Oxford Textbook of Urological Surgery [1st ed.] 9780192518354

Table of contents :
Section 1
1.1. Pathogenesis of urinary tract infection, Ased Ali
1.2. Antimicrobial agents, Kathy Walton, Sally Ager
1.3. Hospital acquired urinary tract infection, Roger Bayston
1.4. Cystitis/pyelonephritis, Bjorn Wullt, Magnus Grabe
1.5. Renal and retroperitoneal abscess, Alice Hartley, Toby Page
1.6. Tuberculosis and parasitic infestations involving the urogenital system, Christiaan F. Heyns
1.7. Inflammation: Prostatitis syndrome, Florian M.E. Wagenlehner, Adrian Pilatz, Th. Bschleipfer, Thomas Diemer, Wolfgang Weidner
1.8. Inflammation: Epididymitis and scrotal abscess, Mary Garthwaite
1.9. Fournier's, Francesco Greco, Paolo Fornara
1.1. Sexually transmitted diseases, Emma J. McCarty, Wallace Dinsmore
1.11. Painful bladder syndrome/Interstitial cystitis, Magnus Fall
Section 2
2.1. Epidemiology of stone disease, Benjamin W. Turney, John Reynard
2.2. Kidney stones: types and predisposing factorsa, Benjamin W. Turney, John Reynard
2.3. Evaluation of stone former, Glenn Preminger, Muhammad Waqas Iqbal, Michael Lipkin
2.4. Prevention of calcium oxalate stone formation, Benjamin W. Turney, John Reynard
2.5. Prevention of other non-calcium stones, Muhammad Waqas Iqbal, Glenn Preminger, Michael Lipkin
2.6. Stone fragmentation techniques: Extracorporal shock wave lithotripsy, Andreas Neisius, Glenn Preminger, Michael Lipkin
2.7. Intracorporeal techniques of stone fragmentation, Gaston M. Astroza, Glenn Preminger, Michael Lipkin
2.8. Kidney stones: presentation and diagnosis, Benjamin W. Turney, John Reynard
2.9. Watchful waiting for stone disease, Benjamin W. Turney, John Reynard
2.10. Retrograde intrarenal surgery: Flexible ureterorenoscopy, Glenn Preminger, Gaston M. Astroza, Michael Lipkin
2.11. Kidney stone treatment: Percutaneous nephrolithotomy (PCNL), Andreas Neisius, Glenn Preminger, Michael Lipkin
2.12. Open stone surgery for kidney stones, Glenn Preminger, Gaston M. Astroza, Michael Lipkin
2.13. Medical therapy (dissolution therapy), Benjamin W. Turney, John Reynard
2.14. Ureteric stones: Presentation and diagnosis, Benjamin W. Turney, John Reynard
2.15. Ureteric stones: Acute management, Samarpit Rai, Zachariah G. Goldsmith, Glenn Preminger, Michael Lipkin
2.16. Ureteral stones: Indications for intervention, Charles D. Scales
2.17. Surgical treatment options for ureteric stones: Techniques and complications, Zachariah G. Goldsmith, Glenn Preminger, Michael Lipkin
2.18. Management of ureteric stones in pregnancy, Benjamin W. Turney, John Reynard
2.19. Bladder stones, Benjamin W. Turney, John Reynard
2.2. Upper urinary tract obstruction, Mark Sullivan, John Henderson, Inderbir Gill
2.21. The principles of endourology, Stephen Keoghane, Mark Sullivan
2.22. Principles of laparoscopic and robotic urological surgery, Mark Sullivan, Nilay Patel, Inderbir Gill
Section 3
3.1. Anatomy, neurophysiology and pharmacological control mechanisms of the bladder, Donna Daly, Christopher Chapple
3.2. Urodynamics, Hashim Hashim, Julie Ellis-Jones
3.3. Urinary incontinence principles, Christopher Chapple, Nadir Osman
3.4. Assessment of urinary incontinence, Marcus Drake
3.5. Stress urinary incontinence, Christopher Chapple, Altaf Mangera
3.6. Pelvic organ prolapse, Roland Morley, Eduardo Cortes, Mohammed Belal, Arun Sahai
3.7. Urgency incontinence and OAB, Christopher Chapple, Altaf Mangera
3.8. Urinary fistula, Christopher Chapple, Nadir Osman
3.9. Urethral diverticula, Christopher Chapple, Nadir Osman
3.1. Faecal incontinence, Christopher Chapple
3.11. Urinary retention in women, Clare Fowler, Jalesh Panicker
3.12. Spinal cord injury, Simon Harrison
3.13. Non-traumatic neurourology, Clare Fowler, Jalesh Panicker
Section 4
4.1. Principles of reconstructive urology, Anthony R. Mundy, Daniela E. Andrich
4.2. Upper urinary tract reconstruction, Anthony R. Mundy, Daniela E. Andrich
4.3. Lower urinary tract reconstruction, Anthony R. Mundy, Daniela E. Andrich
4.4. Urethral strictures, Anthony R. Mundy, Daniela E. Andrich
4.5. Upper urinary tract trauma, Anthony R. Mundy, Daniela E. Andrich
4.6. Lower urinary tract trauma, Anthony R. Mundy, Daniela E. Andrich
4.7. Genital trauma, Anthony R. Mundy, Daniela E. Andrich
4.8. General principles of trauma, Graham Sleat, David Noyes
Section 5
5.1. Bladder outflow obstruction, Christopher Chapple, Altaf Mangera
5.2. Retention in men, Mark Speakman
5.3. Benign prostatic hyperplasia, Nikesh Thiruchelvam
Section 6
6.1. Epidemiology of prostate cancer, Tim Key, Alison J. Price
6.2. Molecular biology of prostate cancer, Ines Teles Alves, Jan Trapman, Guido Jenster
6.3. Prostate Cancer: Pathology, Rodolfo Montironi, Liang Cheng, Antonio Lopez-Beltran, Roberta Mazzucchelli, Matteo Santoni
6.4. Prostate-Specific Antigen and Biomarkers for Prostate Cancer, Hans Lilja
6.5. Screening for prostate cancer, Fritz H. Schroder
6.6. Clinical features, assessment and imaging of prostate cancer, Anders Bjartell, David Ulmert
6.7. Prostate cancer: treatment of localised disease, Matthew Cooperberg, Peter Carroll
6.8. Focal therapy for prostate cancer, Hashim Uddin Ahmed, Louise Dickinson, Mark Emberton
6.9. High risk prostate cancer, S. Joniau, S. Van Bruwaene, J. Karnes, G. De Meerleer, P. Gontero, M. Spahn, A. Briganti
6.1. Technology and prostatectomy, Giacomo Novara, Alexander Mottrie, Filiberto Zattoni, Vincenzo Ficarra
6.11. Metastatic disease in prostate cancer, Noel W. Clarke
6.12. Novel therapies and emerging strategies for the treatment of patients with castration-resistant prostate cancer (CRPC), Deborah Mukherji, Johann De Bono, Aurelius Omlin, Carmel Pezaro
6.13. Bladder and upper urinary tract cancer, Mieke Goossens, Frank Buntin, Maurice P. Zeegers
6.14. Molecular biology of bladder cancer, Dan Theodorescu, Neveen Said
6.15. Pathology of bladder and upper urinary tract tumours, Arndt Hartmann, Simone Bertz
6.16. Screening for bladder cancer, Maurice P. Zeegers, Maree Brinkman
6.17. General overview of bladder cancer, Richard J. Bryant, James W. Catto
6.18. The investigation of haematuria, Richard J. Bryant, James W. Catto
6.19. Low and intermediate risk non-muscle invasive bladder cancer, Yair Lotan, Aditya Bagrodia
6.2. Bladder cancer: high-grade non-muscle invasive disease, Richard P. Meijer, B.W.G. van Rhijn, Alexandre R. Zlotta
6.21. Muscle invasive bladder cancer (pT2-4), George Thalmann, Pascal Zehnder
6.22. Chemotherapy in the treatment of invasive and metastatic bladder cancer, Cora N. Sternberg, Fabio Calabro
6.23. Squamous cell bladder cancer, Max Burger, Roman Mayr
6.24. Adenocarcinoma of the bladder, Ofer Yossepowitch, Roy Mano
6.25. Urothelial carcinomas of the upper urinary tract, Morgan Roupret, Pierre Colin, Tarek P. Gonheim
6.26. The aetiology, epidemiology, clinical features and investigation of kidney cancer, David Cranston, Mark Sullivan, Nilay Patel
6.27. Genetics and molecular biology of renal cancer, Eamonn Maher, Mariam Jafri
6.28. Pathology of renal cancer and other tumours affecting the kidney, Antonio Lopez-Beltran, Rodolfo Montironi, Liang Cheng
6.29. Treatment of localized renal cell cancer, Michael Jewett, Ashraf Almatar
6.3. Ablative technologies for renal cancer, Jeffrey A. Cadeddu, Ephrem Olweny, Stephen Faddegon
6.31. Kidney cancer: Treatment of locally advanced and low volume metastatic disease, Tim O'Brien, Amit Patel
6.32. Treatment of metastatic renal cancer, Tim Eisen, Han Wong
6.33. Testicular cancer, Christian Winter, Peter Albers
6.34. Pathology of testicular tumours, John Goepel
6.35. Testis cancer, Axel Heidenreich
6.36. Penile cancer, Simon Horenblas, Rosa Djajadiningrat
6.37. Adrenocortical cancer, Steve Ball, Sajid Kalathil
6.38. Treatment of adrenal tumours, Saba Balasubramanian, A. Bagul
Section 7
7.1. Infertility: Assessment, Gert R. Dohle
7.2. Surgical treatment of male infertility, Gert R. Dohle
7.3. Sperm retrieval, Oliver Kayes, Akwasi Amoako
7.4. Vasectomy, Yacov Reisman
7.5. The management of fertility in spinal cord injury, Mikkel Fode, Jens Sonksen
7.6. Mechanism of penile erection, Selim Cellek
7.7. Pathophysiology and assessment, Antonino Sacca, Andrea Salonia
7.8. Medical therapy, Hartmut Porst
7.9. Surgical therapy, Carlo Bettocchi, Marco Spilotros
7.1. Ejaculatory disorders, Chris G. McMahon
7.11. Priapism, Asif Muneer, David John Ralph
7.12. The ageing male, Geoff Hackett
7.13. Peyronie s Disease, congenital curvature, and chordee: Epidemiology, pathophysiology, evaluation, and treatment, Laurence A. Levine, William Brant, Stephen M. Larsen
7.14. Male genital injury, Giulio Garaffa, Salvatore Sansalone, David John Ralph
7.15. Scrotal swelling, Ates Kadioglu, Emre Salabas
7.16. Penile reconstruction, Giulio Garaffa, David John Ralph
7.17. Penile augmentation, Salvatore Sansalone, Giulio Garaffa, Ian Eardley, David John Ralph
Section 8
8.1. Prenatal diagnosis and perinatal urology, David F.M. Thomas
8.2. Urinary tract infection in children, David F.M. Thomas
8.3. Vesico ureteric reflux, David F.M. Thomas
8.4. Disorders of the kidney and upper urinary tract in children, Kim Hutton
8.5. Disorders of the urethra, Kim Hutton, Ashok Daya Ram
8.6. Neuropathic bladder and anorectal anomalies, Henrik Steinbrecher
8.7. Urinary incontinence and bladder dysfunction, Henrik Steinbrecher
8.8. Abnormalities of the bladder, Peter Cuckow
8.9. Hypospadias, Peter Cuckow
8.1. Disorders of the prepuce, Kim Hutton, Ahmed A. Darwish
8.11. Undescended testis and inguino-scrotal conditions in children, David F.M. Thomas
8.12. Disorders of sex development, David F.M. Thomas
8.13. Urological malignancies in children, Roly Squire
Section 9
9.1. Renal function, Chris A. O'Callaghan
9.2. Acute kidney injury, Edward Sharples, Wim van Biesen
9.3. Chronic kidney disease and dialysis, Richard J. Haynes, James A. Gilbert
9.4. Obstructive uropathy, Nilay Patel, John M. Henderson
9.5. Kidney transplantation, Jeff A. Lafranca, Dennis A. Hesselink, Frank J.M.F. Dor
Section 10
10.1. Ionising radiation and radiation protection, Jeannette Kathrin Kraft, Peter Howells,
10.2. Ultrasound, Simon Freeman, Toby Wells
10.3. CT, Eugene Teoh, Michael Weston
10.4. Magnetic resonance imaging in urology, Uday Patel, Raj Das, Susan Heenan
10.5. Interventional radiology, Steven Kennish
10.6. Radioisotopes in urology, Sobhan Vinjamuri

Citation preview

 i

Oxford Textbook of

Urological Surgery

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Oxford Textbook of

Urological Surgery Edited by

Freddie C. Hamdy Ian Eardley Section Editors James W. F. Catto Christopher R. Chapple Anthony R. Mundy Rob Pickard Rutger Ploeg David John Ralph John Reynard David F. M. Thomas Michael Weston

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1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2017 The moral rights of the authors‌have been asserted First Edition published in 2017 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2017934227 ISBN 978–​0–​19–​965957–​9 Printed in Great Britain by Bell & Bain Ltd., Glasgow Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

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Series Preface from Professor Sir Peter J. Morris

This is a new development in surgical publishing; the first two editions of the Oxford Textbook of Surgery are to be replaced by a series of specialty-specific textbooks in surgery. This change was precipitated by the ever-increasing size of a single textbook of surgery which embraced all specialties (the second edition of the Oxford Textbook of Surgery was three volumes), and a decision to adapt the textbooks to meet the needs of the audience; firstly, to suit the requirements of Higher Surgical trainees and, secondly, to make it available online. Thus, we have produced a key book to deal with the fundamentals of surgery, such as Anatomy, Physiology, Biochemistry, Evaluation of Evidence, and so forth. Then there are to be separate volumes covering individual specialties, each appearing as an independent textbook and available on Oxford Medicine Online. It is planned that each textbook in each specialty will be independent although there obviously will be an overlap between different specialties and, of course, the core book on Fundamentals of Surgery will underpin the required scientific knowledge and practice in each of the other specialties.

This ambitious programme will be spread over several years, and the use of the online platform will allow for regular updates of the different textbooks. Each textbook will include the proposed requirements for training and learning as defined by the specialist committees (SACs) of surgery recognized by the four Colleges of Surgery in Great Britain and Ireland, and will continue to be applicable to a global audience. This ambitious programme will be spread over several years, and the use of the online platform will allow for regular updates of the different textbooks. When completed, the Oxford Textbooks in Surgery series will set standards for a long time to come. Professor Sir Peter J. Morris Nuffield Professor of Surgery Emeritus, and former Chairman of the Department of Surgery and Director of the Oxford Transplant Centre, University of Oxford and Oxford Radcliffe Hospitals, UK

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Preface

Urology is a rich, diverse, and varied specialty. For certified urological surgeons, it is becoming increasingly challenging to remain updated in such a wide range of assorted conditions with expanding multidisciplinary treatment options, and it is doubly difficult for the trainee to understand what they need to know, and gain a comprehensive knowledge base which will equip them to become certified specialists. The welcome initiative by Oxford University Press to create a series of specialty-specific textbooks mapped to the UK postgraduate surgical curricula has directly led to the production of this textbook. The urology curriculum describes the range of knowledge, skills, and behaviours that a trainee is expected to have acquired by the time that they are certified. We have taken the syllabus from within that urology curriculum in the United Kingdom and used it as the template for this textbook, which we hope will serve trainees and established colleagues across the world. While the syllabus provides the basic architecture of urological surgery, the level of knowledge in each of the chapters goes beyond that which will be required for certification. The Oxford Textbook of Urological Surgery will be of value not only to trainees, but also to established urologists who wish to keep up-to-date with advances in urological care in one or more areas specific to their day-to-day practice. We have recruited able expert section editors with an international reputation in their respective field, who led the development and composition of the varying components of this textbook. They, in turn, have relied on rich contributions from many national and international expert colleagues. The authors were specifically mandated to be concise as well as broadly comprehensive in covering their topic from the basics to the current limits of established

knowledge, and to highlight areas of controversy, where they exist. Whereas detail may be lacking at times due to space constraints, the concepts and principles that direct modern urological practice are all included. Urological science progresses continuously and the extent of knowledge described in this book is only a snapshot in time. However, with modern information technology allowing, we have asked all authors to provide frequent updates of their chapter at regular intervals for an exciting online version of the textbook, as well as future editions. Each chapter is accompanied by a long comprehensive reference list, as well as a short one for those interested in a specific theme. We are confident that the Oxford Textbook of Urological Surgery will provide a novel, easy-to read, and useful source of knowledge and strong foundation both for the practising urologist and for trainees seeking to obtain entry into a wonderful specialty that we both continue to find challenging, fascinating, and enjoyable. Freddie C. Hamdy Nuffield Professor of Surgery and Professor of Urology, Chairman, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7DQ, Director of Surgery & Oncology, Oxford University Hospitals NHS Foundation Trust, United Kingdom Ian Eardley Consultant Urologist, St James’s Hospital, Leeds Teaching Hospitals NHS Trust, Former Chairman Joint Committee on Surgical Training, Vice-President, Royal College of Surgeons of England

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Acknowledgements

Delivering a textbook is always an exciting challenge, which one paradoxically relishes and fears to take at the same time. The Oxford Textbook of Urological Surgery was no exception, and we are most grateful to our section editors and authors for their generous time and effort in providing such a rich and high-quality series of chapters. We thank Oxford University Press and its staff for helping us to deliver this textbook and for their patience during the lengthy preparation of the final manuscripts. We are particularly grateful to Sir Peter Morris whose vision was to map this series of textbooks

to the United Kingdom’s established training surgical curricula. We are both honoured to have been invited to deliver this important task, and proud to have completed it in this first edition. Finally, we are indebted to our families for their forbearance for the time that we have spent on this enterprise, most importantly our wives Bettina and Michelle. Freddie C. Hamdy and Ian Eardley Oxford and Leeds

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Brief contents

Abbreviations  xix

SECTION 6

Contributors  xxiii

Oncology  443 Section editor: James W.F. Catto

SECTION 1

Inflammation  1 Section editor: Rob Pickard

SECTION 7

Andrology  837 Section editor: David John Ralph

SECTION 2

Stones and endourology  97 Section editor: John Reynard

SECTION 8

Paediatrics  943 Section editor: David F.M. Thomas

SECTION 3

Functional and female  213 Section editor: Christopher R. Chapple

SECTION 9

Renal function  1025 Section editor: Rutger Ploeg

SECTION 4

Reconstruction  327 Section editor: Anthony R. Mundy

SECTION 10

Radiology  1075 Section editor: Michael Weston

SECTION 5

Benign prostatic hyperplasia  407 Section editor: Christopher R. Chapple

Index  1151

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Contents

Series Preface from Professor Sir Peter J. Morris  v

1.9 Inflammation: Fournier’s gangrene  76

Preface  vii

1.10 Sexually transmitted infection  80

Acknowledgements  ix Abbreviations  xix Contributors  xxiii

SECTION 1

Inflammation 1.1 Pathogenesis of urinary tract infection  3 Ased Ali

1.2 Antimicrobial agents  10 Katherine E. Walton and Sally Ager

1.3 Hospital-​acquired urinary tract infection  26 Roger Bayston

1.4 Urinary tract infection: Asymptomatic bacteriuria, cystitis, and pyelonephritis in adults  31 Magnus Grabe and Björn Wullt

1.5 Renal and retroperitoneal abscess  45 Alice E. Hartley and Toby Page

1.6 Tuberculosis and parasitic infestations involving the urogenital system  51 Chris Heyns†

1.7 Inflammation: Prostatitis syndrome  65 Florian M.E. Wagenlehner, Adrian Pilatz, Thomas Bschleipfer, Thorsten Diemer, and Wolfgang Weidner

1.8 Inflammation: Epididymitis and scrotal abscess  72 Mary Garthwaite

Francesco Greco and Paolo Fornara Emma J. McCarty and Wallace Dinsmore

1.11 Bladder pain syndrome: Interstitial cystitis  88 Magnus Fall

SECTION 2

Stones and endourology 2.1 Epidemiology of stone disease  99 Ben Turney and John Reynard

2.2 Kidney stones: Types and predisposing factors  101 Ben Turney and John Reynard

2.3 Evaluation of stone formers  104 Muhammad Waqas Iqbal, Ghalib Jibara, Michael E. Lipkin, and Glenn M. Preminger

2.4 Prevention of idiopathic calcium stones  112 Ben Turney and John Reynard

2.5 Prevention of other non-​calcium stones  114 Muhammad Waqas Iqbal, Ghalib Jibara, Michael E. Lipkin, and Glenn M. Preminger

2.6 Stone fragmentation techniques: Extracorporal shock wave lithotripsy  120 Andreas Neisius, Ghalib Jibara, Micheal E. Lipkin, Glenn M. Preminger, and James F. Glenn

