86: undertaken by amateur surgeons without the from the spermatic cord is not without 1050–3 use of the refined techniques of complications, especially in a small child. For 5 Gurdal M, Karaman MI, Kanberoglu H, magnification and fine instrumentation? example, both the vas and testicular vessels Kirecci S. Tunica vaginalis reinforcement are at risk of injury during inguinal hernia flap in reoperative Snodgrass procedure. I agree that dissecting a tunica vaginalis flap repairs in children [6]. Is it reasonable to Pediatr Surg Int 2003; 19: 649–51 is not a difficult task, but my policy has been expose a child with virgin distal hypospadias 6 Lloyd DA, Rintala RJ. Inguinal hernia and to use it while repairing severe hypospadias to this risk, however low it may be, when hydrocele. In O’Neill JA, Rowe MI, Grosfeld (where the dartos fascia has been used for alternative, reliable, safe and time-tested JL, Fonkalsrud EW, Coran AG eds, Pediatric vascularized skin flaps) and in salvage techniques are available? Nevertheless, I Surgery. 5th Edn, Chapt 69. Mosby, 1998: hypospadias repairs. It is not the first choice congratulate the authors on this interesting 1071–86 in my institution of tissue for neourethral study. cover in primary and especially distal hypospadias repair. A literature search also VEMURI V.S.S. CHANDRASEKHARAM, reveals that the principal uses of tunica Department of Paediatric Surgery & Paediatric vaginalis are in re-operative and salvage Urology, Rainbow Children’s Hospital, hypospadias repairs, e.g. [5]. Hyderabad, Andhra Pradesh, India

Blackwell Science, LtdOxford, UKBJUBJU International1464-410XBJU InternationalApril 2005 956 surgery Article SURGERY ILLUSTRATED HORNINGER et al.

Surgical Atlas Radical retropubic prostatectomy: apical preparation and curtain dissection of the neurovascular bundle

WOLFGANG HORNINGER, HANNES STRASSER and GEORG BARTSCH Medical University of Innsbruck, Department of Urology, Innsbruck, Austria

ILLUSTRATIONS by STEPHAN SPITZER, www.spitzer-illustration.com

PATIENT SELECTION AND INDICATION are assessed; in the afternoon patients are shaved and receive one colonic enema. On the Radical prostatectomy should be reserved for day of surgery patients wear compression men diagnosed with localized prostate cancer stockings. with a total PSA level of <15 ng/mL who are likely to be cured and have a life-expectancy of ≥10 years. Surgery is deferred for SPECIAL INSTRUMENTS ≥2 months after prostate biopsy and for 3 months after TURP. This delay enables Radical retropubic prostatectomy requires inﬂammation or haematoma to resolve so few special instruments. A headlight and that the anatomical relationships between the magnifying loupes are very useful for the prostate and the surrounding tissue return to procedure, especially for a sufﬁcient nerve- a near-normal state. sparing procedure. We use a standard Balfour retractor to provide cranial and posterior retraction on the peritoneum and bladder. A PATIENT PREPARATION right-angle clamp (Scott McDougal), a coagulating forceps and small clips are the Patients are admitted to the hospital 1 day only special instruments that should be before surgery, and blood and urine samples available.

HORNINGER ET AL.

Figure 1

The patient is placed in a hyperextended supine position to increase the distance from the umbilicus to the symphysis, supplemented by a mild Trendelenburg position.

The skin incision is a lower abdominal midline incision and starts above the symphysis and extends upwards for some centimetres below the umbilicus. Antibiotic prophylaxis with amoxicillin is started during surgery, and subcutaneous prophylaxis for deep vein thrombosis on the evening of the same day.

SURGERY ILLUSTRATED

Figures 2 and 3

After incising the endopelvic fascia the anterior aspect of the prostate is dissected free of fatty tissue, and the superﬁcial branch of the deep dorsal penile vein dissected. Then the puboprostatic ligaments are cut and the dorsal vein complex under-run and ligated.

HORNINGER ET AL.

SURGERY ILLUSTRATED

Figure 4

Subsequently, the anterior surface of the membranous urethra is incised ≈2 mm anterior to the apex of the prostate. The ﬁrst anastomotic suture (poliglecaprone 2/0, double-armed UR-6 needle) is passed at the 1 o’clock position, taking care not to include the rhabdosphincter but only the urethra. The second anastomotic suture is passed in the same fashion at the 11 o’clock position.

HORNINGER ET AL.

Figures 5 and 6

By alternately pulling the catheter to the left and right with a forceps, the third and fourth anastomotic sutures are passed at 3 and 9 o’clock positions, respectively, also taking care not to include the rhabdosphincter or the neurovascular bundle in the suture.

SURGERY ILLUSTRATED

HORNINGER ET AL.