2.7 Intracorporeal techniques of stone fragmentation  127 Gastón M. Astroza, Ghalib Jibara, Michael E. Lipkin, and Glenn M. Preminger

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contents

2.8 Kidney stones: Presentation and diagnosis  132 John Reynard and Ben Turney

2.9 Watchful waiting for stone disease  134 John Reynard and Ben Turney

2.10 Retrograde intrarenal surgery: Flexible ureterorenoscopy  137 Gaston M. Astroza, Ghalib Jibara, Michael E. Lipkin, and Glen M. Preminger

2.11 Kidney stone treatment: Percutaneous nephrolithotomy  142 Andreas Neisius, Ghalib Jibara, Michael E. Lipkin, and Glenn M. Preminger

2.12 Open stone surgery for kidney stones  152 Gastón M. Astroza, Ghalib Jibara, Michael E. Lipkin, and Glenn M. Preminger

2.13 Medical therapy (dissolution therapy)  156 Ben Turney and John Reynard

2.14 Ureteric stones: Presentation and diagnosis  158 Ben Turney and John Reynard

2.15 Ureteric stones: Acute management  160 Samarpit Rai, Ghalib Jibara, Zachariah G. Goldsmith, Michael E. Lipkin, and Glenn M. Preminger

2.16 Ureteric stones: Indications for intervention  165 Charles D. Scales

2.17 Surgical treatment options for ureteric stones: Techniques and complications  167 Zachariah G. Goldsmith, Ghalib Jibara, Michael E. Lipkin, and Glenn M. Preminger

2.18 Management of ureteric stones in pregnancy  175 Ben Turney and John Reynard

2.19 Bladder stones  177 John Reynard and Ben Turney

2.20 Upper urinary tract obstruction  179 Mark Sullivan, John Henderson, Inderbir Gill, and Nilay Patel†

2.21 The principles of endourology  197 Stephen Keoghane and Mark Sullivan

2.22 Principles of laparoscopic and robotic urological surgery  205

Mark Sullivan, Nilay Patel†, and Inderbir Gill

SECTION 3

Functional and female 3.1 Anatomy, neurophysiology, and pharmacological control mechanisms of the bladder  215 Donna Daly and Christopher R. Chapple

3.2 Urodynamics  230 Julie Ellis Jones and Hashim Hashim

3.3 Urinary incontinence principles  244 Nadir I. Osman and Christopher R. Chapple

3.4 Assessment of urinary incontinence  251 Marcus Drake

3.5 Stress urinary incontinence  261 Christopher R. Chapple and Altaf Mangera

3.6 Pelvic organ prolapse  269 Eduardo Cortes, Mohammed Belal, Arun Sahai, and Roland Morley

3.7 Urgency incontinence and overactive bladder  282 Christopher R. Chapple and Altaf Mangera

3.8 Urinary fistula  289 Nadir I. Osman and Christopher R. Chapple

3.9 Urethral diverticula  295 Nadir I. Osman and Christopher R.Chapple

3.10 Faecal incontinence  300 Keith Chapple

3.11 Urinary retention in women  304 Clare J. Fowler and Jalesh N. Panicker

3.12 Spinal cord injury  309 Simon C.W. Harrison

3.13 Non-​traumatic neurourology 

319

Jalesh N. Panicker and Clare J. Fowler

SECTION 4

Reconstruction 4.1 Principles of reconstructive urology  329 Anthony R. Mundy and Daniela E. Andrich

4.2 Upper urinary tract reconstruction  337 Anthony R. Mundy and Daniela E. Andrich

4.3 Lower urinary tract reconstruction  344 Anthony R. Mundy and Daniela E. Andrich

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4.4 Urethral strictures  361 Anthony R. Mundy and Daniela E. Andrich

4.5 Upper urinary tract trauma  373 Anthony R. Mundy and Daniela E. Andrich

4.6 Lower urinary tract trauma  380 Anthony R. Mundy and Daniela E. Andrich

4.7 Genital trauma  393 Daniela E. Andrich and Anthony R. Mundy

4.8 General principles of trauma  397 Graham Sleat and David Noyes

SECTION 5

Benign prostatic hyperplasia 5.1 Bladder outflow obstruction  409 Christopher R. Chapple and Altaf Mangera

5.2 Urinary retention in men  414 Mark Speakman

5.3 Benign prostatic hyperplasia  426 Nikesh Thiruchelvam

SECTION 6

Oncology 6.1 Epidemiology of prostate cancer  445 Alison J. Price and Timothy J. Key

6.2 Molecular biology of prostate cancer  455 Ines Teles Alves, Jan Trapman, and Guido Jenster

6.3 Prostate cancer: Pathology  463 Rodolfo Montironi, Liang Cheng, Antonio Lopez-​Beltran, Roberta Mazzucchelli, Matteo Santoni, and Marina Scarpelli

6.4 Prostate-​specific antigen and biomarkers for prostate cancer  474 Sven Wenske and Hans Lilja

6.5 Screening for prostate cancer  483 Fritz H. Schröder

6.6 Clinical features, assessment, and imaging of prostate cancer  493 Anders Bjartell and David Ulmert

6.7 Prostate cancer: Treatment of localized disease  501 Matthew Cooperberg and Peter Carroll

contents

6.8 Focal therapy for prostate cancer  512 Hashim Uddin Ahmed, Louise Dickinson, and Mark Emberton

6.9 High-​risk prostate cancer  521 Steven Joniau, Siska Van Bruwaene, R. Jeffrey Karnes, Gert De Meerleer, Paolo Gontero, Martin Spahn, and Alberto Briganti

6.10 Technology and prostatectomy  538 Giacomo Novara, Alexander Mottrie, Filiberto Zattoni, and Vincenzo Ficarra

6.11 Metastatic disease in prostate cancer  551 Noel W. Clarke

6.12 Novel therapies and emerging strategies for the treatment of patients with castration-​resistant prostate cancer  561 Deborah Mukherji, Aurelius Omlin, Carmel Pezaro, and Johann De Bono

6.13 Bladder and upper urinary tract cancer  569 Maria E. Goossens, Frank Buntinx, and Maurice P. Zeegers

6.14 Molecular biology of bladder cancer  579 Neveen Said and Dan Theodorescu

6.15 Pathology of bladder and upper urinary tract tumours  592 Simone Bertz and Arndt Hartmann

6.16 Screening for bladder cancer  603 Maree Brinkman and Maurice Zeegars

6.17 General overview of bladder cancer  615 Richard J. Bryant and James W.F. Catto

6.18 The investigation of haematuria  620 Richard J. Bryant and James W.F. Catto

6.19 Low and intermediate risk non-​muscle-​invasive bladder cancer  Aditya Bagrodia and Yair Lotan

6.20 Bladder cancer: High-​grade non-​muscle-​invasive disease 

638

Richard P. Meijer, Alexandre R. Zlotta, and Bas W.G. van Rhijn

6.21 Muscle-​invasive bladder cancer  644 Pascal Zehnder and George N. Thalmann

625

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contents

6.22 Treatment of metastatic bladder cancer  657 Fabio Calabrò and Cora N. Sternberg

6.23 Squamous cell bladder cancer  669 Roman Mayr and Maximilian Burger

6.24 Adenocarcinoma of the bladder  675 Roy Mano and Ofer Yossepowitch

6.25 Urothelial carcinomas of the upper urinary tract  683 Tarek P. Ghoneim, Pierre Colin, and Morgan Rouprêt

6.26 The aetiology, epidemiology, clinical features, and investigation of kidney cancer  696

Nilay Patel†, David Cranston, and Mark Sullivan

6.27 Genetics and molecular biology of renal cancer  710 Mariam Jafri and Eamonn R. Maher

6.28 Pathology of renal cancer and other tumours affecting the kidney  719 Antonio Lopez-​Beltran, Rodolfo Montironi, and Liang Cheng

6.29 Treatment of localized renal cell cancer  732 Ashraf Almatar and Michael A.S. Jewett

6.30 Ablative technologies for renal cancer  743 Stephen Faddegon, Ephrem O. Olweny, and Jeffrey A. Cadeddu

6.31 Kidney cancer: Treatment of locally advanced and low volume metastatic disease  752 Tim O’Brien and Amit Patel

6.32 Treatment of metastatic renal cancer  757 Han Hsi Wong, Basma Greef, and Tim Eisen

6.33 Testicular cancer  776 Christian Winter and Peter Albers

6.34 Pathology of testicular tumours  786 John Goepel

6.35 Testis cancer: Treatment  793 Axel Heidenreich

6.36 Penile cancer  810 Rosa Djajadiningrat and Simon Horenblas

6.37 Adrenocortical cancer  822 Steve Ball and Sajid Kalathil

6.38 Treatment of adrenal tumours  829 Atul Bagul, Saba Balasubramanian

SECTION 7

Andrology 7.1 Infertility: Assessment  839 Gert R. Dohle

7.2 Surgical treatment of male infertility  844 Gert R. Dohle

7.3 Infertility: Sperm retrieval  849 Oliver Kayes and Akwasi Amoako

7.4 Infertility: Vasectomy  854 Yacov Reisman

7.5 The management of fertility in spinal cord injury  857 Mikkel Fode and Jens Sønksen

7.6 Mechanism of penile erection  860 Selim Cellek

7.7 Erectile dysfunction: Pathophysiology and assessment  865 Antonino Saccà and Andrea Salonia

7.8 Erectile dysfunction: Medical therapy  871 Hartmut Porst

7.9 Erectile dysfunction: Surgical therapy  876 Carlo Bettocchi and Marco Spilotros

7.10 Ejaculatory disorders  879 Chris G. McMahon

7.11 Priapism  888 Asif Muneer and David Ralph

7.12 The ageing male  894 Geoffrey I. Hackett

7.13 Peyronie’s disease, congenital curvature, and chordee: Epidemiology, pathophysiology, evaluation, and treatment  909 Laurence A. Levine, William Brant, and Stephen M. Larsen

7.14 Male genital injury  920 Giulio Garaffa, Salvatore Sansalone, and David J. Ralph

7.15 Scrotal swelling  927 Ates Kadioglu and Emre Salabaş

7.16 Penile reconstruction  933 Giulio Garaffa and David John Ralph

7.17 Penile augmentation  939 Salvatore Sansalone, Giulio Garaffa, Ian Eardley, and David Ralph

 xvi

 

SECTION 8

SECTION 9

Paediatrics

Renal function

8.1 Prenatal diagnosis and perinatal urology  945 David F.M. Thomas

8.2 Urinary tract infection in children  950 David F.M. Thomas

8.3 Vesicoureteric reflux  954 David F.M. Thomas

8.4 Disorders of the kidney and upper urinary tract in children  958

contents

9.1 Renal function  1027 Chris A. O’Callaghan

9.2 Acute kidney injury  1040 Edward Sharples

9.3 Chronic kidney disease and dialysis  1046 Richard J. Haynes and James A. Gilbert

9.4 Kidney transplantation  1056 Jeff A. Lafranca, Dennis A. Hesselink, and Frank J.M.F. Dor

Kim Hutton

8.5 Disorders of the urethra  970 Kim Hutton and Ashok Daya Ram

8.6 Neuropathic bladder and anorectal anomalies  976 Henrik Steinbrecher

8.7 Urinary incontinence and bladder dysfunction  984 Henrik Steinbrecher

8.8 Abnormalities of the bladder  991 Peter Cuckow

8.9 Hypospadias  996 Peter Cuckow

8.10 Disorders of the prepuce  1001 Ahmed A. Darwish and Kim A.R. Hutton

8.11 Undescended testis and inguinoscrotal conditions in children  1005 David F.M. Thomas

8.12 Disorders of sex development  1015 David F.M. Thomas

8.13 Urological malignancies in children  1019 Roly Squire

SECTION 10

Radiology 10.1 Ionising radiation and radiation protection  1077 Jeannette Kathrin Kraft and Peter Howells

10.2 Ultrasound  1083 Toby Wells and Simon J. Freeman

10.3 Computed tomography  1096 Eugene Teoh and Michael Weston

10.4 Magnetic resonance imaging in urology  1106 Raj Das, Susan Heenan, and Uday Patel

10.5 Interventional radiology  1117 Steven Kennish

10.6 Radioisotopes in urology  1128 Sobhan Vinjamuri

10.7 Plain radiography, excretion radiography, and contrast radiography  1142 Robert P. Hartman, Akira Kawashima, and Andrew J. LeRoy

Index  1151

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 xi

Abbreviations

AAST ABLC ABU ACE ACOG

American Association for the Surgery of Trauma amphotericin B-​lipid complex asymptomatic bacteriuria angiotensin converting enzyme American Congress of Obstetricians and Gynecologists ADEM acute disseminated encephalomyelitis ADH antidiuretic hormone ADPKD autosomal dominant polycystic kidney disease AFB acid-​fast bacilli AHA acetohydroxamic acid AIDS acquired immunodeficiency syndrome AIS Abbreviated Injury Scale AKI acute kidney injury ALT alanine aminotransferase AMB amphotericin B APF antiproliferative factor AR androgen receptor ARHAI Antimicrobial Resistance and Healthcare Associated Infection ART assisted reproductive techniques AST aspartate aminotransferase ATN acute tubular necrosis AUA American Urological Association AUR acute urinary retention AUS artificial urethral sphincter BASICS British Association for Immediate Care BAUS British Association of Urological Surgeons BCG Bacille Calmette-​Guérin BCI bladder contractility index BMA bulbomembranous anastomosis BMI body mass index BNC bladder neck contracture BOO bladder outlet obstruction BOOI bladder outlet obstruction index BOOP bronchiolitis obliterans organizing pneumonia BPE benign prostatic enlargement BPH benign prostatic hyperplasia BPO benign prostatic obstruction BPS bladder pain syndrome BRCA breast cancer predisposition gene BTX botulinum toxin

BUO BVE BXO CAASB cAMP CAUTI CBT CCD CCU CDC CDI CGH CIPO cGMP CIS CISC CKD CKD-​EPI

bilateral ureteric obstruction bladder voiding efficiency balanitis xerotica obliterans catheter-​associated asymptomatic bacteriuria cyclic adenosine monophosphate catheter-​associated urinary tract infection cognitive behavioural therapy charge-​coupled device camera control unit disease control and prevention clostridium difficile infection comparative genomic hybridization chronic idiopathic pseudo-​obstruction cyclic guanosine monophosphate carcinoma in situ clean intermittent self-​catheterization chronic kidney disease Chronic Kidney Disease-​Epidemiology Collaboration CNF1 cytotoxic necrotizing factor 1 CNS central nervous system COLA cystine, ornithine, lysine, and arginine COPD chronic obstructive pulmonary disease COX cyclooxygenase CP/​CPPS chronic prostatitis/​chronic pelvic pain syndrome CPPS chronic pelvic pain syndrome CRP C-​reactive protein CRPC castration-​resistant prostate cancer CSU catheter specimen of urine CT computed tomography CTU CT urography CUR chronic urinary retention DBD donation after brain death DBU double balloon urethrography DCD donation after circulatory death DCS damage control surgery DEC diethylcarbamazine DGF delayed graft function DIT doxazosin, ibuprofen, and thiocolchicoside DMSO dimethylsulphoxide DRE digital rectal examination DSD disorders of sex development

x

xx

abbreviations DTPA diethyltetrapenta-​acetic acid DVIU direct vision internal urethrotomy EAU European Association of Urology EBRT external beam radiotherapy ED erectile dysfunction EEJ electroejaculation eGFR estimated glomerular filtration rate EHL electrohydraulic lithotripsy ELPAT Ethical, Legal, and Psychosocial Aspects of Transplantation EMT epithelial–​mesenchymal transition eNOS endothelial nitric oxide synthase EORTC European Organisation for Research and Treatment of Cancer EPS expressed prostatic secretion ESBL extended spectrum beta-​lactamase ESRD end-​stage renal disease ESWL extracorporeal shock wave lithotripsy EUCAST European Committee on Antimicrobial Susceptibility Testing FAST focused assessment with sonography for trauma FDA US Food and Drug Administration FG Fournier’s gangrene FGF fibroblast growth factor FGSI Fournier’s Gangrene Severity Index FNAC fine needle aspiration cytology FSH follicle-​stimulatuing hormone FTSG full-​thickness skin graft f-​URS flexible ureterorenoscopy FVC frequency volume chart GAG glucosamine glycan layer GCS Glasgow Coma Scale GFR glomerular filtration rate GI gastrointestinal GRE glycopeptide-​resistant enterococci GuF genitourinary fistulae GWAS genome-​wide association studies H&E haematoxylin and eosin HAI healthcare-​associated infections HALDN hand-assisted laparoscopic donor nephrectomy HARP hand-assisted retroperitoneoscopic donor nephrectomy HA-​UTI hospital-​acquired urinary tract infection HAV Hepatitis A virus HBD heart-beating donation HCAI healthcare-​associated infections HES Hospital Episodes Statistics HG-​NMIBC high-​grade non-​muscle invasive bladder cancer HGPIN high-​grade prostatic intraepithelial neoplasia HIFU high-​intensity focused ultrasound HIV human immunodeficiency virus HLA human leukocyte antigen HlyA α-​haemolysin HPCR high-​pressure chronic retention HPV human papilloma virus HRPC hormone-​refractory prostate cancer HRQoL health-​related quality of life HSV herpes simplex virus IBC intracellular bacterial communities

IC interstitial cells ICC interstitial cells of Cajal ICIQ International Consultation on Incontinence Questionnaire ICP intracranial pressure ICS International Continence Society ICSI intracytoplasmic sperm injection ICU-​VS International Consultation on Incontinence Vaginal Symptoms questionnaire IDO idiopathic detrusor overactive IL-​1 interleukin INH isoniazid iNOS inducible nitric oxide synthase INR international normalized ratio IPP leak point pressures IPP intravesical prostatic protrusion IPSS International Prostate Symptom Score ISC intermittent self-​catheterization ISD intrinsic sphincter deficiency ISS Injury Severity Score IUI intrauterine insemination IVF in vitro fertilization IVP intravenous pyelography IVU intravenous urography JGA juxtaglomerular apparatus KTx kidney transplantation KTXs kidney transplants KUB kidney, ureter, and bladder L-​AMB liposomal amphotericin B LFT liver function test LESS laparoendoscopic single site surgery LGV lymphogranuloma venereum LH lutenizing hormone LPCR low-​pressure chronic retention LPS lipopolysaccharide LRP laparoscopic radical prostatectomy LSCS low segment caesarian section LUT lower urinary tract LUTD lower urinary tract dysfunction LUTS lower urinary tract symptoms MAG3 mercaptoactyl-​triglycine MAP magnesium ammonium phosphate MCUG micturating cystourethrogram MDRD modification of diet in renal disease MDR-​TB multidrug-​resistant tuberculosis MET medical expulsive therapy MHRA Medicines & Healthcare products Regulatory Agency (UK) MIC minimum inhibitory concentration MRHA mannose-​resistant haemagglutination MLCK myosin light chain kinase MRI magnetic resonance imaging MRSA methicillin-​resistant Staphylococcus aureus MRU magnetic resonance urography MSA multiple system atrophy MSHA mannose-​sensitive haemagglutination MSM men having sex with men MSSU midstream specimen of urine MSU midstream uine

 xxi

 

MTOPS MUCP MUI MUP MVAC

medical therapy of prostatic symptoms maximum urethral closure pressure mixed urinary incontinence maximum urethral pressure methotrexate, vinblastine, doxorubicin, and cisplatin NAAT nucleic acid amplification test NA noradrenaline NADPH nicotinamide adenine dinucleotide phosphate NANC non-​adrenergic non-​cholinergic NBI narrow band imaging NCCN National Comprehensive Cancer Network NCCT non-​contrast computed tomography NDO neurogenic detrusor overactivity NGS next generation sequencing NHBD non-heart-beating donation NIAID National Institute for Allergy and Infectious Diseases NICE National Institute for Health and Care Excellence NIDDK National Institute of Diabetes and Digestive and Kidney Diseases NIH National Institutes of Health NIH-​CPSI National Institutes of Health Chronic Prostatitis Symptom Index NMIBC non-​muscle invasive bladder cancer NNIS National Nosocomial Infections Surveillance nNOS neuronal nitric oxide synthase NNRTI non-​nucleoside reverse transcriptase inhibitors NO nitric oxide NOS nitric oxide synthase NOTES natural orifice transluminal endoscopic surgery NRTI nucleoside reverse transcriptase inhibitors NSAID non-​steroidal anti-​inflammatory drug OAB overactive bladder OABS overactive bladder symptom syndrome OCC urothelial cell carcinoma PAH p-​aminohippuric acid PAI pathogenicity islands PAIR puncture, aspiration, injection and reaspiration PAMP pathogen-​associated molecular pattern PAS para-​aminosalicylic acid PBP penicillin-​binding protein PCa prostate cancer PCN percutaneous nephrostomy PCNL percutaneous nephrolithotomy PCR polymerase chain reaction PD peritoneal dialysis PDD photodynamic diagnosis PDE-5 phosphodiesterase type 5 PDT photodynamic therapy PET positron emission tomography PFDI Pelvic Floor Distress Inventory PFS pressure flow studies PI protease inhibitors PID pelvic inflammatory disease PLUTO percutaneous shunting in lower urinary tract obstruction PMC pontine micturition centre PMD post-​micturition dribble

abbreviations

PN pneumatic lithotripsy PNE percutaneous nerve evaluation POP pelvic organ prolapse POPIQ POP Impact Questionnaire PPD purified protein derivative PPMT pre-​ and post-​massage test PPS sodium pentosan polysulphate PSA prostate-​specific antigen PSF probability of stone formation PTB pulmonary tuberculosis PTNS percutaneous tibial nerve stimulation PUJ pelviureteric junction PUJO pelviureteric junction obstruction PUV posterior urethral valve disorder PVR post-​void residual PVS penile vibratory stimulation PZA pyrazinamide QoL quality of life RADN robot-assisted laparoscopic donor nephrectomy RALP robotic-​assisted laparoscopic prostatectomy RARP robotic-​assisted laparoscopic radical prostatectomy RBF renal blood flow RCC renal cell carcinoma RCT randomized controlled trial RI resistive index RIRS retrograde intrarenal surgery RNA ribonucleic acid RP radical prostatectomy RPF renal plasma flow RRP robotic radical prostatectomy RRt renal replacement treatment RTA renal tubular acidosis RTX repeats in toxin RUG retrograde urethrogram RVT renal vein thrombosis SAT secreted autotransporter toxin SCC squamous cell cancer SCI spinal cord injury SEER Surveillance, Epidemiology, and End Results programme SIRS systemic inflammatory response syndrome sGC soluble guanylate cyclase SJS Stevens–​Johnson syndrome SLED slow low-​efficiency dialysis SNARE sensitive factor attachment protein receptor SNM sacral neuromodulation SPC suprapubic catheterization STARR stapled transanal rectal resection STI sexually transmitted infection STSG split-​thickness skin graft SUI stress urinary incontinence SVI seminal vesicle invasion SWL shockwave lithotripsy TCC transitional cell carcinoma TEAP transurethral ethanol ablation of the prostate TEN toxic epidermal necrolysis TENS transcutaneous electrical nerve stimulation TGF transforming growth factor TH tyrosine hydroxylase

xxi

xxi

xxii

abbreviations THP TIN TIR TLR TNM TRUS TUR TURB TURBT

Tamm-​Horsfall protein testicular intraepithelial neoplasia Toll/​interleukin receptor Toll-​like receptor tumour-​node metastases system transrectal ultrasonography transurethral resection transurethral resection of the bladder transurethral resection of a bladder tumour TURP transurethral resection of prostate TUU transureteroureterostomy TWOC trial without catheter UBC urothelial bladder cancer UD urethral diverticula UDIF urothelium-​derived inhibitory factor UDT undescended testis UE ureteroscopic endopyelotomy UGTB urogenital tuberculosis UI urinary incontinence UICC Union for International Cancer Control UK United Kingdom UL ultrasonic lithotripsy UPEC uropathogenic Escherichia coli UPJ ureteropelvic junction

UPOINT

urinary, psychosocial, organ specific, infection, neurological and muscle tenderness UPOINTS urinary, psychosocial, organ specific, infection, neurological and muscle tenderness, and sexual dysfunction UPP urethral pressure profiles URS ureteroscopy UrVF ureterovaginal fistula USS ultrasound scan UTI urinary tract infection UTUC upper urinary tract urothelial carcinoma UUI urgency urinary incontinence UVF urethrovaginal fistula VAS visual analogue scales VCUG voiding cystourethrography VEGF vascular endothelial growth factor VHL Von Hippel-​Lindau VIP vasoactive intestinal polypeptide VUA vesicourethral anastomosis VUF vesicouterine fistula VUR vesicoureteric reflux VVF vesicovaginal fistula WHO World Health Organization WIT warm ischaemia time XDR-​TB extensively drug-​resistant tuberculosis

 xxi

Contributors

Sally Ager, Leeds Teaching Hospital Trust, UK Hashim Uddin Ahmed, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, UK Peter Albers, Department of Urology, University Clinic Düsseldorf Peter Albers, Urologische Klinik, Universitätsklinikum Düsseldorf, Germany Ased Ali, Department of Urology, Mid Yorkshire Hospitals NHS Trust, UK Ashraf Almatar, Department of Surgical Oncology, Division of Urology, Princess Margaret Hospital, Toronto, Ontario, Canada Ines Teles Alves, Department of Urology, Erasmus MC, Rotterdam, the Netherlands Akwasi Amoako, Department of Urology and Reproductive Medicine, Leeds Teaching Hospitals, Leeds, UK Daniela E. Andrich, University College London Hospitals NHS Foundation Trust; London Bridge Hospital, both London, UK Gastón M. Astroza, Duke University School of Medicine, Durham, NC, USA Aditya Bagrodia, Department of Urology, The University of Texas Southwestern Medical Center, Dallas, USA & Urology Fellow, The David Solit Lab, Memorial Sloan Kettering Cancer Center, NY Atul Bagul, Endocrine Surgery, Department of General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, UK Saba Balasubramanian, Academic Surgical Oncology Unit, University of Sheffield, Royal Hallamshire Hospital, UK Steve Ball, Department of Endocrinology, Central Manchester University Hospitals and Manchester Academic Health Science Centre, Manchester, UK Roger Bayston, School of Medicine, University of Nottingham, UK Mohammed Belal, University Hospitals Birmingham, Edgbaston, Birmingham, UK Simone Bertz, Institute of Pathology, University Erlangen, Erlangen, Germany

Carlo Bettocchi, Institute of Urology, St. Peter’s Hospital, UCH London, UK and University of Bari Aldo Morom, Italy Anders Bjartell, Department of Urology, Skåne University Hospital, Lund University, Sweden William Brant, University of Utah, Salt Lake City, Utah, USA Alberto Briganti, Vita-​Salute San Raffaele Hospital, Department of Urology, Milan, Italy Maree Brinkman, Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia Richard J. Bryant, The Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, UK Thomas Bschleipfer, Clinic for Urology, Pediatric Urology and Andrology, Justus-​Liebig-​University Giessen, Germany Frank Buntin, Department of General Practice, Katholieke Universiteit Leuven, ACHG-​KULeuven, Kapucijnenvoer, Leuven, Belgium Max Burger, St Josef Medical Centre, Department of Urology of Regensburg University, Regensburg, Germany Jeffrey A. Cadeddu, Department of Urology, UT Southwestern Medical Center, Dallas, Texas, USA Fabio Calabrò, Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy Peter Carroll, University of California, San Francisco, CA, USA James W.F. Catto, Department of Oncology, The Medical School, Beech Hill Road, Sheffield, UK Selim Cellek, Anglia Ruskin University, Faculty of Medical Science UK Christopher R. Chapple, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, UK Keith Chapple, Colorectal Surgical Unit, Sheffield Teaching Hospitals NHS Foundation Trust, UK Liang Cheng, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

xvi

xxiv

contributors Noel W. Clarke, The Christie and Salford Royal Hospitals NHS Trusts, Manchester, UK Pierre Colin, Academic Department of Urology, CHRU Lille, Univ Lille Nord de France, Lille, France Matthew Cooperberg, Departments of Urology and Epidemiology & Biostatistics, UCSF; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA Eduardo Cortes, Department of Urogynaecology, Kingston Hospital NHS Foundation Trust, London, UK

Magnus Fall, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sweden Vincenzo Ficarra, O.L.V. Robotic Surgery Institute, Aalst, Belgium Mikkel Fode, University of Copenhagen and Department of Urology, Herlev and Gentofte Hospital Paolo Fornara, Faculty of Medicine, University Hospital, Halle (Saale), Germany

David Cranston, The Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK

Clare Fowler, University College London, UK; the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

Peter Cuckow, Department of Paediatric Urology, Great Ormond Street Hospital NHS Trust, London, UK

Simon Freeman, Department of Radiology, Derriford Hospital, Plymouth, Devon, UK

Donna Daly, Department of Biomedical Science, University of Sheffield, UK

Giulio Garaffa, St Peter’s Andrology, University College London Hospitals, London, UK

Ahmed A. Darwish, Ain Shams University, Cario, Egypt and Senior Clinical Fellow Pediatric Surgery and Urology, University Hospital of Wales, Cardiff, UK

Mary Garthwaite, James Cook University Hospital, Middlesborough, UK

Raj Das, Department of Radiology, St. George’s Hospital and Medical School, London, UK Johann De Bono, The Royal Marsden Foundation Trust, The Institute of Cancer Research, UK Gert De Meerleer, University Hospital of Ghent, Department of Radiation Oncology, Ghent, Belgium Louise Dickinson, Department of Urology, UCLH NHS Foundation Trust, London, UK

Tarek P. Ghoneim, Academic Department of Urology, CHRU Lille, University Lille Nord de France, Lille, France James A. Gilbert, OUH NHS Trust and Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford; and Oxford Kidney Unit, Oxford University Hospitals, UK Inderbir Gill, University of Southern California, Los Angeles, USA John Goepel, Sheffield Teaching Hospitals, Sheffield, UK

Thorsten Diemer, Pediatric Urology and Andrology, Justus-​Liebig-​ University Giessen, Germany

Zachariah G. Goldsmith, Department Urology, St. Luke’s Center, USA

Rosa Djajadiningrat, Netherlands Cancer Institute -​Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

Paolo Gontero, University of Torino, Department of Surgival Sciences and Urology, Turin, Italy

Gert R. Dohle, Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands

Mieke Goossens, Department of General Practice, Katholieke Universiteit Leuven, ACHG-​KULeuven, Kapucijnenvoer, Leuven, Belgium

Frank J.M.F. Dor, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK Marcus Drake, Bristol Urological Institute, School of Clinical Sciences, University of Bristol, UK

Magnus Grabe, Department of Microbiology, Immunology and Glycobiology (MIG), Lund University, Sweden

Ian Eardley, Leeds Teaching Hospital Trust, UK

Francesco Greco, Department of Urology and Mini-​Invasive Centre, Romolo Hospital, Crotone, Italy

Tim Eisen, Department of Oncology, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Cambridge University Health Partners, Cambridge, UK

Basma Greef, Department of Oncology, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Cambridge University Health Partners, Cambridge, UK

Julie Ellis-​Jones, University of the West of England; and Southmead Hospital, North Bristol Trust, Bristol, UK Mark Emberton, Division of Surgery and Interventional Science University College London, UK

Geoffrey I. Hackett, Consultant in Sexual Medicine, Heartlands Hospital, Birmingham, UK; Emeritus Professor of Men’s Health and Diabetes, University of Bedfordshire, UK; occasional speaker for Bayer and v Besins Pharmaceuticals.

Stephen Faddegon, University of Texas Southwestern Medical Center, Dallas, USA

Simon Harrison, Department of Urology, Pinderfields Hospital, Wakefield, UK

 xv

 

Alice Hartley, Freeman Hospital, Newcastle upon Tyne, UK Arndt Hartmann, Institute of Pathology, Erlangen University Hospital, Erlangen, Germany; Department of Pathology, Friedrich-​Alexander University Medical Centre, Erlangen, Germany Robert P. Hartman, Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA Hashim Hashim, Bristol Urological Institute, Southmead Hospital, Bristol, UK Richard J. Haynes, Clinical Trial Service Unit, Oxford, UK Susan Heenan, Department of Radiology, St. George’s Hospital and Medical School, London, UK Axel Heidenreich, Department of Urology, RWTH University Aachen, Germany John Henderson, Churchill Hospital, Oxford Dennis A. Hesselink, Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

contributors

R. Jeffrey Karnes, Mayo Clinic, Department of Urology, Rochester, USA Oliver Kayes, Department of Urology and Reproductive Medicine, Leeds Teaching Hospitals, Leeds, UK Akira Kawashima, Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Scottsdale, AZ, USA Steven Kennish, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, UK Stephen Keoghane, Portsmouth Hospitals NHS Trust, UK Timothy J. Key, Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, UK Jeannette Kathrin Kraft, Clarendon Wing Radiology Department, Leeds General Infirmary, Leeds Teaching Hospitals Trust, Leeds, UK Jeff A. Lafranca, Department of Surgery, division of Transplant Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands Stephen M. Larsen, Rush University Medical Center, Chicago, IL, USA

Christiaan F. Heyns, Formally of Department of Surgical Sciences, Division of Urology, Stellenbosch University, South Africa

Andrew J. LeRoy, Department of Radiology, Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA

Simon Horenblas, Department of Urology, the Netherlands Cancer Institute-​Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

Laurence A. Levine, Rush University Medical Center, Chicago, IL, USA

Peter Howells, Department of Medical Physics, Leeds General Infirmary, Leeds Teaching Hospitals Trust, Leeds, UK Kim Hutton, Department of Paediatric Surgery, University Hospital of Wales, Cardiff, UK Muhammad Waqas Iqbal, Duke University Medical Centre, Durham, North Carolina Mariam Jafri, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, Medical and Molecular Genetics, University of Birmingham, UK Guido Jenster, Department of Urology, Erasmus MC, Rotterdam, the Netherlands Michael Jewett, Department of Surgical Oncology, Division of Urology, Princess Margaret Hospital, Toronto, Ontario, Canada Ghalib Jibara, Urology Resident, Division of Urology, Department of Surgery, Duke University Hospital, Durham, NC, USA Steven Joniau, University Hospital of Leuven, Department of Urology, Leuven, Belgium Ates Kadioglu, Department of Urology, Medical Faculty of Istanbul, Istanbul University, Turkey Sajid Kalathil, Department of Diabetes and Endocrine, University of Newcastle, International Centre for Life, Newcastle upon Tyne

Hans Lilja, Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Translational Medicine, Lund University, Malmö, Sweden Michael E. Lipkin, Duke University Medical Center, Department of Surgery, Division of Urology, Durham, NC, USA Antonio Lopez-​Beltran, Anatomical Pathology Unit, Department of Surgery, Faculty of Medicine and Nursing, University of Cordoba, Cordoba, Spain & Department of Pathology, Champalimaud Clinical Center, Lisbon, Portugal Yair Lotan, Department of Urology, The University of Texas Southwestern Medical Center, Dallas, USA Eamonn Maher, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, Medical and Molecular Genetics, University of Birmingham, UK Altaf Mangera, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK Roy Mano, Institute of Urology, Rabin Medical Center, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Roman Mayr, St Josef Medical Centre, Department of Urology of Regensburg University, Regensburg, Germany Roberta Mazzucchelli, Università Politecnica delle Marche, Italy

xxv

xvi

xxvi

contributors Emma J. McCarty, Department of Genitourinary Medicine, Royal Victoria Hospital, Belfast, UK

Hartmut Porst, Private Urological/​Andrological Practice, Hamburg, Germany

Chris G. McMahon, Australian Center for Sexual Health, Sydney, Australia

Glenn M. Preminger, Department of Urologic Surgery, Duke University Medical Center, Durham, NC, USA

Richard P. Meijer, Department of Urology, University Medical Centre Utrecht, Utrecht, the Netherlands

Alison J. Price, Cancer Epidemiology Unit, University of Oxford, UK

Rodolfo Montironi, Section of Pathological Anatomy, Polytechnic University of the Marche Region (Ancona), School of Medicine, United Hospitals, Ancona, Italy

Samarpit Rai, Division of Urology, University of Miami Miller School of Medicine, Miami, USA

Roland Morley, Imperial College NHS Trust, London, UK Alexander Mottrie, O.L.V. Robotic Surgery Institute, Aalst, Belgium Deborah Mukherji, The Royal Marsden Foundation Trust, UK, American University of Beirut Medical Center, Riad El-​Solh, Beirut, Lebanon

David John Ralph, St Peter’s Andrology, University College London Hospitals, London, UK Ashok Daya Ram, Consultant Paediatric and Neonatal Surgeon, Department of Paediatric Surgery, Norfolk and Norwich University Hospital, Norwich, UK Yacov Reisman, Urologist, Amstelland Hospital, Laan van de Helende Meesters 8, Amstelveen, the Netherlands

Anthony R. Mundy, Institute of Urology, University College Hospital, UCLH NHS Foundation Trust Headquarters, London

John Reynard, Nuffield Department of Surgical Sciences, University of Oxford, UK

Asif Muneer, Department of Urology and NIHR Biomedical Research Centre, University College London Hospital, UK

Morgan Roupret, Academic Department of Urology of la Pitié-​ Salpêtrière Hospital, Assistance Publique-​Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France

Andreas Neisius, Department of Urology, University Medical Center, Johannes Gutenberg University, Mainz, Germany Giacomo Novara, University of Padua, Padua, Italy

Antonino Saccà, Department of Urology, Ospedali Riuniti di Bergamo, Bergamo, Italy

David Noyes, Consultant in Orthopaedic Trauma Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Arun Sahai, Department of Urology, Guy’s Hospital, Guy’s and St Thomas’ NHS Trust, King’s Health Partners, London, UK

Tim O’Brien, Guys and St Thomas’ Hospital, London, UK

Neveen Said, Department of Radiation Oncology, University of Virginia, USA

Chris A. O’Callaghan, Nuffield Department of Medicine, University of Oxford, UK Ephrem Olweny, Departments of Urology, Rutgers-​Robert Wood Johnson Medical School, New Brunswick, NJ Aurelius Omlin, The Royal Marsden Foundation Trust, The Institute of Cancer Research, UK Nadir Osman, Department of Urology, Royal Hallamshire Hospital, Sheffield, UK Jalesh Panicker, University College London; The National Hospital for Neurology and Neurosurgery; UCL Institute of Neurology, all in London, UK Amit Patel, Consultant in Urology, Guys and St Thomas’ Hospital, London, UK Nilay Patel, The Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK Uday Patel, Department of Radiology, St. George’s Hospital and Medical School, London, UK Carmel Pezaro, The Royal Marsden Foundation Trust, The Institute of Cancer Research, UK Adrian Pilatz, Clinic for Urology, Pediatric Urology and Andrology, Justus-​Liebig-​University Giessen, Germany

Emre Salabaş, Department of Urology, Medical Faculty of Istanbul, Istanbul University, Turkey Andrea Salonia, University Vita-​Salute San Raffaele-​Department of Urology, Milan, Italy Salvatore Sansalone, Department of Urology, School of Medicine Tor Vergata University of Rome, Rome, Italy Matteo Santoni, Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-​Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy Charles D. Scales, David Geffen School of Medicine, UCLA Marina Scarpelli, Università Politecnica delle Marche, Italy Fritz H. Schröder, Department of Urology, Erasmus University Rotterdam, the Netherlands Edward Sharples, Oxford University Hospitals NHS Trust, UK Graham Sleat, Specialty Registar, Trauma & Orthopaedics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Jens Sonksen, University of Copenhagen and Department of Urology, Herlev and Gentofte Hospital

 xxvi

 

contributors

Martin Spahn, Inselspital, Department of Urology, Bern, Switzerland

Siska Van Bruwaene, University Hospital of Leuven, Department of Urology, Leuven, Belgium

Mark Speakman, Department of Urology, Taunton and Somerset Hospital, Taunton, UK

Bas W.G. Van Rhijn, Department of Surgical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital

Marco Spilotros, Institute of Urology, St. Peter’s Hospital, UCH London, UK

Sobhan Vinjamuri, Department of Nuclear Medicine, Royal Liverpool University Hospital, Liverpool, UK

Roly Squire, Leeds Children’s Hospital, Leeds, UK

Florian M.E. Wagenlehner, Clinic for Urology, Pediatric Urology and Andrology, Justus-​Liebig-​University Giessen, Germany

Henrik Steinbrecher, Department of Paediatric Surgery, Southampton University Hospital, Southampton, UK Cora N. Sternberg, Department of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy Mark Sullivan, The Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK

Katherine E. Walton, Department of Microbiology, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK Wolfgang Weidner, Clinic for Urology, Pediatric Urology and Andrology, Justus-​Liebig-​University Giessen, Germany Toby Wells, Department of Radiology, Derriford Hospital, Plymouth, Devon, UK

Eugene Teoh, Department of Radiology, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, and Department of Oncology, University of Oxford, UK

Sven Wenske, MD. Department of Urology, Columbia University Medical Center, College of Physicians & Surgeons, New York, NY, USA

George Thalmann, Department of Urology, University of Bern, Inselspital, Switzerland

Michael Weston, Leeds Teaching Hospitals NHS Trust, UK

Dan Theodorescu, University of Colorado, Comprehensive Cancer Center, Aurora, Colorado, USA Nikesh Thiruchelvam, Department of Urology, Addenbrookes Hospital, Cambridge, UK; Cambridge University Hospitals NHS Trust, UK David F.M. Thomas, Leeds Teaching Hospitals NHS Trust, Leeds, UK Page Toby, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK Jan Trapman, Erasmus MC, Rotterdam, the Netherlands Benjamin W. Turney, Department of Urology, Nuffield Department of Surgical Sciences, The Churchill Hospital, Oxford, UK David Ulmert, Molecular Pharmacology and Chemistry Program, Memorial Sloan-​Kettering Cancer Center, NY, USA, and Department of Surgery (Urology), Skåne University Hospital, Malmö, Sweden