Figure 7

The nerve-sparing approach is then attempted; the prostate is ﬁrst pushed to the left or to the right below the bladder neck so that the lateral pelvic fascia can be incised. Using magnifying lenses, dissection of the neurovascular bundles starts very far anteriorly to preserve all the nerve ﬁbres that are spread out concavely as described (‘bob run’ or ‘curtain’ shape) along the surface of the lobes of the prostate (Fig. 7a). With this type of preparation the vast majority of cavernosal nerves forming the neurovascular bundles can be preserved. The neurovascular bundles are teased away to the distal third of the prostate.

a (correct)

b (incorrect)

SURGERY ILLUSTRATED

Figure 8

The posterior surface of the urethra and the underlying perineal body are then dissected. As most of the cavernosal nerves are situated dorsolateral to the membranous urethra at no time is the urethra under-run with a clamp. Subsequently, the apex of the prostate is dissected from the neurovascular bundle and the rectal fascia. After cutting half of the posterior surface of the urethra a traction suture is placed at the 6 o’clock position.

HORNINGER ET AL.

Figure 9

Pulling on this traction suture facilitates placing the ﬁfth anastomotic suture line at the 5 o’clock position and medial to the neurovascular bundle. The sixth anastomotic suture line is passed in a similar fashion at the 7 o’clock position.

SURGERY ILLUSTRATED

Figures 10 and 11

After removing the surgical specimen on both sides of the rectum the neurovascular bundles are visible; the previously placed urethral sutures are passed through the vesical neck at the corresponding positions and tied over a 20 F urethral catheter to complete the vesico- urethral anastomosis.

HORNINGER ET AL.

SURGERY ILLUSTRATED

ANATOMICAL CONSIDERATIONS OF THE sleigh run, and lie adjacent to the terms of continence and potency rates. We CAVERNOSAL NERVES membranous urethra. According to these consider the use of magnifying loupes and anatomical findings, the modified apical a correctly positioned headlight to be According to anatomical studies in 29 male preparation and the dissection of the very important, as they aid in identifying fetuses, at our institution, the original course neurovascular bundle is described and the neurovascular bundles and external of the cavernosal nerves could be detected illustrated. striated sphincter. By using these two during the early stages of fetal development, devices a bloodless operating field is as the prostate does not start to develop more likely. This enables the surgeon to before fetal week 13. Because there is no POSTOPERATIVE MANAGEMENT meticulously dissect the prostatic apex and prostate and the nervous structures are preserve the complex of the rhabdosphincter relatively thick, the cavernosal nerves were Drains are routinely removed 3 days after and the distal part of the neurovascular visible running downward lateral and dorsal surgery; the diet is advanced as tolerated, bundles containing the cavernosal nerves, as to the prostatic and the membranous urethra, with normal intake by 3 days in most patients. well as the branches of the pudendal nerve. and the omega-shaped rhabdosphincter, Antibiotic prophylaxis with amoxicillin The integrity of the rhabdosphincter tendon which covered the ventrolateral aspects of the continues after surgery until the catheter is and pudendal nerve supply is important for prostatic and membranous urethra between removed. On the 10th day gravity cystography preserving continence. Thus, manipulating the bulb of the penis and the bladder neck. is used under fluoroscopic control. The the urethra should be minimized so that all bladder is filled with 150–250 mL of a periurethral tissue distal to the apex remains After 13 weeks of gestation the prostate contrast agent until the patient experiences a intact. begins to develop. Because of the growth and sense of fullness and slight discomfort. The increasing volume of the prostate, the course urinary catheter is removed if there is no Radical retropubic prostatectomy by an of the cavernosal nerves begins to change. By extravasation. During gravity cystography all experienced surgeon is safe, with fewer contrast, the prostate increasingly displaces patients are instructed how to exercise the complications during and afterward; the the cavernosal nerves dorsolaterally. In this rhabdosphincter. It is essential that patients duration is usually <2.5 h. With proper region the nerve fibres and vessels are can see the elevation of the anastomotic site patient selection, positive surgical margins increasingly dispersed along the convex while contracting the rhabdosphincter, and are <10%, with pathologically organ- surface of the prostatic capsule. Therefore, therefore understand and participate confined prostate cancers in 85–90%. the cavernosal nerves running in the cognitively in these exercises. At 11 days In experienced centres, continence rates neurovascular bundles increasingly assume a patients are discharged from the hospital. reach 95% and potency rates ≥80% after shape that can best be compared to the surgery. concave ‘steep turn of a bob-sleigh run’ or a concave ‘curtain’ covering both prostatic SURGEON TO SURGEON Correspondence: Wolfgang Horninger, lobes. At the apex of the prostate the nerve Medical University of Innsbruck, Department fibres of the neurovascular bundles converge Every surgeon has their way of improving of Urology, Innsbruck, Austria. again, like the exit of a steep turn of a bob- the results of radical prostatectomy in e-mail: [email protected]

Blackwell Publishing LtdOxford, UKBJUBJU International1464-40962005 BJU INTERNATIONAL2005 956 errata ERRATAERRATA