Christian Winter, Department of Urology, University Clinic Düsseldorf Peter Albers, Urologische Klinik, Universitätsklinikum Düsseldorf, Germany Han Hsi Wong, Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK Björn Wullt, Department of Microbiology, Immunology and Glycobiology (MIG), Lund University, Sweden Ofer Yossepowitch, Institute of Urology, Rabin Medical Center, Petah Tikva, Israel Filiberto Zattoni, University of Padua, Padua, Italy Maurice P. Zeegers, Nutrition and Translational Research in Metabolism (School NUTRIM), Maastricht University, the Netherlands; Care and Public Health Research Institute (School CAPHRI), Maastricht University, the Netherlands Pascal Zehnder, Department of Urology, University of Bern, Inselspital, Switzerland Alexandre R. Zlotta, Division of Urology, Mount Sinai Hospital, Toronto, Canada

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SECTION 1

Inflammation Section editor: Rob Pickard

1.1 Pathogenesis of urinary tract infection 3 Ased Ali 1.2 Antimicrobial agents 10 Katherine E. Walton and Sally Ager 1.3 Hospital-​acquired urinary tract infection 26 Roger Bayston 1.4 Urinary tract infection: Asymptomatic bacteriuria, cystitis, and pyelonephritis in adults 31 Magnus Grabe and Björn Wullt 1.5 Renal and retroperitoneal abscess 45 Alice E. Hartley and Toby Page 1.6 Tuberculosis and parasitic infestations involving the urogenital system  51 Chris Heyns†

1.7 Inflammation: Prostatitis syndrome  65 Florian M.E. Wagenlehner, Adrian Pilatz, Thomas Bschleipfer, Thorsten Diemer, and Wolfgang Weidner 1.8 Inflammation: Epididymitis and scrotal abscess  72 Mary Garthwaite 1.9 Inflammation: Fournier’s gangrene 76 Francesco Greco and Paolo Fornara 1.10 Sexually transmitted infection  80 Emma J. McCarty and Wallace Dinsmore 1.11 Bladder pain syndrome: Interstitial cystitis 88 Magnus Fall

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Pathogenesis of urinary tract infection Ased Ali Introduction to urinary tract infection Urinary tract infection (UTI) is one of the most common bacterial infections to affect humans. Its incidence increases with age and the cumulative probability of a woman having had a UTI by the age of 50 is approximately 50%.1 The normally sterile urinary tract is the site of an ongoing but complex interplay between an evolving pathogen and a highly developed host immune defence system, such that the pathogenesis of a UTI generally requires either greater virulence in the pathogen or deficient host defence. Typically, the process of infection begins with attachment of the uropathogen to the epithelial surface; it subsequently forms colonies, which then disseminate and invade through the urothelial tissue. This dissemination may be associated with ascent up the urinary tract, which may manifest symptomatically as cystitis (in the bladder) or pyelonephritis (in the kidney). Symptomatic infection indicates a powerful immune response and the interplay between pathogen and host will continue, influencing the extent and level of invasion, the duration of infection, and the degree of tissue damage. An understanding of bacterial pathogenesis and anti-​adherence defence mechanisms is important for clinicians so that appropriate strategies for the management and prevention of UTI are used. This section outlines current understanding of the pathogenesis of UTI, with particular emphasis on bacterial virulence and interaction with host defences, together with other factors which increase susceptibility to UTI.

Routes of infection The ascending route is the commonest mode of infection of the urinary tract with most bacteria originating from the individual’s own lower bowel and subsequently colonizing the periurethral tissue before ascending through the urethra and into the bladder.2 Colonization of the periurethral mucosa with bowel flora is particularly problematic in females, where the shorter urethra provides a convenient conduit for invading pathogens and rapid entry to the lower urinary tract. Even small variations in perineal anatomy in females can increase susceptibility; for example, women with an anal to urethral distance of less than 4.5 cm are at increased risk of UTI.3 These anatomical risks can be further increased by the influence of external agents such as spermicides, faecal contamination of the perineum, and the use of urethral catheters.4,5 Symptomatic UTI is usually confined to the bladder (cystitis), but in up to a half of cases there are signs indicating upper urinary tract involvement such as fever and loin pain.6 Pyelonephritis is

most frequently caused by the ascent of bacteria from the bladder up the ureter and into the renal pelvis, with subsequent invasion of the renal parenchyma through the collecting ducts and disruption of the renal tubules. Certain pathogenic bacterial virulence factors including P-​fimbriae and endotoxins can enhance the ability of bacteria to ascend the urinary tract, as can host susceptibility factors such as pregnancy and ureteral obstruction, which inhibit peristalsis. Haematogenous infection of the urinary tract is uncommon in normal individuals. However, patients with primary foci of infection elsewhere in the body involving Staphylococcus aureus, Candida spp., Salmonella spp., and Mycobacterium tuberculosis can suffer secondary kidney infection. The risk of such infection is enhanced when urine drainage from the kidney is obstructed.7 Infection via the lymphatic route is rare but can be caused by direct invasion of bacteria from adjacent organs in conditions that result in retroperitoneal sepsis and suppuration. The lymphatic route is not thought to play a significant role in the majority of UTIs.

Pathogenic bacterial virulence factors The interplay between host and pathogen is at the heart of any UTI. Uropathogenic Escherichia coli (UPEC) strains for example encode a number of virulence factors, which enable the bacterial clone to colonize the urinary tract and persist in the face of host defences. In recent years, great advances have been made in the understanding of these virulence factors. Prior to their migration, these bacteria will typically have come from a commensal site, such as the bowel. The role of virulence factors is therefore critical in the understanding of how commensals at one site act as pathogens at another. UPEC strains exhibit a high degree of genetic diversity facilitated by the possession of specialized virulence genes located on specific transferable genetic elements known as pathogenicity islands, which may be as large as 170 kb and can increase the size of the pathogen genome by about 20% over a commensal strain.8,9 Virulence factors may be broadly divided into two groups according to whether or not they are involved in bacterial adhesion to host epithelium.

Adhesive virulence factors The presentation of cell surface adhesive organelles (adhesins) by UPEC is one of the most significant determinants of pathogenicity. UPEC may express several adhesins that allow it to attach to urinary tract tissues and contribute to virulence in different ways which

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include: directly triggering host and bacterial cell signalling pathways; facilitating the delivery of other bacterial products to host tissues; and promoting bacterial invasion.10 The best characterized group of adhesins are the fimbriae.

Type I fimbriae Type I  fimbriae are the most commonly expressed fimbriae on E. coli (Fig. 1.1.1) and are composed of a helical rod with repeating FimA subunits that are bound to a distal tip structure containing the FimH adhesin.11 Classically these fimbriae (also called type I pili) were shown to mediate haemagglutination of guinea pig erythrocytes12 and the reaction could be inhibited by the addition of mannose; mannose-​sensitive haemagglutination (MSHA).13,14 However, while type I  fimbriae have been shown to function as virulence factors in animal models of UTI where they facilitate bacterial colonization, their function in human infection is less clear.10,15–17 This uncertainty arises from the observation that type I fimbriae are expressed in both pathogenic and commensal strains18,19; furthermore, there is no significant difference in the Fim gene frequency between more or less virulent strains in the urinary tract.20 In the mouse model, type I fimbriae bind to the urothelial mannosylated glycoproteins uroplakin Ia (UPIa) and Ib (UP1b) via the adhesin subunit FimH, located at the fimbrial tip.21 Uroplakins are membrane proteins that are found on the luminal surface of the umbrella cells of bladder epithelium. Interaction between FimH and uroplakins stimulates signalling pathways involved in bacterial invasion and epithelial cell apoptosis and may also contribute to mucosal inflammation.17,22–24 In humans, the main evidence for the role of type I fimbriae comes from the analysis of urinary bacterial isolates from patients with UTI, which were found to express mannose-​sensitive adhesins.25 Murine studies show that after binding to the urothelial surface, bacteria with FimH adhesins are quickly internalized within the epithelium as a result of localized actin rearrangement and engulfment of the bound bacterium by the epithelial cell membrane.26 Within the superficial urothelium, UPEC is able to establish a new niche as a mechanism to avoid host innate immune response.

Within the epithelial cell, UPEC proliferates in the cytosol to form clusters known as intracellular bacterial communities (IBCs).27 After six to eight hours, the morphology of the bacteria changes to an engulfing biofilm phenotype that further protects the uropathogen from the host immune response.28 This process has yet to be demonstrated in human cells however. The biofilm phenotype is characterized by decreased growth rate, allowing the formation of a biofilm matrix. This matrix is able to prevent attack from neutrophils and is also effective at preventing penetration by both host antimicrobials and external antibiotics. Animal models also suggest that bacteria at the edge of IBCs are able to detach and become motile again to re-​enter the urine and then re-​adhere to the superficial urothelium and reinvade cells to form further IBCs.29 Ultimately, after a few days, possibly as a result of ongoing immune activity, the invasive bacteria enter a quiescent state, but may persist in a dormant state in IBCs before re-​emerging later to cause recurrent infection.27

P-​fimbriae P-​fimbriae (named from their interaction with P-​blood group antigens) mediate haemagglutination of human erythrocytes that is not altered by mannose, which is thus termed mannose-​ resistant haemagglutination (MRHA). P-​fimbriae are believed to play a key role in ascending UTI and pyelonephritis.30,31 They are heteropolymeric fibres made up of various peptides encoded by the papA-​K gene.32 The adhesin PapG, at the tip of these fimbriae, recognizes  ­kidney  glycosphingolipids carrying the α-​d-​ galactopyranosyl-​(1–4)-​β-​d-​galactopyranoside determinant on renal epithelia.30,33,34 The attachment of P-​fimbriae leads to the release of ceramide, which acts as an agonist of Toll-​like receptor 4 (TLR 4), a receptor involved in activation of the innate immune response including antimicrobial peptide and cytokine production.35 This then activates an inflammatory response cascade producing the symptoms of pyelonephritis.16 P-​fimbriae may also work synergistically with type I  fimbriae by enhancing early colonization of the tubular epithelium, while the latter mediates colonization of the tubular lumen by forming a biofilm. This colony then disrupts tubular filtration, leading to obstruction of nephron and the symptoms of pyelonephritis.36 P-​fimbriae have also been implicated as one of the key virulence factors involved in acute kidney dysfunction in renal transplant patients.37

Other adhesins

Fig. 1.1.1  Electron micrograph of a uropathogenic E. coli cell bearing type 1 fimbriae. Reprinted from Microbes and Infection, Volume 8, Issue 8, Guido Capitani et al., ‘Structural and functional insights into the assembly of type 1 pili from Escherichia coli’, pp. 2284–​2290, Copyright © 2006 Elsevier SAS, with permission from Elsevier, http://​www.sciencedirect.com/​ science/​journal/​12864579

S-​fimbriae and F1C fimbriae have also been shown to play a role in UTI. S-​fimbriae bind to sialic acid residues via the SfaS adhesin; this facilitates bacterial dissemination within host tissues and is often associated with E. coli strains that cause sepsis, meningitis, and ascending UTIs.10 F1C fimbriae bind to glycosphingolipids in renal epithelial cells and induce an interleukin-​8 inflammatory response.38 Fimbrial Dr and afimbrial Afa adhesins of E. coli are associated with recurrent UTI and UTI during pregnancy.39–42 Murine models suggest that that Dr and Afa adhesins play a role in the development of chronic kidney infection.43,44

Non-​adhesive virulence factors UPEC, in common with other Gram-​negative organisms, also has cell wall modifications, motility enhancements, and secreted toxins that further enhance pathogenicity.

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pathogenesis of urinary tract infection

(RTX) family that are common among Gram-​negative pathogens.53,54 At high concentrations it lyses erythrocytes and host cells, enabling bacteria to cross epithelial barriers, damage immune cells, and gain access to host iron stores.45,55,56 At low concentrations, it can induce apoptosis of host immune cells and promote the exfoliation of bladder epithelial cells.57,58 It can also affect intracellular calcium levels in renal epithelial cells, with consequent increases in IL-​6 and IL-​8 production.59 Cytotoxic necrotizing factor 1 (CNF1) is produced by around one-​third of all pyelonephritis UPEC strains.60 Experimental data suggest that CNF1 disrupts the epithelial cell membrane, allowing bacterial invasion.61 In addition, it has been shown to interfere with polymorphonuclear phagocytosis and cause apoptosis of bladder epithelial cells, thus increasing bladder exfoliation and exposure of vulnerable underlying cells.62,63 Other secreted proteins include secreted autotransporter toxin (SAT) and Toll/​interleukin (IL-​1) receptor (TIR) domain-​ containing protein (Tcp). In vitro, SAT has toxic activity against bladder and kidney cells, suggesting a role in the early pathogenesis of UTI.64 Recent work has found that Tcp is able to subvert epithelial Toll-​like receptor (TLR) signalling, preventing early initiation of the innate immune response, thereby facilitating bacterial survival and kidney infection (Fig. 1.1.2).65

Polysaccharides The bacterial capsule and lipopolysaccharide (LPS) both act as virulence factors. The capsule is a polysaccharide covering for the bacteria that protect it from the host immune system’s responses, particularly phagocytic engulfment and complement-​mediated attack. Some capsular subtypes, such as K1 and K5 mimic components of host tissue, preventing effective immune response.45 LPS is a core component of the cell wall of Gram-​negative bacteria, and in UPEC is an important activator of pro-​inflammatory epithelial response via the induction of nitric oxide, as well as antimicrobial peptide and cytokine production.46,47 However, the systemic immune response evoked by UPEC LPS may also have detrimental effects by causing acute kidney injury, particularly in renal transplant patients with UTI.48,49

Flagellum Flagellum, the organelle made up of flagellin protein and responsible for bacterial motility plays a role in the virulence of many UPEC strains for both lower and upper urinary tract infection. Flagella activity may allow bacteria to ascend from the bladder and cause pyelonephritis. These UPEC strains may invade renal collecting duct cells through flagellin acting as an epithelial invasion through interaction with the TLR 5 receptor.50 Mice deficient in TLR5 are more susceptible to UPEC infection in both the bladder and the kidney, suggesting that flagellin may be involved in the original ascent into the bladder.51

Host defences against uropathogenic Escherichia coli colonization of the urinary tract

Secreted factors

The constant challenge of microbial invasion of the urinary tract epithelium from the host’s own bowel has mobilized a variety of host defensive mechanisms to prevent bacterial colonization and survival. The first line of defence is aimed at preventing or limiting bacterial adherence to the epithelium. Once adhesion has occurred, further responses are activated.

Secretion of toxins by UPEC and other Gram-​negative bacteria is often responsible for inflammatory response and symptoms. The most significant toxin is a lipoprotein called α-​haemolysin (HlyA) which is frequently associated with pyelonephritis and renal scarring.52 α-​haemolysin is a pore-​forming toxin of the repeats in toxin

Siderophore

Cytotoxic necrotizing factor

Hemolysin

Fe

LPS

Fe

FIC Capsule Fimbriae Flagellum 5

Type 1 B

P

Fig 1.1.2  Diagram of a uropathogenic E. coli cell bearing type I fimbriae. Reproduced from Springer, The Atlas of Infectious Diseases, Volume 9, 2004, Chapter 1, Edward S. Wong, Jack Sobel, and Gerald Mandell, Figure: Virulence determinants of uropathogenic Escherichia coli, Copyright © 2004. With kind permission from Springer Science+Business Media B.V.

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Constitutive defences The normal urinary tract has a number of constitutive (continually present) physiological and immune defences to prevent or avert bacterial colonization. First is the ‘washout’ effect of urine flow. This rinses away loosely adherent or non-​attached pathogens from the epithelial surface.66 Adherence is further limited by the secretion of glucosamines by the urothelium, which form a protective layer on the luminal surface. The high urinary osmolality and low pH make it difficult for poorly adapted bacteria to survive. Within the urine there are also a number of larger proteins, which have been identified as important in innate urinary immune defence. The most characterized is Tamm–​Horsfall protein (THP), a glycoprotein secreted by the loop of Henlé epithelium present at high concentrations in the urine. THP acts as an anti-​adhesive urinary factor by complexing with UPEC type I fimbriae, which is then cleared by voiding.67 THP knockout mice have been shown to clear E. coli less rapidly and go on to develop chronic bladder wall inflammation suggestive of persistent infection.68 Other renal epithelial proteins, such as lactoferrin and lipocalin also show antimicrobial activity through the sequestering of iron. Cathelicidin and defensins; small, highly cationic antimicrobial peptides, are also secreted by urothelium in response to pathogens.47 These peptides work in a non-​specific manner by attachment to the anionic phospholipids on the bacterial cell wall—​disrupting their cell membrane, increasing cell permeability, and causing cell death.69

Activated responses Bacteria that overcome these initial defences are able to have prolonged contact with the urothelium, resulting in the activation of further host immune defence mechanisms. These include epithelial exfoliation and the induction of a local and systemic inflammatory response.

Exfoliation of infected cells One of the most notable observations of the host response during UTI is disruption of the epithelial barrier by the exfoliation of infected cells.70,71 In the absence of infection, the urothelium is relatively quiescent, with the umbrella cell layer only renewed every few months. However, the normally repressed proliferation and differentiation processes are rapidly activated by the FimH component of fimbriae, resulting in an exfoliation mechanism that involves activation of caspases and cysteine proteases in a pathway similar to apoptosis.72,73 Following activation of this pathway, there is potential for the umbrella cell layer to regenerate within 24 hours. Experiments in which the exfoliation mechanism was dampened using a pan-​caspase inhibitor showed greatly reduced bacterial expulsion from the bladder. This allowed intracellular bacteria to transfer from dying superficial cells to infect other cells.74 In mouse studies, a mild exfoliation process in response to UPEC was more likely to result in biofilm formation that migrated into deeper ­layers.27 Consequently, it is clear that rapid exfoliation is a key mechanism in the eradication of both attached and internalized bacteria from urothelium.

Inflammatory response Successful bacterial adherence to urothelium triggers a variety of other innate immune responses. These are characterized by the production of a number of pro-​inflammatory mediators, including

cytokines and chemokines.75–77 Bladder and kidney epithelial cells appear to be a major source of interleukin-​6 (IL-​6) and interleukin-​8 (IL-​8) after infection with UPEC, which are important in the development of local tissue damage.78–​79 IL-​6 possesses a variety of pro-​inflammatory functions, including neutrophil recruitment and production of acute phase proteins.80 IL-​8 is also a potent neutrophil chemotactic agent. In humans, induction of IL-​8 correlates with appearance of neutrophils in the urine.75 Neutrophil recruitment to the site of infection has been shown to be critical for bacterial clearance from both the bladder and kidney, and their presence is a clinical diagnostic for UTI. Other immune competent cells, such as macrophages, eosinophils, and natural killer cells are also recruited and granulocytes synthesize nitric oxide, which can kill invading bacteria.81 Neutrophil migration to the site of infection is initiated by specific bacterial components, which activate pathogen-​associated molecular pattern receptors (PAMPs) such as Toll-​like receptors (TLRs).82,83 This triggers a signalling pathway that initiates epithelial antimicrobial and wider inflammatory responses. The primary receptors expressed on urothelium are TLR 2, 4, and 5. TLR 2 is activated by peptidoglycan, part of the cell wall of bacteria. TLR 4 and its co-​receptors (CD14 and MD2) recognize bacterial LPS and TLR 5 is activated by flagellin. Bacteria can evade these responses by expressing virulence factors such as Tcp to inhibit some TLR-​ activated pathways.65,84 The importance of these early interactions between bacterium and epithelial cell has been further highlighted by the effect of gene polymorphisms. In mice, polymorphisms of the TLR 4 gene are associated with reduced sensitivity to LPS, absence of neutrophil recruitment, and delayed clearance of bacteria from the urinary tract.85 Recently, it was also observed that infected mouse urothelial cells were over time able to expel intracellular E.  coli via a TLR 4-​initiated and cyclic AMP-​mediated mechanism.86 In humans, a TLR 4 polymorphism has been shown to increase susceptibility to septic shock and Gram-​negative bacteraemia.87 Other studies have suggested a role for reduced TLR 4 expression in promoting a clinically beneficial tolerance state in asymptomatic bacteriuria, rather than a more harmful situation of severe disease.88 In population studies of women with recurrent cystitis, a TLR 5 stop-​codon polymorphism is associated with increased UTI susceptibility.89

Antibody response Due to the relatively short duration of most UTI and the constantly evolving expression profile of invading bacteria, adaptive immunity is not thought to play a significant role in host defence. However, in ascending infections of longer duration, the adaptive immune response is activated with the production of high-​affinity antibodies by B and T lymphocytes. In pyelonephritis, there is serum and kidney immunoglobulin synthesis with antibodies targeting type I and P-​fimbriae detectable in serum, and in IgG and SIgA antibodies in the urine.90 Local synthesis of these antibodies enhances opsonization and reduces adherence of E.  coli.91 These findings have encouraged attempts to create vaccines against fimbrial components of UPEC to reduce colonization and ascending infections in susceptible female patients.92

Further reading Ali AS, Townes CL, Hall J, Pickard RS. Maintaining a sterile urinary tract: the role of antimicrobial peptides. J Urol 2009; 182(1):21–8.

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Anderson GG, Dodson KW, Hooton TM, Hultgren SJ. Intracellular bacterial communities of uropathogenic Escherichia coli in urinary tract pathogenesis. Trends Microbiol 2004; 12(9):424–30. Bower JM, Eto DS, Mulvey MA. Covert operations of uropathogenic Escherichia coli within the urinary tract. Traffic 2005; 6(1):18–31. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 2000; 10(8):509–15. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003; 3(9):710–20. Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996; 335(7):468–74. Johnson JR. Virulence factors in Escherichia coli urinary tract infection. Clin Microbiol Rev 1991; 4(1):80–128. Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nat Rev Microbiol 2004; 2(2):123–40. Le Bouguénec C. Adhesins and invasins of pathogenic Escherichia coli. Int J Med Microbiol 2005; 295(6–7):471–8. Mulvey MA. Adhesion and entry of uropathogenic Escherichia coli. Cell Microbiol 2002; 4(5):257–71. Oelschlaeger TA, Dobrindt U, Hacker J. Pathogenicity islands of uropathogenic E. coli and the evolution of virulence. Int J Antimicrob Agents 2002; 19:517–21. Reid G, Sobel JD. Bacterial adherence in the pathogenesis of urinary tract infection: a review. Rev Infect Dis 1987; 9(3):470. Schilling JD, Mulvey MA, Hultgren SJ. Dynamic interactions between host and pathogen during acute urinary tract infections. Urology 2001; 57(6 Suppl 1):56–61. Serafini-Cessi F, Malagolini N, Cavallone D. Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003; 42:658–76. Song J, Abraham SN. TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol 2008; 11(1):66–73. Wiles TJ, Kulesus RR, Mulvey MA. Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp Mol Pathol 2008; 85(1):11–9.

References 1. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-​reported incidence and associated costs. Ann Epidemiol 2000; 10(8):509–​15. 2. Handley MA, Reingold AL, Shiboski S, Padian NS. Incidence of acute urinary tract infection in young women and use of male condoms with and without nonoxynol-​9 spermicides. Epidemiology 2002; 13(4):431–​6. 3. Hooton TM, Stapleton AE, Roberts PL, et al. Perineal anatomy and urine-​voiding characteristics of young women with and without recurrent urinary tract infections. Clin Infect Dis 1999; 29(6):1600–​1. 4. Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996; 335(7):468–​74. 5. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 2002; 113(Suppl 1A):5S–​13S. 6. Busch R, Huland H. Correlation of symptoms and results of direct bacterial localization in patients with urinary tract infections. J Urol 1984; 132(2):282. 7. Smellie J, Edwards D, Hunter N, Normand IC, Prescod N. Vesico-ureteric reflux and renal scarring. Kidney Int Suppl 1975; 4:S65–​72. 8. Wiles TJ, Kulesus RR, Mulvey MA. Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp Mol Pathol 2008; 85(1):11–​9. 9. Oelschlaeger TA, Dobrindt U, Hacker J. Pathogenicity islands of uropathogenic E. coli and the evolution of virulence. Int J Antimicrob Agents 2002; 19:517–​21. 10. Mulvey MA. Adhesion and entry of uropathogenic Escherichia coli. Cell Microbiol 2002; 4(5):257–​71.

pathogenesis of urinary tract infection

11. Jones CH, Pinkner JS, Roth R, et al. FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae. Proc Natl Acad Sci U S A 1995; 92(6):2081–​5. 12. Duguid JP, Clegg S, Wilson MI. The fimbrial and non-​fimbrial haemagglutinins of Escherichia coli. J Med Microbiol 1979; 12:213–​27. 13. Svenson SB, Hultberg H, Källenius G, Korhonen TK, Möllby R, Winberg J. P-​fimbriae of pyelonephritogenic Escherichia coli: identification and chemical characterization of receptors. Infection 1983; 11(1):61–​7. 14. Reid G, Sobel JD. Bacterial adherence in the pathogenesis of urinary tract infection: a review. Rev Infect Dis 1987; 9(3):470. 15. Hultgren SJ, Porter TN, Schaeffer AJ, Duncan JL. Role of type 1 pili and effects of phase variation on lower urinary tract infections produced by Escherichia coli. Infect Immun 1985; 50(2):370–​7. 16. Bergsten G, Wullt B, Svanborg C. Escherichia coli, fimbriae, bacterial persistence and host response induction in the human urinary tract. Int J Med Microbiol 2005; 295(6–​7):487–​502. 17. Connell I, Agace W, Klemm P, Schembri M, Mărild S, Svanborg C. Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract. Proc Natl Acad Sci U S A. 1996; 93(18):9827–​32. 18. Hagberg L, Jodal U, Korhonen TK, Lidin-​Janson G, Lindberg U, Svanborg Edén C. Adhesion, hemagglutination, and virulence of Escherichia coli causing urinary tract infections. Infect Immun 1981; 31(2):564–​70. 19. Duguid JP, Old D. Adhesive properties of enterobacteriaceae. In: Bacterial Adherence, Receptors and Recognition, pp. 185–​217. Beachey E (ed). London, UK: Chapman & Hall, 1980. 20. Plos K, Lomberg H, Hull S, Johansson I, Svanborg C. Escherichia coli in patients with renal scarring: genotype and phenotype of Gal alpha 1–​4Gal beta-​, Forssman-​and mannose-​specific adhesins. Pediatr Infect Dis J 1991; 10(1):15–​9. 21. Wu XR, Sun TT, Medina JJ. In vitro binding of type 1-​fimbriated Escherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc Natl Acad Sci U S A 1996; 93(18):9630–​5. 22. Oelschlaeger TA, Dobrindt U, Hacker J. Virulence factors of uropathogens. Curr Opin Urol 2002; 12(1):33–​8. 23. Schembri MA, Klemm P. Biofilm formation in a hydrodynamic environment byel fimh variants and ramifications for virulence. Infect Immun 2001; 69(3):1322–​8. 24. Thumbikat P, Berry RE, Zhou G, et al. Bacteria-​induced uroplakin signaling mediates bladder response to infection. PLoS Pathog 2009; 5(5):e1000415. 25. Ljungh A, Wadstrom T. Fimbriation of Escherichia coli in urinary tract infections: Comparisons between bacteria in the urine and subcultured bacterial isolates. Curr Microbiol 1983; 8:263. 26. Martinez JJ, Hultgren SJ. Requirement of Rho-​family GTPases in the invasion of type 1-​piliated uropathogenic Escherichia coli. Cell Microbiol 2002; 4:19–​28. 27. Anderson GG, Dodson KW, Hooton TM, Hultgren SJ. Intracellular bacterial communities of uropathogenic Escherichia coli in urinary tract pathogenesis. Trends Microbiol 2004; 12(9):424–​30. 28. Justice SS, Hung C, Theriot JA, et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc Natl Acad Sci U S A 2004; 101(5):1333–​8. 29. Schilling JD, Mulvey MA, Hultgren SJ. Dynamic interactions between host and pathogen during acute urinary tract infections. Urology 2001; 57(6 Suppl 1):56–​61. 30. Leffer H, Svanborg-​Edén C. Glycolipid receptors for uropathogenic Escherichia coli on human erthrocytes and uroepithelial cells. Infect Immun 1981; 34(3):920–​9. 31. Vaisanen V, Elo J, Tallgren LG, Mannose-​resistant haemagglutination and P antigen recognition are characteristic of Escherichia coli causing primary pyelonephritis. Lancet 1981; 2(8260–​8261):1366–​9. 32. Hull RA, Gill RE, Hsu P. Construction and expression of recombinant plasmids encoding type 1 or D-​mannose-​resistant pili from a urinary tract infection Escherichia coli isolate. Infect Immun 1981; 33(3):933–​8.

7

8

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Section 1  inflammation

33. Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nat Rev Microbiol 2004; 2(2):123–​40. 34. Lund B, Lindberg F, Marklund BI, Normark S. The PapG protein is the alpha-​D-​galactopyranosyl-​(1-​-​-​-​4)-​beta-​D-​galactopyranose-​binding adhesin of uropathogenic Escherichia coli. Proc Natl Acad Sci U S A 1987; 84(16):5898–​902. 35. Fischer H, Ellström P, Ekström K, Gustafsson L, Gustafsson M, Svanborg C. Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4. Cell Microbiol 2007; 9(5):1239–​51. 36. Melican K, Sandoval RM, Kader A, et al. Uropathogenic Escherichia coli P and Type 1 fimbriae act in synergy in a living host to facilitate renal colonization leading to nephron obstruction. PLoS Pathog 2011; 7(2):e1001298. 37. Rice JC, Peng T, Kuo YF, et al. Renal allograft injury is associated with urinary tract infection caused by Escherichia coli bearing adherence factors. Am J Transplant 2006; 6(10):2375–​83. 38. Bäckhed F, Alsén B, Roche N, et al. Identification of target tissue glycosphingolipid receptors for uropathogenic, F1C-​fimbriated Escherichia coli and its role in mucosal inflammation. J Biol Chem 2002; 277(20):18198–​205. 39. Foxman B, Zhang L, Tallman P, et al. Virulence characteristics of Escherichia coli causing first urinary tract infection predict risk of second infection. J Infect Dis 1995; 172(6):1536–​41. 40. Nowicki B, Labigne A, Moseley S, Hull R, Hull S, Moulds J. The Dr hemagglutinin, afimbrial adhesins AFA-​I and AFA-​III, and F1845 fimbriae of uropathogenic and diarrhea-​associated Escherichia coli belong to a family of hemagglutinins with Dr receptor recognition. Infect Immun 1990; 58(1):279–​81. 41. Garcia MI, Gounon P, Courcoux P, Labigne A, Le Bouguénec C. The afimbrial adhesive sheath encoded by the afa-​3 gene cluster of pathogenic Escherichia coli is composed of two adhesins. Mol Microbiol 1996; 19(4):683–​93. 42. Servin AL. Pathogenesis of Afa/​Dr diffusely adhering Escherichia coli. Clin Microbiol Rev 2005; 18(2):264–​92. 43. Goluszko P, Moseley SL, Truong LD, et al. Development of experimental model of chronic pyelonephritis with Escherichia coli O75:K5:H-​bearing Dr fimbriae: mutation in the dra region prevented tubulointerstitial nephritis. J Clin Invest 1997; 99(7):1662–​72. 44. Le Bouguénec C. Adhesins and invasins of pathogenic Escherichia coli. Int J Med Microbiol 2005; 295(6–​7):471–​8. 45. Johnson JR. Virulence factors in Escherichia coli urinary tract infection. Clin Microbiol Rev 1991; 4(1):80–​128. 46. Bäckhed F, Söderhäll M, Ekman P, Normark S, Richter-​Dahlfors A. Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ-​and cell-​specific expression of Toll-​like receptors within the human urinary tract. Cell Microbiol 2001; 3(3):153–​8. 47. Ali AS, Townes CL, Hall J, Pickard RS. Maintaining a sterile urinary tract: the role of antimicrobial peptides. J Urol 2009; 182(1):21–​8. 48. Wolfs TG, Buurman WA, van Schadewijk A, et al. In vivo expression of Toll-​like receptor 2 and 4 by renal epithelial cells: IFN-​gamma and TNF-​alpha mediated up-​regulation during inflammation. J Immunol 2002 1; 168(3):1286–​93. 49. Samuelsson P, Hang L, Wullt B, Irjala H, Svanborg C. Toll-​like receptor 4 expression and cytokine responses in the human urinary tract mucosa. Infect Immun 2004; 72(6):3179–​86. 50. Pichon C, Héchard C, du Merle L, et al. Uropathogenic Escherichia coli AL511 requires flagellum to enter renal collecting duct cells. Cell Microbiol 2009; 11(4):616–​28. 51. Andersen-​Nissen E, Hawn TR, Smith KD, et al. Cutting edge: Tlr5-​/​-​ mice are more susceptible to Escherichia coli urinary tract infection. J Immunol 2007; 178(8):4717–​20. 52. Mobley HL, Green DM, Trifillis AL, et al. Pyelonephritogenic Escherichia coli and killing of cultured human renal proximal tubular

53. 54. 55. 56. 57.

58.

59. 60.

61. 62.

63.

64.

65.

66. 67. 68. 69. 70. 71.

epithelial cells: role of hemolysin in some strains. Infect Immun 1990; 58(5):1281–​9. Eberspächer B, Hugo F, Bhakdi S. Quantitative study of the binding and hemolytic efficiency of Escherichia coli hemolysin. Infect Immun 1989; 57(3):983–​8. Bhakdi S, Mackman N, Nicaud JM, Holland IB. Escherichia coli hemolysin damage target cell membranes by generating transmembrane pores. Infect Immun 1986; 52(1):63–​9. Keane WF, Welch R, Gekker G, Peterson PK. Mechanism of Escherichia coli alpha-​hemolysin-​induced injury to isolated renal tubular cells. Am J Pathol 1987; 126(2):350–​7. Cavalieri SJ, Bohach GA, Snyder IS. Escherichia coli alpha-​ hemolysin: characteristics and probable role in pathogenicity. Microbiol Rev 1984; 48(4):326–​43. Smith YC, Grande KK, Rasmussen SB, O’Brien AD. Novel three-​ dimensional organoid model for evaluation of the interaction of uropathogenic Escherichia coli with terminally differentiated human urothelial cells. Infect Immun 2006; 74(1):750–​7. Russo TA, Davidson BA, Genagon SA, et al. E. coli virulence factor hemolysin induces neutrophil apoptosis and necrosis/​lysis in vitro and necrosis/​lysis and lung injury in a rat pneumonia model. Am J Physiol Lung Cell Mol Physiol 2005; 289(2):L207–​16. Uhlén P, Laestadius A, Jahnukainen T, et al. Alpha-​haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells. Nature 2000; 405(6787):694–​7. Landraud L, Gauthier M, Fosse T, Boquet P. Frequency of Escherichia coli strains producing the cytotoxic necrotizing factor (CNF1) in nosocomial urinary tract infections. Lett Appl Microbiol 2000; 30(3):213–​6. Bower JM, Eto DS, Mulvey MA. Covert operations of uropathogenic Escherichia coli within the urinary tract. Traffic 2005; 6(1):18–​31. Mills M, Meysick KC, O’Brien AD. Cytotoxic necrotizing factor type 1 of uropathogenic Escherichia coli kills cultured human uroepithelial 5637 cells by an apoptotic mechanism. Infect Immun 2000; 68(10):5869–​80. Fiorentini C, Fabbri A, Matarrese P, Falzano L, Boquet P, Malorni W. Hinderance of apoptosis and phagocytic behaviour induced by Escherichia coli cytotoxic necrotizing factor 1: two related activities in epithelial cells. Biochem Biophys Res Commun 1997; 241(2):341–​6. Guyer DM, Radulovic S, Jones FE, Mobley HL. Sat, the secreted autotransporter toxin of uropathogenic Escherichia coli, is a vacuolating cytotoxin for bladder and kidney epithelial cells. Infect Immun 2002; 70(8):4539–​46. Cirl C, Wieser A, Yadav M, et al. Subversion of Toll-​like receptor signaling by a unique family of bacterial Toll/​ interleukin-1 receptor domain-​containing proteins. Nat Med 2008; 14(4):399–​406. Sobel JD. Pathogenesis of urinary tract infection. Role of host defenses. Infect Dis Clin North Am 1997; 11(3):531–​49. Serafini-​Cessi F, Malagolini N, Cavallone D. Tamm-​Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003; 42:658–​76. Bates JM, Raffi HM, Prasadan K, et al. Tamm-​Horsfall protein knockout mice are more prone to urinary tract infection: Rapid communication. Kidney Int 2004; 65: 791–​7. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003; 3(9):710–​20. Fukushi Y, Orikasa S, Kagayama M. An electron microscopic study of the interaction between vesical epitherlium and E. Coli Invest Urol 1979; 17(1):61–​8. Mysorekar IU, Mulvey MA, Hultgren SJ, Gordon JI. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. J Biol Chem 2002; 277(9):7412–​9.

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Chapter 1.1 

72. Mulvey MA, Lopez-​Boado YS, Wilson CL, et al. Induction and evasion of host defenses by type 1-​piliated uropathogenic Escherichia coli. Science 1998; 282(5393):1494–​7. 73. Klumpp DJ, Weiser AC, Sengupta S, Forrestal SG, Batler RA, Schaeffer AJ. Uropathogenic Escherichia coli potentiates type 1 pilus-​ induced apoptosis by suppressing NF-​kappaB. Infect Immun 2001; 69(11):6689–​95. 74. Mulvey MA, Schilling JD, Hultgren SJ. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun 2001; 69(7):4572–​9. 75. Agace W, Hedges S, Andersson U, Andersson J, Ceska M, Svanborg C. Selective cytokine production by epithelial cells following exposure to Escherichia coli. Infect Immun 1993; 61(2):602–​9. 76. Schilling JD, Mulvey MA, Vincent CD, Lorenz RG, Hultgren SJ. Bacterial invasionments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-​dependent mechanism. J Immunol 2001; 166(2):1148–​55. 77. Schilling JD, Martin SM, Hunstad DA, et al. CD14-​and Toll-​ like receptor-​dependent activation of bladder epithelial cells by lipopolysaccharide and type 1 piliated Escherichia coli. Infect Immun 2003; 71(3):1470–​80. 78. Hedges S, Anderson P, Lidin-​Janson G, de Man P, Svanborg C. Interleukin-​6 response to deliberate colonization of the human urinary tract with gram-​negative bacteria. Infect Immun 1991; 59(1):421–​7. 79. Ko YC, Mukaida N, Ishiyama S, et al. Elevated interleukin-​8 levels in the urine of patients with urinary tract infections. Infect Immun 1993; 61(4):1307–​14. 80. Otto G, Braconier J, Andreasson A, Svanborg C. Interleukin-​6 and disease severity in patients with bacteremic and nonbacteremicrile urinary tract infection. J Infect Dis 1999; 179(1):172–​9. 81. Jantausch BA, O’Donnell R, Wiedermann BL. Urinary interleukin-​6 and interleukin-​8 in children with urinary tract infection. Pediatr Nephrol 2000; 15(3–​4):236–​40. 82. Gabay C. Interleukin-​6 and chronic inflammation. Arthritis Res Ther 2006; 8(Suppl 2):S3.

pathogenesis of urinary tract infection

83. Poljakovic M, Persson K. Urinary tract infection in iNOS-​deficient mice with focus on bacterial sensitivity to nitric oxide. Am J Physiol Renal Physiol 2003; 284(1):F22–​31. 84. Albiger B, Dahlberg S, Henriques-​Normark B, Normark S. Role of the innate immune system in host defence against bacterial infections: focus on the Toll-​like receptors. J Intern Med 2007; 261(6):511–​28. 85. Song J, Abraham SN. TLR-​mediated immune responses in the urinary tract. Curr Opin Microbiol 2008; 11(1):66–​73. 86. Billips BK, Schaeffer AJ, Klumpp DJ. Molecular basis of uropathogenic Escherichia coli evasion of the innate immune response in the bladder. Infect Immun 2008; 76(9):3891–​900. 87. Haraoka M, Hang L, Frendéus B, et al. Neutrophil recruitment and resistance to urinary tract infection. J Infect Dis 1999; 180(4):1220–​9. 88. Song J, Bishop BL, Li G, Duncan MJ, Abraham SN. TLR4-​initiated and cAMP-​mediated abrogation of bacterial invasion of the bladder. Cell Host Microbe 2007; 1(4):287–​98. 89. Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-​negative shock. Arch Intern Med 2002; 162(9):1028–​32. 90. Ragnarsdóttir B, Jönsson K, Urbano A, et al. Toll-​like receptor 4 promoter polymorphisms: common TLR4 variants protect against severe urinary tract infection. PLoS One 2010; 5(5):e10734. 91. Hawn TR, Scholes D, Li SS, et al. Toll-​like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS One 2009; 4(6):e5990. 92. Rene P, Dinolfo M, Silverblatt FJ. Serum and urogenital antibody responses to Escherichia coli pili in cystitis. Infect Immun 1982; 38(2):542–​7. 93. de Ree JM, van den Bosch JF. Serological response to the P fimbriae of uropathogenic Escherichia coli in pyelonephritis. Infect Immun 1987; 55(9):2204–​7. 94. Uehling DT, Hopkins WJ, Dahmer LA, Balish E. Phase I clinical trial of vaginal mucosal immunization for recurrent urinary tract infection. J Urol 1994; 152(6 Pt 2):2308–​11.