In [1], the following error occurred on page FIG. 3. (a) A schematic of the effect of urgency on the micturition cycle. During an urgency episode, the desire 337. to void increases abruptly, resulting in a void and shortening the intervoid interval, and reducing the volume voided. Therapy can eliminate urgency episodes and thus normalize the intervoid interval. (b) A schematic Figure 3 was reproduced incorrectly. The of two micturition cycles terminated by voids associated with urgency episodes. A refractory period, deﬁned correct version appears below. as the interval between voiding and the next urgency episode, can be measured and may be affected by therapy. A warning or deferral time can also be measured as the time from the onset of urgency to voiding. We apologize for this error. a Normal Urgency Reduction in desire Presumed normal REFERENCES volume voided to void void volume due to urgency 1 Chapple CR, Artibani W, Cardozo LD,

Castro-Diaz D, Craggs M, Haab F, ) Khullar V, Versi E. The role of urinary — Intensity urgency and its measurement in the overactive bladder symptom syndrome: current concepts and future prospects. Void BJU Int 2004; 95: 335–40 Bladder volume ( (voluntary and/or involuntary)

Reduction of intervoid interval

b Normal Urgency Void desire to void Void (voluntary and/or involuntary) ) — Intensity Bladder volume (

Refractory (urgency free) period

Warning time Intervoid interval

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 TGFtransforming 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 | 95, 925 925 may 3|4 may 13|16 may 21|26 Comprehensive Urological Laparoscopy: VIIth International Congress of the American Urological Association An intermediate Level Training Course Pan African Urological Association, Annual Meeting, San Antonio, TX, incorporating ‘Different Techniques Cairo, Egypt. USA. of Nephrectomy’. Course Director: Mr A. Rané. Venue: Aesculapium, Contact: Mrs Ingrid El-Damanhoury T +1 800 908 9414 Tuttlingen, Germany. E [email protected] E [email protected] Organizer and for further information: W http://www.aua2005.org Aesculap Akademie GmbH, Am Aesculap Platz, W http://www.PAUSA2005.org 78532 Tuttlingen, Germany

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926 2005 june 27|july 1 july 6|9 july 28|august 1 BAUS Annual Meeting Glasgow, UK. 31st Annual Meeting of the XXV Biannual Congress of the International Academy of Sex Urological Association of South Contact: BAUS, 35-43 Lincoln’s Inn Research (IASR) Ottawa, Canada. Africa, Sun City, Pilanesberg, South Fields, London WC2A 3PE, UK. Africa. Contact: IASR, Lucia F. O’Sullivan, PhD, HIV Center for Clinical and Behavioral T +1 44 020 7869 6950 Contact: Toucan Communications Studies, New York State Psychiatric F +1 44 020 7404 5048 Institute, Unit 15, 1051 Riverside Drive, E [email protected] T +1 27 11 886 9895 New York, NY 10032-2695, USA W http://www.baus.org.uk/ F +1 27 11 886 9897 T +1 212 92 86 111 W http://www.urosa.co.za F +1 212 92 86 161 E [email protected] W http://www.iasr.org

august 26| september 1 sepetmber 30 | october 1 october 5|8 35th Annual Meeting of the 4th Biennial World Congress on Men’s 10th Biennial Meeting of the Asia International Continence Society, Health & Gender (WCMH), Vienna, Austria. Pacific Society for Sexual & Montreal, Canada. Organization: WCMH Health & Impotence Research(APSSIR) Cairns, Congressmanagement, Lazarettgasse 9/5, Australia. T +1 847 605 0850 1090 Vienna, Austria Contact: Promaco Conventions Pty Ltd., E [email protected] E [email protected] P.O. Box 890, Canning Bridge, Western W http://www.icsoffice.org W http://www.wcmh.info Australia 6153 Congress Office: PROCON Conference, Incentive & Event Management, T + 61 8 93 32 29 00 Odoakergasse 34-36/3, 1160 Vienna, Austria F + 61 8 93 32 29 11 E [email protected] E [email protected] F +43 1 486 40 40 46 W http://www.promaco.com.au/ W http://www.proconference.at conference/2005/apssir/

october 27|30 october 31|november 4 november 17|18 5th Meeting of the International Urology Specialist Registrars’ Spinal Comprehensive Urological Laparoscopy: An Society for the Study of Women’s Injuries Course. Twice Annually. Intermediate Level Training Course Sexual Health (ISSWSH), Las Vegas, Sheffield/Wakefield, UK. incorporating ‘Different Techniques of Nevada, USA. Nephrectomy’. Course Director: Mr A. Contact: Carole Gregory (secretary to Mr Rané. Venue: Aesculapium, Tuttlingen, Germany. Contact: ISSWSH, 1111 N. Plaza Drive, P R Tophill, Consultant Urological Surgeon), Princess Royal Spinal Injuries Suite 550, Schaumburg, IL 60173, USA Organizer and further information: Unit, Northern General Hospital, Herries Aesculap Akademie GmbH, Am Aesculap Platz, T +1847 517 7225 Road, Sheffield, S5 7AU, UK 78532 Tuttlingen, Germany F +1847 517 7229 E [email protected] T 0114 271 5645 T + 49 7461 95 2001 W http://www.isswsh.org F 0114 271 5649 E [email protected] E [email protected] W www.aesculap-academy.com

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