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CHAPTER 1.2

Antimicrobial agents Katherine E. Walton and Sally Ager Introduction to antimicrobial agents

Indications for antimicrobial prescribing

Urinary tract infections (UTIs) are common and they are experienced more frequently by women than men.1 It is estimated that up to half of all women will have at least one UTI during their lifetime.1 Healthcare-​associated infections (HCAI) are recognized as important, potentially preventable causes of morbidity, mortality, and healthcare costs. In a recent prevalence survey, UTIs were the second commonest type of HCAI in English hospitals.2 Escherichia coli is the commonest cause of UTI3 and the urinary tract is the commonest source for E. coli bacteraemia (Fig. 1.2.1).4 Important risk factors for the development of UTI include sex, age, structural and functional abnormalities of the urinary tract, and catheterization or urinary tract instrumentation. Safe urological practice therefore relies on an understanding of the prevention and management of UTI, including judicious antimicrobial prescribing. Antimicrobial agents are substances that kill or inhibit the growth of microorganisms, such as bacteria, fungi, or protozoa. Antibacterial agents affect bacteria. Strictly speaking, the term ‘antibiotic’ refers to antimicrobials produced by a microorganism, thus excluding synthetic antibacterials, although the terms ‘antibiotic’, ‘antibacterial’, and ‘antimicrobial’ are often used interchangeably.

Antimicrobial agents are prescribed for the following reasons: ◆ Empirical ◆ Directed

therapy

therapy

◆ Prophylaxis

Empirical therapy Antimicrobials are given based on the most likely causative organism(s) and local resistance patterns, before confirmation of the pathogen’s identity. Empirical therapy is required for severe or life-​threatening infection; it is important that appropriate, broad-​ spectrum antibiotics are started quickly, ideally within one hour of the presumptive diagnosis. Whenever possible, relevant diagnostic specimens should be collected prior to starting antimicrobial therapy (Fig. 1.2.2).

Directed therapy Wherever possible, empirical therapy using broad-​spectrum agents should be de-​escalated to directed therapy using narrow spectrum antimicrobials once the identity and sensitivities of the pathogen are known. For less severe infections, particularly if the diagnosis is uncertain, it may be appropriate to await culture and sensitivity results before prescribing directed therapy, facilitating targeted treatment with narrow spectrum antimicrobials.

Prophylaxis Prophylactic antimicrobials are given in circumstances where the risk or consequences of an infection are sufficiently severe to justify preventative action. It should be noted that the use of antibiotics is only part of a range of infection prevention measures.

Surgical prophylaxis

Fig. 1.2.1  Escherichia coli (E. coli) growing on chromogenic agar. E. coli is the commonest cause of urinary tract infections. Chromogenic media may be used in the laboratory to aid identification of potential uropathogens. With kind permission of Jesmond IT.

Antimicrobial prophylaxis is recommended for surgical procedures with a recognized risk of infection; generally, clean-​contaminated or contaminated operations, and clean surgery involving implantation of prosthetic material.5–​7 Opening of the urinary tract is considered clean-​contaminated surgery.8 Local guidelines are based on the likely organisms associated with the procedure and local antimicrobial susceptibility patterns. Where possible, narrow spectrum agents should be chosen. Many guidelines advise avoidance of agents such as cephalosporins, quinolones, and clindamycin to minimize the risk of Clostridium difficile infection.9 In order to achieve maximum serum concentration during the procedure, intravenous antimicrobial prophylaxis should be

 1

Chapter 1.2 

administered at induction of anaesthesia or within 30–​60 minutes before the operation starts.5–​8 Single-​dose prophylaxis is usually adequate. A second dose may be indicated for significant intraoperative blood loss (more than 1.5 L) or prolonged operations.5,6,8 Oral agents with good bioavailability can be considered but this may be less reliable and logistically more difficult to administer at the appropriate time.6,7 There is good evidence supporting antibacterial prophylaxis for transurethral resection of prostate (TURP) and transrectal prostate biopsy but there have been few studies for other urologic interventions.10 Nevertheless, antimicrobial prophylaxis is currently recommended for a number of invasive urological procedures (see Table 1.2.1).6–​8,11

Post-​exposure prophylaxis Post-​exposure prophylaxis may be advised for contacts of certain communicable diseases in order to prevent transmission of the infection, for example meningococcal meningitis, pertussis, and tuberculosis.11

Prophylaxis of special patient groups Antibacterial prophylaxis may also be recommended for certain individuals with factors that put them at higher risk for specific infections. For example, asplenic patients may receive phenoxymethylpenicillin in order to prevent pneumococcal infection.11 Prophylactic antibacterials may sometimes be prescribed for specific individuals in an attempt to prevent recurrent UTIs,

antimicrobial agents

for example in children with vesicoureteric reflux. Prophylaxis should generally only be considered following a risk assessment if other approaches are not possible. Long-​term low-​dose therapy is administered, basing the choice of agent on previous urinary culture and sensitivity results. Nitrofurantoin or trimethoprim may be considered as options.11 Long-​term antibiotic exposure may result in adverse drug effects and the development of antimicrobial resistance.

Principles of antimicrobial prescribing Antimicrobial stewardship Careful consideration must be given before antimicrobial agents are prescribed. They may cause allergic or other adverse reactions, and harm an individual’s normal protective microbial flora.12 Broad-​spectrum antibacterial use is associated with the acquisition of resistant organisms such as extended spectrum beta-​lactamase (ESBL)-​producing Gram-​negative bacteria13,14 or methicillin-​ resistant Staphylococcus aureus (MRSA)15–​18 and the development of Clostridium difficile infection (CDI).9,19–22 Adverse effects can be minimized by the introduction of antimicrobial stewardship programmes such as ‘Start smart—​then focus’.23 Antibacterial drugs should not be prescribed unless there is an accepted prophylactic indication or clinical evidence of a bacterial infection requiring treatment. At the same time, patients with severe or life-​threatening infections must receive prompt treatment with appropriate, often

Table 1.2.1  Prophylaxis for urological procedures Procedure

Antibiotic prophylaxis recommended?

Likely pathogens

EAU

AUA

SIGN

Transurethral resection of prostate

Yes

Yes

Yes

Enterobacteriaceae and enterococci

Transrectal biopsy of prostate

Yes

Yes

Yes

Enterobacteriaceae and enterococci, possibly anaerobes

Transurethral resection of bladder tumour

No1

Yes

No

Enterobacteriaceae and enterococci

Percutaneous nephrolithotomy

Yes

Yes

Yes/​No2

Enterobacteriaceae, enterococci, and staphylococci

Ureteroscopy for stone removal/​fragmentation

Yes/​No3

Yes

Yes

Enterobacteriaceae, enterococci, and staphylococci

Shock wave lithotripsy

Yes/​No4

Yes

Yes

Enterobacteriaceae and enterococci

Cystoscopy/​urodynamic investigation

No5

Yes/​No6

No5

Enterobacteriaceae, enterococci, and staphylococci

Clean open or laparoscopic procedures (urinary tract not opened, e.g. nephrectomy)

No5

No5

No7

Skin organisms, catheter-​associated organisms

Clean-​contaminated procedures (urinary or gastrointestinal tracts opened, e.g. pyeloplasty, vaginal surgery, cystectomy)

Yes

Yes

Yes

Enterobacteriaceae, enterococci, and staphylococci

Implantation of prosthetic device

Yes

Yes

Yes

Enterobacteriaceae, enterococci, and skin organisms (e.g. staphylococci)

Contaminated open procedures (use of bowel segments)

Yes

Yes

Yes

Enterobacteriaceae, enterococci anaerobes, and skin organisms (e.g. staphylococci)

EAU = European Association of Urology; SIGN = Scottish Intercollegiate Guidelines Network; AUA = American Urological Association. 1: Consider in cases with high risk factors for UTI and for large necrotic tumours; 2: Recommended for stones 20 mm or greater or with pelvicalyceal dilation (one week preoperative fluoroquinolone recommended); 3: Recommended for proximal/​impacted stone. Not recommended for uncomplicated distal stone (but consider in high-​risk patients); 4: Not recommended for uncomplicated cases. Recommended in cases complicated by stent or nephrostomy catheter; 5: Consider in patients with high risk factors (bacteriuria, indwelling catheters, history of urogenital infection/​abnormalities, immunosuppressed/​post-​transplant patients, diabetes mellitus, long inpatient stay, poor nutritional status, smoking, recent hospitalization, coexistent infection at other sites, older age, obesity); 6: Not if negative urine culture pre-​procedure; 7: In children.

11

12

12

Section 1  inflammation

effects, and cost. Pharmacokinetics is the study of the effects of the body on a drug, including absorption, distribution, metabolism, and elimination, while pharmacodynamics is the study of the effect of the drug on the patient. Both factors help to determine optimal dosing regimens. Some antibacterial agents, such as the beta-​lactams, are able to kill bacteria (bactericidal), while others only inhibit replication (bacteriostatic), for example sulphonamides. This may be a consideration when choosing therapy. The minimum inhibitory concentration (MIC) provides an assessment of an individual antibacterial agent’s activity against a particular organism. Antimicrobials may show time-​dependent or concentration-​dependent killing. Dosing regimens that expose bacteria to drug concentrations above their MIC for as long as possible are preferred for time-​dependent killing (e.g. penicillin therapy). To optimize concentration-​dependent killing, peak serum concentrations should exceed the MIC of the target bacterium. This is important for aminoglycoside treatment.

Combination therapy Fig. 1.2.2  Specimen of urine and urine test strip. Near-​patient testing of urine samples, including analysis for the presence of leucocyte esterase, nitrites, protein, and blood, may be carried out using urine reagent strips (dipsticks) to give an early indication of the likelihood of urinary infection. With kind permission of Jesmond IT.

broad-​spectrum agents. If indicated, the choice of antimicrobial agent should normally be directed by local or national evidence-​ based guidelines and, whenever possible, diagnostic specimens should first be collected. Antimicrobial prescriptions should be accompanied by a clear record of the clinical indication, route of administration, duration, and review date. Oral administration is generally preferred, however, if intravenous antimicrobial treatment is required, it should be switched to oral medication as soon as this is safe. The duration of therapy depends on the type and nature of the infection and the clinical response to treatment. Local guidelines should specify standard durations for specific infections and courses should generally be kept to the minimum consistent with safety. Regular review of clinical progress and microbiology results facilitates the de-​escalation of therapy, allowing patients who were initially commenced on broad-​spectrum agents to be switched to targeted treatment with narrower spectrum antimicrobials. There should be regular review of local antimicrobial guidelines and audit of adherence to the key principles of judicious antimicrobial prescribing.

Antimicrobial choice Local antimicrobial guidelines should be evidence-​based and refer to available national guidelines.23 Antibacterial choice will depend on the site and severity of the infection, the likely pathogens, and their local antimicrobial resistance patterns. Patient factors should also be considered, including age, clinical status, special factors such as pregnancy or immunosuppression, co-​morbidities, allergies, medication which may result in potential drug interactions, previous microbiology results, and antimicrobial treatment history. Important antimicrobial characteristics include the drug’s spectrum of activity, routes of administration, potential side

Treatment with a single antimicrobial agent is generally preferred, however, combination therapy is sometimes indicated. It may provide a broad spectrum of activity for mixed infections or be used for severe infections in immunocompromized patients, empirical treatment of life-​threatening infections, or treatment of serious, deep-​seated infections, such as prosthetic valve endocarditis. Combination therapy is also indicated for a few specific infections, such as tuberculosis, to prevent the development of resistant bacterial clones.11

Therapeutic drug monitoring Measurement of serum concentration is advisable for some antimicrobials in order to minimize toxicity or determine whether effective concentrations have been achieved.24 This is particularly important for drugs with a narrow therapeutic index, such as aminoglycosides, where the therapeutic band between effective and toxic concentrations is narrow. The correct timing of the sample is important: pre-​dose (trough) concentrations are usually measured, although post-​dose (peak) levels may sometime be helpful. Therapeutic drug monitoring is required for courses of parenteral gentamicin and vancomycin as well as other, less frequently used agents.11,25 Local guidelines should be followed and the advice of a clinical microbiologist or other infection specialist sought in cases of uncertainty.

Prescribing for special patient groups Patient factors are important when prescribing antimicrobial agents. Examples of special considerations for certain patient groups are given below:

Children The pharmacokinetics and pharmacodynamics of drugs are often different in children. There may be a greater risk of adverse effects, particularly in the neonate, as a result of reduced drug clearance and different tissue sensitivities to toxins. Certain antimicrobial agents such as tetracyclines are contraindicated in children, while others should be used with caution (e.g. ciprofloxacin). When prescribing for children, the doses of antimicrobial agents must be carefully calculated.26

 13

Chapter 1.2 

Pregnancy and breast feeding A risk assessment should be carried out before drugs are prescribed during pregnancy as there may be the potential for teratogenicity or other harmful effects on the embryo or foetus. For example, tetracyclines, quinolones, and aminoglycosides should be avoided throughout pregnancy, trimethoprim should be avoided during the first trimester, and nitrofurantoin should be avoided at term.11 It is important to check whether individual antimicrobial agents may be safely prescribed to a breast-​feeding mother. Some antimicrobial agents appear only as trace amounts in breast milk, while others reach higher concentrations and are therefore likely to be transmitted to the breast-​feeding infant.11

The elderly Serum and tissue concentrations may be increased in the elderly as a result of pharmacokinetic changes, such as reduced renal clearance. Older patients may have several co-​morbidities and may also take multiple drugs, increasing the potential for adverse effects and drug interactions.

Hepatic impairment Hepatic metabolism and elimination of drugs such as metronidazole may be impaired in patients with severe liver disease. In addition, drugs associated with dose-​related or idiosyncratic hepatotoxicity may produce their adverse effects more frequently in patients with pre-​existing hepatic impairment. For example, flucloxacillin and nitrofurantoin should be used with caution because of the risk of cholestatic jaundice. Monitoring of liver function tests is advised when some antibacterials (e.g. co-​amoxiclav) are prescribed for patients with liver disease.

Renal impairment Dose adjustment is required if reduced renal excretion may lead to drug or metabolite accumulation and toxicity (see Table 1.2.2). Aminoglycosides and glycopeptides should be avoided, or used with caution and careful therapeutic drug monitoring. Some antimicrobial agents, such as nitrofurantoin, will be ineffective for the treatment of UTIs if renal function is impaired because the drug will not achieve therapeutic concentrations in the urine. Expert advice should be sought about the appropriate dosing of antimicrobial agents in patients receiving renal replacement therapy.

The immunocompromized patient Immunocompromized patients are at greater risk of severe and opportunistic infections. The type and severity of the immunodeficiency or immunosuppression determines the spectrum of likely infections; for example, neutropenic patients are particularly vulnerable to severe bacterial infections, including Gram-​negative sepsis. Clinical signs and symptoms of infection may appear atypical as a result of the impaired host immune response. It is therefore important to remain vigilant for evidence of infection, obtain appropriate diagnostic samples, and institute empirical treatment as soon as a clinical diagnosis of severe bacterial infection is made (Fig. 1.2.3). Bactericidal agents are generally preferred for the treatment of severe infections in immunocompromized patients.

antimicrobial agents

common, occurring in up to 10% of exposed individuals, however anaphylaxis is reported in less than 0.05%.11 All penicillins should be avoided by patients allergic to one type of penicillin because of the risk of cross-​hypersensitivity. Cephalosporins and other beta-​ lactams should also be avoided if there is a history suggesting an immediate hypersensitivity reaction to penicillins.11

Clostridium difficile infection (CDI) Antibiotic exposure should be minimized, and avoided if possible, in patients with a past history of CDI. The Department of Health of England has advised that the use of some antibacterial drugs, such as cephalosporins, clindamycin, and ciprofloxacin, should be avoided in order to minimize the risk of CDI.9 If antibacterial treatment must be given, then it is preferable to choose agents other than these and to keep the course as short as possible.

Colonization or infection with multiresistant bacteria A history of previous colonization or infection with multi­resistant organisms such as MRSA, glycopeptide-​resistant enterococci (GRE), or multiresistant Gram-​negative bacteria including ESBL-producers and carbapenemase-producing Enterobacteriaceae (CPE) should be considered if empirical therapy or prophylaxis is prescribed. It is useful to establish the patient’s recent antimicrobial history because prolonged antibacterial therapy or exposure to multiple antibiotics, particularly in the inpatient setting, may predispose to colonization or infection with multidrug resistant bacteria. A travel history should be obtained to ascertain if the patient has travelled to countries or to areas of the UK known to have problems with the spread of CPE, and if they were treated in healthcare premises in these places. In England, hospital admissions must be risk assessed for MRSA and CPE carriage, and high-risk patients should be screened and isolated until screening results are available.27,28 Patients colonized with MRSA may be given topical decolonization therapy.29 Local guidelines will indicate the circumstances under which this should be attempted, and the recommended topical agents. Preoperative screening ensures that appropriate antibacterial prophylaxis may be chosen for MRSA-​positive patients and provides the opportunity to administer perioperative decolonization therapy.

Extremes of body weight The 2015 health survey for England found that 27% of adults were obese, and the prevalence of morbid obesity was 2% in men and 4% in women.30 Although treatment of patients at extremes of body weight is an increasing occurrence, there is limited data available to guide dosing. The site of infection is important. While the ideal body weight may help guide dosing in some circumstances, calculated doses may be inadequate for optimal treatment of certain severe infections in morbid obesity, particularly those that involve adipose tissue, such as necrotising fasciitis.31

Antibacterial agents Mechanisms of action Most antibacterial agents affect one of four targets:

Antibiotic allergy

◆ Cell

Before prescribing, it is important to ensure that there is no history of drug hypersensitivity. Attempts should be made to establish the nature of the allergic reaction and this should be clearly documented in the medical records. Penicillin allergy is relatively

◆ Protein

synthesis

◆ Nucleic

acid synthesis

◆ Cell

wall synthesis

membrane integrity

13

14

Table 1.2.2  Antibacterial agents commonly used in urological practice7,8,11,34 Antibacterial agent

Usual dosing regimen

Common indications

Notes

Nitrofurantoin

◆

Treatment: 50–​100 mg QDS PO or 100 mg BD for the modified-​release formulation ◆ Prophylaxis: 50–​100 mg PO nocte

Treatment and prophylaxis of lower urinary tract infection

◆

Trimethoprim

◆

Treatment: 200 mg BD PO Prophylaxis: 100 mg nocte PO ◆ Reduce dose in severe renal impairment

Treatment and prophylaxis of lower urinary tract infection

Avoid during the first trimester of pregnancy

◆

Treatment: 960 mg BD PO Reduce dose in severe renal impairment

Consider as second-​line directed therapy for lower urinary tract infection if pathogen sensitive and there is justification for use in place of trimethoprim

◆

250–​500 mg TDS PO or 500 mg–​1 g tds IV Reduce dose in severe renal impairment

Treatment of uncomplicated urinary tract infection where uropathogen is known to be sensitive

250–​500 mg QDS PO or 500 mg QDS IV Reduce dose in severe renal impairment

Treatment of uncomplicated urinary tract infection where uropathogen is known to be sensitive

500 mg QDS PO or 500 mg–​2 g QDS IV Reduce dose in severe renal impairment (eGFR 75%), with S. saprophyticus second (5–​10%).22,23 Other pathogens are uncommon. The resultant lower urinary tract symptoms are frequency, urgency, dysuria (pain or discomfort passing urine), suprapubic tenderness or pain, urine odour, and occasionally cloudy urine and visible haematuria (Table 1.4.2). Urine analysis usually shows positive nitrite test, leucocyte esterase, and presence of blood cells. There is no requirement for urine culture, although it will be helpful to establish pathogen sensitivity and provide local bacterial ecology information for public health purposes. A short antibiotic course is usually effective for symptom resolution and clearance of the pathogen (Table 1.4.5). Guidance recommends avoidance of the use of broad-​spectrum antibiotics such as cephalosporins and fluoroquinolones due to increasing community E. coli resistance levels and overgrowth of gut Clostridium difficile.28,36 Acute cystitis is uncommon in males. It may also be difficult to differentiate from inflammation of the prostate (see Chapter 1.7) as the symptoms are similar and a raised prostate-​specific antigen (PSA) commonly occurs.6 A  urine culture is recommended in males, as well as a careful history of urogenital infections.

Recurrent acute cystitis Recurrent acute cystitis is common following the initial episode and may severely affect a women’s quality of life.38 It is usually defined as three or more UTIs per year, or at least two in a six-​month period. Recurrent UTIs (rUTI) are caused by the re-​emergence of the same organism (persistent pathogen) or re-​infection by a new strain (recurrent ascending colonization from the bowel flora). Recurrence is often seen in women with otherwise normal anatomic and functional urinary tracts, but risk factors such as a maternal history of UTI, onset of sexual activity, postmenopausal status, and diabetes may be present. Use of contraceptive pessaries and spermicides, low fluid intake, and infrequent, incomplete bladder emptying are also considered as risk factors. Urine culture should be repeated regularly to determine the pattern of bacterial strains and antibiotic sensitivities. If recurrences are frequent and bothersome, and particularly where risk factors for more health-​threatening disease are present such as visible haematuria or

37

38

38

Section 1  inflammation

Table 1.4.5  Most frequent bacterial strains, recommended antibiotics, and treatment regimens for most standard types of UTI Type of UTI

Pathogens

Antibiotics

Treatment length (days)

Remarks

Asymptomatic bacteriuria (lower UT)

E. coli Others spp. (rare)

According to susceptibility

No Individualized when required

No treatment in general Two main exceptions: pregnancy and prior to urological surgery

Acute sporadic cystitis in women

E. coli (75–​80%) Proteus (7.5 may indicate urinary tract infection with urea splitting organisms (Proteus, Pseudomonas, Klebsiella, or staphylococcal species), which are associated with formation of struvite stones. The presence of a positive leukocyte esterase, nitrite, and white blood cells may indicate an infection warranting urine culture. Urine microscopy of sediments may identify various crystal types. The presence of hexagonal crystals indicates cystinuria, while the presence of rectangular coffin lid crystals indicates struvite stones. Tetrahedral envelope-​shaped calcium oxalate crystals can be a normal finding in a number of non-​stone formers.

Urine analysis ◆ pH ◆ Crystals ◆ WBC, RBC, Leukocyte esterase, Nitrite Urine culture Stone analysis Urine for qualitative cystine if stone analysis not available Radiological imaging ◆ Stone protocol CT scan (CT-​KUB)

hypocitraturia, gouty diathesis, or enteric hyperoxaluria, thus increasing the risk of calcium oxalate and uric acid stone disease. ◆ A history

of recurrent urinary tract infections may indicate the presence of struvite stones.

◆ Abdominal

pain, bony pain, polyuria, and polydypsia may indicate primary hyperparathyroidism with hypercalcaemia and possible calcium phosphate stones.

◆ Malignant

tumours and granulomatous lung diseases (sarcoidosis, tuberculosis), may cause hypercalcaemia, and hence stone disease.

◆

Gout or cancer chemotherapy are associated with uric acid stones.

◆ Diabetics

are more prone to stone disease because of altered ammonia metabolism in the renal tubules and hypocitraturia.

◆ A  focused

dietary history should include query about animal protein content, consumption of high oxalate foods, excessive calcium products, and fluid intake.

◆ Finally,

the patients’ occupation may identify occupational risk factors for stone disease (e.g. heavily physical labour).

Physical examination Physical exam may give clues to bony diseases like hypophosphataemic rickets; lymphadenopathy may identify metastatic processes, or haematological or lymphoproliferative disorders. Patients may have undergone gastrointestinal surgery and may have an ileostomy or colostomy, or may appear malnourished secondary to malabsorption syndromes. Immobility may predispose to hypercalciuria and calcium stone disease (spinal cord injury, for example). Patients with neurologic deficits, urinary incontinence, and history of urinary tract infections may have infectious (struvite) stones.

Stone analysis Stone analysis is an important parameter, giving clues not only to potential metabolic disorders predisposing to stone formation, but also determines whether a specific metabolic evaluation is needed in a particular patient. It may even guide the surgeon towards choosing the ideal modality of treatment, or direct future surgical therapy to remove similar stones in the future. Patients with pure uric acid and cystine stones require a modified evaluation, whereas patients with 100% struvite stones do not need a 24-​hour urine for evaluation. Patients with calcium phosphate stones may require an ammonium chloride loading test to identify occult renal tubular acidosis. The generally accepted methods of stone analysis are X-​ray diffraction and infrared spectroscopy. Polarization microscopy is also a reliable method, but may only be available in highly specialized centres. Stone type identification by assessment of Hounsfield readings on CT imaging are unreliable because of significant overlap among various stone types. Recent evidence suggests that dual energy CT may be able to predict in vivo stone composition.20

Radiological evaluation Plain abdominal radiography, also referred to as flat plate or KUB radiography (‘kidneys, ureter, bladder’), is useful for a rapid assessment of total stone burden, size, shape, composition, and location of urinary calculi in a single image. The majority of upper urinary tract calculi are radio-​opaque (since most contain calcium oxalate), but pure uric acid, indinavir, and cystine calculi are relatively radiolucent on plain radiography. Plain abdominal imaging has relatively low sensitivity (40–​50%) and specificity for renal and ureteral calculi. Many patients have pelvic calcifications that make specific

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stone diagnosis difficult. Calcific densities on a KUB radiograph that overlie the course of the ureter may not be a stone. While not completely extinct in high-​income countries, intravenous urography is far less frequently used in the era of the CT-​KUB (also known as a non-​contrast CT—​NCCT), now considered the gold standard for diagnosis of urolithiasis because of its high sensitivity and specificity.21 The CT-​KUB can reliably detect all stone types except indinavir stones, provides detailed anatomic information with regard to atone location and renal anatomy, and can identify obstruction (hydronephrosis, perinephric stranding) without the need for any bowel preparation or intravenous contrast. The radiation dose with modern CT stone protocols is comparable to an intravenous urogram (IVU). In addition, CT can identify non-​urological causes of flank pain such as acute appendicitis, diverticulitis, or leaking abdominal aortic aneurysms. CT is considered the imaging modality of choice to document stone-​free status after stone intervention. Ultrasonography avoids radiation exposure, but has considerably poorer sensitivity and specificity for identifying stones. A recent meta-​analysis comparing CT to ultrasonography indicated a sensitivity of 44.5% and specificity of 93.8% for ureteric calculi, and 44.7% sensitivity (55.3% false negatives; i.e. more than half of stones not identified) and 87.5% specificity for renal calculi.22 The combination of renal ultrasound with X-​ray KUB improves sensitivity to 77–​96% and specificity to 91–​93%.23,24

Radiological evaluation in the context of suspected ureteric stone disease According to the recent American Urological Association (AUA) imaging guidelines for patients presenting with severe flank pain, a non-​contrast CT (NCCT) is the preferred initial imaging modality of choice (level A evidence).25 Low-​dose CT (30 due to lower sensitivity and specificity. Renal ultrasonography combined with plain KUB X-​ray is a reasonable alternative to NCCT in known stone formers previously known to have had radio-​opaque stones. Sensitivities of 58–​100% and specificities of 37.2–​100% have been reported for this combination of modalities (level C evidence).26–28 The AUA imaging guidelines recommend a standard KUB X-​ray be performed if the stone is not visible on the CT scout image, so that patients with stones identifiable on the initial KUB X-​ray, but not on the CT scout film can be followed by KUB X-​ray.29,30 The preferred initial imaging modality in children is renal ultrasound, to eliminate radiation risk. Low-​dose CT should be considered where a ureteric stone is still suspected but ultrasound is non-​diagnostic. For the same reason, renal ultrasonography is the initial imaging modality of choice during pregnancy. In the first trimester where the diagnosis is not established, MRI without contrast should be considered as second-​line imaging modality. MRI helps us to identify the level of obstruction and may provide an estimate of stone size. The AUA guidelines further recommend that low-​dose CT may be performed for women in the second and third trimesters if ultrasonography is not diagnostic. This recommendation is further endorsed by the American Congress of Obstetricians and Gynecologists (ACOG), which suggests that an exposure of

less than 5 rads, a threshold well above the average for a low-​dose CT, is not associated with the development of foetal anomalies.31

Radiological evaluation in the context of medical expulsive therapy for ureteric stones The AUA imaging guidelines for ureteral calculi also provide recommendations for follow-​up imaging after medical expulsive therapy (MET) or definitive treatment. Patients with a known radio-​opaque ureteral calculus on MET can be followed by a combination of ultrasonography and plain KUB. However, for patients who continue to have symptoms, without evidence of stone passage, and where ultrasound and KUB X-​ray fail to demonstrate hydronephrosis or a persistent stone, further imaging either with oblique plain radiographs or low-​dose NCCT limited to the area of interest is indicated. Patients with known radiolucent stones on MET, who continue to have symptoms without evidence of stone passage, require repeated low-​dose NCCT to confirm stone passage.

Radiological evaluation post-​stone treatment Patients who have undergone ureteroscopy with stone fragmentation should undergo follow-​up imaging with a ultrasound (for radiolucent stones in an asymptomatic patient) or an ultrasound and KUB X-​ray (for radio-​opaque stones) to detect any residual fragments and/​or hydronephrosis. For patients with an initially radiolucent stone who remain symptomatic or who have hydronephrosis on an ultrasound, a low-​dose NCCT to identify obstructing residual fragments is indicated. For patients treated post-​ESWL (extracorporeal shock wave lithotripsy), a follow-​up KUB X-​ray for radio-​opaque stones or renal ultrasound for those with radiolucent stones should be performed. For the asymptomatic patient where the KUB X-​ray and ultrasound are negative, no further imaging is required. If hydronephrosis and/​ or residual fragments are identified, further observation with repeat imaging or secondary treatment are necessary. Patients with radiolucent stones and no hydronephrosis who remain symptomatic or those who are asymptomatic, but have not passed fragments should be further observed with repeat imaging or intervention as indicated.

Metabolic evaluation There continues to be debate as to which patients should undergo comprehensive metabolic evaluation. In a meta-​analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis versus placebo, Pearle found clinical benefit in terms of reduced stone recurrence rates only in the groups offered specific medical therapy targeted at specific metabolic defects.32 Hence, allopurinol was effective only in studies with hyperuricosuria; thiazides worked best in patients with hypercalciuria; potassium citrate was effective only in patients with hypocitraturia. Conservative therapy alone without comprehensive metabolic evaluation does decrease stone recurrence. Dietary management alone decreases the rate of stone recurrence in 58% of patients with a range of metabolic conditions. A 71% and 47% reduction in stone formation in patients with hypercalciuria and hyperuricosuria while on high fluid intake and avoiding dietary excesses has been reported.33 That said, several studies report drug therapy to be more cost-​effective.34–37 Of note, the majority of models of cost-​ effectiveness are based on idiopathic calcium oxalate stone formers.

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Chapter 2.3 

Cost-​effectiveness of metabolic evaluation Concerns have been raised about the cost of preventive medical therapy versus no such treatment. Chandhoke evaluated the cost of metabolic evaluation, drugs, and doctor office visits with the cost of acute stone management.38 Data was collected from academic centres in 10 countries, which showed there was great variability in cost of medical and surgical therapies across various countries. For a recurrent stone former, the frequency of stone recurrence, at which medical therapy on the one hand and the cost of managing an acute stone episode on the other becomes equal for calcium stone disease ranged from 0.58 stones/​year in the United Kingdom to 4.4 in Germany. In other words—​medical prophylaxis becomes cost-​effective only if a stone recurs at least once every two years. With less frequent recurrence, the benefits at least in terms of cost, of metabolic evaluation combined with medical therapy, are questionable. However, the benefits in terms of enhanced quality of life and time lost from work, neither of which the study addressed, may shift the balance in favour of metabolic evaluation combined with medical therapy. First-​time stone formers are keen to pursue stone prevention strategies (metabolic evaluation and preventive therapy),39 which suggests that stone disease has a very significant impact on quality of life.

Patients requiring comprehensive metabolic evaluation Patients with non-​calcium stones, notably pure uric acid and cysteine stones, have additional significant metabolic abnormalities that require a more extensive metabolic evaluation. With the caveats noted above, patients with recurrent, multiple, bilateral, or residual calcium stone disease are likely to benefit from metabolic evaluation. Patients with stones that are difficult to treat (e.g. those with spinal deformities, other anatomic abnormalities that make renal access problematic, or morbid obesity) are also likely to benefit from a more thorough metabolic evaluation aiming at a preventive strategy. Box 2.3.2 gives a detailed list of patients at increased risk of stone recurrence, who are more likely to benefit from a comprehensive metabolic evaluation.

Metabolic evaluation in patients forming non-​calcium stones Patients with pure uric acid stones should have a 24-​hour urine for quantification of uric acid, pH, and creatinine (to assess adequacy of collection). Patients with cystine stones should also complete a 24-​ hour urine collection because they have an increased likelihood of associated metabolic abnormalities. Pure struvite stones do not require a metabolic evaluation. However, patients with stones with a mixed calcium component should undergo a comprehensive evaluation.

Metabolic evaluation for calcium stone formers A comprehensive metabolic evaluation currently involves collection of one or two 24-​hour urine studies on random diet.40 The major difference between this evaluation and the original comprehensive evaluation first described by Pak, is that different types of absorptive and renal leak hypercalciuria cannot be differentiated. All patients with normal serum calcium and hypercalciuria are treated with thiazide diuretics.

evaluation of stone formers

Box 2.3.2  Patients at high risk for recurrent stone disease ◆ History of recurrent stone formation ◆ Multiple stones ◆ Bilateral stones ◆ Children with stones ◆ Mixed struvite stones ◆ Uric acid stones ◆ Cystine stones ◆ Brushite stones ◆ Hyperparathyroidism ◆ Gastrointestinal diseases (inflammatory bowel disease, short bowel, gut diversions, malabsorption syndromes, bariatric surgery) ◆ Family history of stone disease ◆ Residual stone fragments (three months after stone therapy) ◆ Solitary kidney ◆ Transplanted kidney ◆ Nephrocalcinosis ◆ Bone disease ◆ Renal tubular acidosis type I ◆ Renal insufficiency ◆ Metabolic diseases (gout, diabetes mellitus type 2, metabolic syndrome) ◆ Stones that are difficult to treat because of anatomic abnormalities that make renal access problematic (e.g. spinal deformity, morbid obesity) ◆ Urinary tract reconstruction, solitary kidney, neuropathic bladder, special professions (e.g. pilots, frequent business travellers)

Prerequisites of 24-​hour urine collection Patients should be on their normal routine of diet and physical activity. Any urinary tract infection should be treated before the collection, as this may lead to abnormally high pH and hypocitraturia. The urine collections should not be performed during an acute stone event, but can be performed four to six weeks after stone passage or a urological intervention. It is not necessary that a patient be stone-​free during the collections, but they should not be obstructed or infected. The adequacy of collection can be checked by measuring total creatinine or creatinine/​kg and compared to standards. At Duke University Stone Center in the United States, we perform two 24-​hour urine collections on a random diet, followed by dietary or medicinal modification of urinary risk factors. Another 24-​hour collection is repeated in four months to confirm compliance, identify the need for dose adjustment, and identify side effects. We repeat the 24-​hour collection every six

107

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stones and endourology

months until urinary risk factors have stabilized, and then yearly thereafter.

Metabolic classification Once we have the results of metabolic evaluation and stone analysis, urological stone disease may be classified as calcium-​based nephrolithiasis and non-​calcium stones. Figure 2.3.1 gives the metabolic classification of nephrolithiasis.

Calcium-​based nephrolithiasis This includes calcium oxalate and calcium phosphate stones. Calcium oxalate stones are further classified into monohydrate and dihydrate. Calcium oxalate accounts for 40–​60% of stone disease, while calcium phosphate accounts for 2–​4% of stones.41 Patients with calcium-​based stones have a variety of metabolic abnormalities on 24-​hour urine samples. The most common diagnosis is low urine volume followed by hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, and gouty diathesis. Hypercalciuria is defined as a 24-​hour urine calcium greater than 250 mg in men and 200 mg in women. This is the most common abnormality found in stone formers. Hypercalciuria may be further classified into absorptive, renal leak, and resorptive hypercalciuria. This categorization is possible only with an extensive metabolic evaluation and the calcium fast and loading tests. Absorptive hypercalciuria results from increased calcium absorption from the intestinal tract, with fasting urinary calcium levels

being normal. Patients with absorptive hypercalciuria have normal serum paratharmone levels. The exact aetiology of absorptive hypercalciuria is not clearly defined, as both vitamin D-​associated as well as independent processes have been invoked to explain this effect. Patients with absorptive hypercalciuria type I  have increased urinary excretion of calcium despite being on a calcium-​restricted diet, whereas in type II, urinary calcium normalizes on diet restricted in calcium, but is high on a regular diet. Type III hypercalciuria is secondary to renal phosphate leak leading to low serum phosphate levels, which in turn stimulate increased vitamin D production, resulting in increased absorption of calcium and phosphate from the intestine. Renal leak hypercalciuria results from an intrinsic defect in the distal renal tubule leading to increased loss of calcium in urine. These patients have normal serum calcium levels, with mildly elevated levels of serum paratharmone to maintain calcium homeostasis. Resorptive hypercalciuria results from increased mobilization of calcium from bone as a result of primary hyperparathyroidism. This condition is diagnosed by increased serum calcium, low phosphate and increased intact parathormone levels (i-​PTH). Primary hyperparathyroidism causes stone disease only in 1–​2% of cases.42 Increased parathyroid hormone causes increased mobilization of calcium and phosphate from bone as well as increased production of vitamin D3 in kidneys, which in turn leads to increased absorption of calcium and phosphate from the intestine. There is selective

Metabolic Diagnosis

Hypercalciuria Hyperoxaluria Calcium-based: Ca-Oxalate Ca PO4

Absorptive hypercalciuria Renal leak hypercalciuria Resorbtive hypercalciuria

Increased absorption of calcium from intestine; renal leak of calcium, hyperparathyroidism

Enteric hyperoxaluria Dietary hyperoxaluria Primary hyperoxaluria

Hyperuricosuria Hypocitraturia

RTA, malabsorption syndromes, metabolic syndrome, drugs, acid ash diet

Hypomagnesuria Nephrolithiasis

Gouty diathesis

Non-calcium stones: Uric acid, Struvite, Cystine

Fig. 2.3.1  Metabolic classification of nephrolithiasis.

Uric acid nephrolithiasis

Gouty diathesis Hyperuricosuria

Cystinuria

Inborn error of metabolism

Struvite stones

Infection with urease producing organisms

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Chapter 2.3 

loss of phosphate from the kidneys. This action causes elevated serum calcium and low serum phosphate levels. Hyperoxaluria is defined as urine oxalate levels greater than 40 mg/​day. Hyperoxaluria occurs as enteric, dietary, and primary forms. Hyperoxaluria is most commonly due to increased oxalate absorption from the intestine—​enteric hyperoxaluria. This defect occurs in conditions leading to intestinal malabsorption. Normally the dietary calcium binds to oxalate to form complexes which are not absorbed. During intestinal malabsorption, excess of fatty acids bind with calcium to form salts, leading to increased availability of free oxalate, which is absorbed from the intestine. Poorly absorbed fatty acids increase the permeability of the colon to oxalate, further increasing oxalate absorption. This action may occur in a number of conditions including inflammatory bowel disease, short gut syndrome, bacterial overgrowth, blind loop syndromes, and so on. Patients with intestinal malabsorption also have a host of other metabolic abnormalities including low urine volumes secondary to intestinal fluid loss, mild metabolic acidosis due to intestinal alkali loss, hypocitraturia, gouty diathesis, and low urinary calcium levels because of complexation with fatty acids. Dietary hyperoxaluria occurs as a result of excessive intake of oxalate-​rich foods, especially in the realm of relative calcium restriction; very high doses of vitamin C (>2,000 mg/​day) may also cause hyperoxaluria because of conversion of ascorbic acid into oxalate in the liver. Hyperoxaluria also occurs as autosomal recessive inherited disorder known as primary hyperoxaluria. Type I hyperoxaluria results from deficiency of the enzyme alanine glyoxylate aminotransferase that catalyses conversion of glyoxylate to glycine in liver. Primary hyperoxaluria type II results from deficiency of the enzyme glyoxylate reductase in the liver, resulting in high oxalate levels. Type II hyperoxaluria has a less aggressive course with less occurrence of renal failure compared to type I, however it may lead to hyperoxaluric nephrolithiasis.43 Patients with primary hyperoxaluria and end-​stage renal failure require a combined kidney and liver transplant to prevent disease recurrence in the graft kidney.

Hyperuricosuric calcium oxalate nephrolithiasis This condition is defined as 24-​hour urine excretion of uric acid of more than 800 mg. Hyperuricosuria can lead to increased calcium oxalate stone disease by providing a nidus for calcium oxalate crystal deposition, a process known as heterogeneous nucleation or epitaxy.44 Rarely, these patients have a history of hyperuricemia and symptomatic gout. Patients with hyperuricosuria with normal urinary pH may form calcium oxalate stones, whereas those with hyperuricosuria and gouty diathesis (urine pH < 5.5) may form calcium oxalate or pure uric acid stones.45 Calcium phosphate stones are commonly associated with hyperparathyroidism and renal tubular acidosis. Such stones occur in two forms—​carbonate apatite and brushite. Carbonate apatite crystallization occurs at pH levels of ≥6.8, may be infection related, or may form mixed stones with calcium oxalate. Brushite crystallizes in a very narrow range of pH between 6.5–​6.8.

evaluation of stone formers

direct inhibitor of calcium oxalate crystallization and prevents heterogeneous nucleation of calcium oxalate by monosodium urate.46 Hypocitraturia has varied aetiologies, but is usually based on acid-​ base balance within the body such as renal tubular acidosis, hypokalaemia, increased animal protein diet, systemic acidosis, chronic diarrheal states, or thiazide diuretics. Renal tubular acidosis (RTA) is a heterogeneous disorder characterized by inability of the nephrons to acidify urine. Distal RTA type I is characterized by non-​anion gap metabolic acidosis with hyperchloremia, which is hypokalaemia with profoundly low urinary citrate levels.47 The urinary pH is consistently more than 6.5. Patients may have the complete or overt version with typical metabolic findings. The covert type or incomplete RTA has less profound hypocitraturia and normal urinary pH. This can be diagnosed by ammonium chloride loading test. The first voided urine specimen is sometimes used to identify type I RTA, these patients typically having a morning urinary pH no lower than 5.5. Renal tubular acidosis may also occur as an acquired disorder in conditions such as obstructive uropathy, pyelonephritis, analgesic nephropathy, acute tubular necrosis, renal transplantation, sarcoidosis, and primary hyperparathyroidism.48

Hypomagnesuria Magnesium is an important inhibitor of calcium oxalate stone disease and may be low in conditions such as inflammatory bowel disorders, excessive laxative use, or chronic thiazide use.

Non-​calcium nephrolithiasis These include patients with pure uric acid, cystine, and struvite stones.

Uric acid nephrolithiasis Uric acid stones are most commonly associated with gouty diathesis, defined as a urine pH less than 5.5. Low urine volumes with a normal acid load from a normal diet may cause significant lowering of urinary pH. The solubility of uric acid depends upon urinary pH, with more than 90% of uric acid being ionized and soluble at a pH of 6.5, but only 50% of uric acid being soluble at a pH of 5.5.49 Hyperuricosuria is rare in pure uric acid stone formers. Patients on cancer chemotherapy are predisposed to hyperuricosuria; however, the modern practice of prescribing allopurinol, a xanthine oxidase inhibitor, prevents high levels of uric acid.

Cystinuria Cystine stones form as a result of an inborn error of metabolism known as cystinuria. It is an autosomal recessive trait resulting in defective transepithelial transport of a number of amino acids at the level of renal tubule including cystine, ornithine, lysine, and arginine (COLA). In addition to cystinuria, patients with cystine stones often have a number of additional metabolic defects including hypocitraturia, hyperuricosuria, and hypercalciuria in 44.4%, 22.2%, and 18.5%, respectively.50

Hypocitraturia

Struvite nephrolithiasis

Hypocitraturia is defined as urinary citrate levels less than 450 in men and 550 in women. Citrate is an important inhibitor of calcium nephrolithiasis. It binds with calcium, decreasing availability of ionic calcium to precipitate oxalate or phosphate. It also acts as a

These stones are composed of magnesium ammonium phosphate. Struvite stones are associated with organisms which produce an enzyme urease, which converts urea, a major metabolite of protein metabolism, into ammonia. The ammonium hydroxide converts

109

10

110

Section 2  

stones and endourology

the urinary pH to alkaline, with pH levels exceeding 7.5 and ensuing precipitation of magnesium ammonium phosphate.51,52 Patients with pure struvite stones do not need a metabolic evaluation, whereas patients with a mixed composition (struvite plus calcium components) may have underlying urinary metabolic abnormalities, which may contribute to stone formation.50

Dietary risk factors identified from metabolic evaluation Low urine volume (20 weeks with torso trauma

2.  Anatomical triggers ◆ Penetrating

◆ >1

◆ Exposure

of patient

◆ Time

of incident

major long bone fracture (humerus/​femur/​tibia)

◆ Suspected ◆ Spinal

pelvic fracture

cord injury

◆ Significant

burn or enclosure with fire

◆ Amuptation

proximal to wrist or ankle

3.  Pre-​hospital triggers ◆ If

pre-​hospital information is reliable and fulfils the above criteria

◆ Multiple

trauma patients

4.  Mechanism triggers ◆

Fall >3 metres (or twice the approximate height of the child)

◆ Significant

Preparation and handover

◆ Age

trauma (except in a limb)

◆ Flail chest

◆ Disability

Most pre-​hospital care systems have a pre-​alert system for informing the likely receiving emergency department of a seriously injured patient coming in. This usually takes the form of a phone call either directly from scene or via the ambulance control room to the emergency department giving details which may include patient age, gender, mechanism of injury, suspected injuries, current observations, and an estimated time of arrival. This allows clinicians in charge of the emergency department to decide whether or not to activate their hospital trauma team, and in many departments, there are protocols to guide this process (see Box 4.8.1 and Table 4.8.1). In most hospitals, the trauma team is led by an emergency physician, and in MTCs in England this is mandated to be a consultant. The remainder of the team varies depending on the hospital, but the core typically consists of emergency physicians, anaesthetists, general surgeons, trauma, and orthopaedic surgeons, nurses, and operating department practitioners. The team leader may choose to involve other specialties at an early stage, such as urologists and neurosurgeons, should a relevant injury be suspected either from the pre-​alert or initial assessments. At the time of arrival in the department, the handover typically follows the ‘ATMIST’ sequence:

adults only:

•​ SBP 200 mL or a pelvic mass is suspected, then these should be undertaken.

Uroflowmetry This is a simple test which can be performed in most outpatient departments with a flow meter and an ultrasound bladder scanner. There are many important parameters which may be obtained from uroflowmetry (Fig. 5.1.1, Fig. 5.1.1A). These include the voided volume, which is the total volume of micturition. This must be greater than 150 mL if the flow rate is to be considered representative. The maximum flow rate (Qmax) is the flow rate at the peak of the curve after correction for artefacts. The flow time is the time over which measureable flow occurs and excludes interruptions when no flow

Investigations The term ‘the bladder is an unreliable witness’ was first coined with the knowledge that LUTS may not be disease specific and can be reported or documented inaccurately by the patient or investigator,

Flow rate (mL/s)

(B)

Flow rate (mL/s)

(A)

Qmax

Time (s)

Time to max flow Flow time

Qmax

Time (s)

(D)

Flow rate (mL/s)

(C)

Flow rate (mL/s)

410

Qmax

Time (s)

Time (s)

Fig. 5.1.1  (A) Normal flow rate recording showing parameters which may be interpreted. (B) A typical flow rate pattern for a patient with BPO: note the reduced Qmax, and prolonged flow time and time to Qmax. (C) A typical flow rate pattern for a patient with a urethral stricture (note the reduced Qmax and flat plateau flow pattern). (D) A typical flow rate pattern for a patient with detrusor sphincter dyssynergia: note the intermittent flow pattern.

 41

Chapter 5.1 

Table 5.1.2  The proportion of patients with BOO for the corresponding Qmax categories Qmax

Patients with BOO

14 mL/​s

30%

bladder outflow obstruction Void phase

Fill phase Cough Pabd

Pves Pdetmax

is recorded. The voiding time is the total time taken for voiding regardless of interruptions. The average flow rate is calculated by dividing the voided volume by the flow time. Time to maximum flow is the time from onset of flow to Qmax. The typical flow pattern in a male with BPO is described as ‘prolonged’ and is shown in Fig. 5.1.1B. The characteristic flow pattern for a urethral stricture is shown in Fig. 5.1.1C and is described as ‘flat’. Inappropriate sphincteric contraction during voiding will lead to an intermittent flow (Fig. 5.1.1D) and is seen in detrusor sphincter dyssynergia. Generally speaking, the Qmax in young healthy males is 30–​40 mL/​s and is 40–​50 mL/​s in females. With age the Qmax lessens and in men aged >60 years, a Qmax of 15 mL/​s may be acceptable and leads to no discernible symptoms. The post-​void residue in a normal individual should be minimal (60 years with the appropriate history, examination, and flow rate findings, a cystoscopy is seldom required. Treatment for benign prostatic obstruction can be commenced without cystoscopic evidence of obstruction, the only indication being a suspected bladder pathology in the context of marked storage symptoms, haematuria or abnormal urinalysis.

Cystometry (see Chapter 3.2) The use of cystometry (also called pressure/​flow urodynamics) in men with clear obstructive symptoms and a classical flow rate patterns is not necessary, prior to instituting pharmacotherapy. Its utility is more often reserved for patients with either mixed LUTS or chronic retention when detrusor overactivity and underactivity are questioned. In addition, patients who have failed bladder outflow obstruction surgery may undergo these studies. Nevertheless, in many centres it is considered useful as a preoperative diagnostic modality prior to surgery, although the evidence base for a predictive role in determining outcome of surgery is not yet proven. Cystometry is therefore the method by which the pressure/​volume relationship of the bladder is assessed. The term is taken to mean the measurement of detrusor pressure during filling and voiding. Put simply, a catheter with a transducer tip is inserted in to the bladder and another similar catheter is inserted in to the

Pdet

PdetQmax

Qmax Q(flow)

Fig. 5.1.2  Simplified cystometrogram demonstrating the calculation of PdetQmax: note the void phase is usually longer, but has been omitted for clarity.

rectum. The intravesical pressure is a consequence of the detrusor pressure and the abdominal pressure. Therefore, subtraction of the abdominal pressure from the intravesical pressure gives the detrusor pressure (Fig. 5.1.2). The remainder of this chapter will discuss the changes in the voiding phase of cystometry as the storage phase has been discussed elsewhere. The void phase produces a flow pattern as well as a detrusor pressure trace (Fig. 5.1.2). The flow patterns have been described above. The urodynamicist should also look at the pattern of detrusor contraction. This should rise, be sustained for a period to allow voiding, and fall as shown in Figure 5.1.2. One must be wary that the detrusor pressure is a calculated (subtracted) and any artefacts in the abdominal or intravesical lines may lead to erroneous interpretation of the detrusor pressure. Correctly subtracting cystometry lines should take account for abdominal straining without affecting the detrusor pressure. The detrusor pressure at the time of maximum flow is known as the PdetQmax. This is important because it allows the calculation of the bladder outlet obstruction index (BOOI). The BOOI has been validated in a male population. The BOOI = PdetQmax−​ (2*Qmax).3 If the BOOI >40 cmH2O then the patient is obstructed. BOOI 20–​40 cmH2O is equivocal and BOOI 40 cmH2O cut off for each Qmax value to signify obstruction, a BOOI150 cmH20 reflects strong bladder contractility, 100–​150 cmH2O is normal and

411

412

Section 5  

benign prostatic hyperplasia (A)

(B) 160 Severe obstruction (Zone 3)

Obstructed 90 40

70 Equivocal

20

PdetQmax (cmH2O)

PdetQmax (cmH2O)

412

110 Moderate obstruction (Zone 2) 60

Obstruction (Zone 1)

Unobstructed

0 Qmax (ml/s)

No obstruction (Zone 0) 25

0

Free Qmax (ml/s)

50

Fig. 5.1.3  (A) International Continence Society nomogram for the bladder outlet obstruction index; and (B) the Blaivas-​Groutz nomogram for female obstruction.

20 cmH2O.

Videocystometry Cystometry may be combined with concurrent fluoroscopic imaging of the bladder outlet which may help with the diagnosis.5 The urodynamicist looks at the bladder neck and urethra during a sustained detrusor contraction. This investigation gives a level for the obstruction, which guides the clinician to what may be causing the obstruction, which can be confirmed by appropriate other investigations.

Non-​invasive cystometry Due to the invasiveness of cystometry, a number of non-​invasive urodynamic investigations have been proposed. These provide either traditional cystometric measures in a non-​invasive manner, or they provide a surrogate marker of obstruction. Indirect isovolumetric bladder pressure may be assessed with the use of a penile cuff6 or a condom catheter.7 Alternatively, measures such as bladder wall thickness/​bladder weight8 and bladder vascular resistance9 as assessed by ultrasound have been reported as proxies to BOO. At the time of writing, all of these techniques are still considered investigational and have not entered routine practice. Ambulatory urodynamics has also been suggested as a potential diagnostic approach, particularly in patients with so-​called ‘bashful voiding’,

who cannot void during a urodynamic study, but also remains investigational at present.

Urethral pressure profilometry and electromyography Both of these two modalities have been evaluated but are not widely used in routine practice for male patients. These tests are reserved for women where neurological, iatrogenic, and local causes of BOO have been excluded. They are not essential and a diagnosis of Fowler’s syndrome can be made based on the history and cystometric findings. These women have high maximum urethral closure pressure, increased sphincteric volume, and characteristic striated urethral sphincter abnormalities.1

Further reading Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Subcommittee of the International Continence Society. Neurourol Urodyn 2002; 21(2):167–78. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: three simple indices to define bladder voiding function. BJU Int 1999; 84(1):14–15. Blaivas JG, Groutz A. Bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. Neurourol Urodyn 2000; 19(5):553–64. Chapple CR, MacDiarmid SA, Patel A. Urodynamics Made Easy, 3rd edition. London, UK: Churchill Livingstone Elsevier, 2009. DasGupta R, Fowler CJ. The management of female voiding dysfunction: Fowler’s syndrome—a contemporary update. Curr Opin Urol 2003; 13(4):293–9. Jones C, Hill J, Chapple C. Management of lower urinary tract symptoms in men: summary of NICE guidance. BMJ 2010; 340:c2354. Nitti VW, Tu LM, Gitlin J. Diagnosing bladder outlet obstruction in women. J Urol 1999; 161(5):1535–40. Sciarra A, D’Eramo G, Casale P, et al. Relationship among symptom score, prostate volume, and urinary flow rates in 543 patients with and without benign prostatic hyperplasia. Prostate 1998; 34(2):121–8.

References 1. DasGupta R, Fowler CJ. The management of female voiding dysfunction: Fowler’s syndrome—​a contemporary update. Curr Opin Urol 2003: 13(4):293–​9.

 413

Chapter 5.1 

2. Sciarra A, D’Eramo G, Casale P, et al. Relationship among symptom score, prostate volume, and urinary flow rates in 543 patients with and without benign prostatic hyperplasia. Prostate 1998: 34(2):121–​8. 3. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: three simple indices to define bladder voiding function. BJU Int 1999: 84(1):14–​15. 4. Blaivas JG, Groutz A. Bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. Neurourol Urodyn 2000; 19(5):553–​64. 5. Nitti VW, Tu LM, Gitlin J. Diagnosing bladder outlet obstruction in women. J Urol 1999; 161(5):1535–​40. 6. Harding C, Robson W, Drinnan M, et al. The penile cuff test: A clinically useful non-​invasive urodynamic investigation to diagnose men with lower urinary tract symptoms. Indian J Urol 2009; 25(1):116–​21.

bladder outflow obstruction

7. Huang Foen Chung JW, Spigt MG, Knottnerus JA, van Mastrigt R. Comparative analysis of the reproducibility and applicability of the condom catheter method for noninvasive urodynamics in two Dutch centers. Urol Int 2008; 81(2):139–​48. 8. Huang T, Qi J, Yu YJ, et al. Predictive value of resistive index, detrusor wall thickness and ultrasound estimated bladder weight regarding the outcome after transurethral prostatectomy for patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Int J Urol 2012; 19(4):343–​50. 9. Wada N, Watanabe M, Kita M, Matsumoto S, Kakizaki H. Analysis of bladder vascular resistance before and after prostatic surgery in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Neurourol Urodyn 2012; 31(5):659–​63.

413

41

CHAPTER 5.2

Urinary retention in men Mark Speakman Introduction to urinary retention Urinary retention continues to be a significant burden for both the patient and healthcare services in the United Kingdom and around the world. It is associated with a significant reduction in patients’ quality of life. In acute urinary retention (AUR), the impact of the pain may be equivalent to renal colic or childbirth; this is due to the sudden onset with the stretching of the bladder causing considerable pain.1,2 In chronic urinary retention (CUR), the onset is usually so slow that there may be no pain. Retention remains a complex subject, presenting in various ways as a result of numerous pathological processes. The abundance of definitions of retention in the literature, particularly for chronic retention, makes this more difficult to comprehend.3,4 In the past (20–​30 years ago) urinary retention was regarded as an immediate indication for surgery and in older reports, 25% to 30% of men who underwent transurethral prostatectomy (TURP) had AUR as their main indication.5 With the introduction of medical treatments and changes in practice for the management of retention, these rates have changed significantly.6

Definitions Let’s start with the basics; retention literally means the act or an instance of retaining (Oxford English Dictionary [OED]); from the Latin retinere to hold back or withhold. It does not, in essence, mean the inability to pass (urine); although this tends to be the medical usage of the term. While this medical definition works well for acute retention, the proper formal definition works better for chronic retention. Urinary retention is the inability of the bladder to empty to completion. This may be acute, chronic, or acute-​on-​chronic. AUR is the sudden painful inability to void. In CUR however, voiding is usually preserved until acute-​on-​chronic retention prevails which only occurs in a relatively small percentage of these patients. CUR is defined by the International Continence Society (ICS) as a non-​ painful bladder, which remains palpable or percussable after the patient has passed urine. In AUR, the volumes are typically between 500 mL and 1 L, while in CUR the retained volumes could be anywhere between 450 mL and 4.5 L, or even more. Abrams chose a residual urine volume of >300 mL to define CUR as the minimum volume at which the bladder becomes palpable suprapubically.4 Caution needs to be exercised in the study of CUR, as much of the knowledge comes from studies of the management of men with lower urinary tract symptoms (LUTS) undergoing medical or surgical treatments and these trials typically exclude men with large residual volumes or chronic retention.4

There are several international coding systems that code retention. The main two are: ◆ The

MeSH—​Medical Subject Headings classification; a comprehensive listing for the indexing scientific submissions in the life sciences and this records urinary retention as D016055.

◆ The

ICD-​9 and ICD-​10, the ninth and tenth editions of the International Classification of Diseases code urinary retention as 788.2 and R33, respectively.

Epidemiology The epidemiology of urinary retention can be studied from two principal sources; ◆ Firstly,

the population-​based longitudinal studies of untreated men—​community-​dwelling men with or without LUTS; and

◆

Secondly, from studies of men diagnosed with LUTS and entered into the placebo arms of randomized controlled trials for the treatment of LUTS.

Most of the epidemiological data in the literature is for AUR; data for chronic retention is relatively sparse.3,4 Older studies showed widely varying incidences of retention from 4 to over 100 per 1,000 person-​years.7,8 More recent and better-​controlled studies have shown that the incidence rate per 1,000 person-​years is more constant around the world; in the order of 5 to 25/​1000 person-​years or 0.5% to 2.5% per year. In the classic Olmsted County paper by Jacobsen and colleagues, it was 6.8/​1000 person-​years and in the famous Medical Therapy of Prostatic Symptoms (MTOPS) study, in the placebo arm it was a remarkably similar 2.4% over four years or 0.6% per year.9,10 However, in a review of placebo-​controlled trials by Emberton and colleagues, it was reported that the rate of AUR in placebo-​treated men in studies of 12–​48 months’ duration was 0.4–​6.6%.11 The explanation for these variations is that the risk of retention is not the same for all men (Box 5.2.1). It grows with increasing age and in men with markers for more significant disease such as increased symptoms or larger prostates. The Olmsted paper9 showed that AUR is relatively rare in younger men and in men with mild LUTS (AUA score 7 or less; broadly equivalent to the newer International Prostate Symptom Score [IPSS]). In this study, the incidence of AUR increased from 2.6/​1,000 person-​years among men 40–​49 years old to almost four times commoner in men 70–​79 years old (9.3/​1,000 person-​years). More significant symptoms at baseline were also a significant risk factor for greater progression to retention. The rate in men with moderate to severe symptoms (AUA score >7) increased from 3.0/​ 1,000 person-​years for men 40 to 49 years old to more than 10-​fold

 415

Chapter 5.2 

Box 5.2.1  Factors that have been identified as predictors of acute urinary retention (and lower urinary tract symptom-​related surgery)

Baseline variables ◆ Age ◆ Severe lower urinary tract symptoms (LUTS) ◆ Bother score ◆ A low peak flow rate ◆ Increased post-​void residual urine volume (PVR) ◆ Prostate size ◆ Serum prostate-​specific antigen (PSA) levels ◆ Prior acute urinary retention (AUR) ◆ Inflammation

Dynamic variables ◆ Worsening symptoms ◆ Increasing post-​void residual volumes in untreated men ◆ Non-​response to medical treatment (IPSS stable or worsening and increasing bother) greater at 34.7/​1,000 person-​years among men 70 to 79 years old. This shows that the impact of age and symptom severity together has a much greater impact than either risk factor alone. These authors also showed that flow rate and prostate volume would also predict for AUR risk with men having a maximum urinary flow rate 12 mL/​s, and that men with a prostate >30 mL had a 3-​fold increase in risk compared with those with smaller prostates.9 While in the important Proscar Long-​Term Efficiency and Safety Study (PLESS) study, analysis of the placebo arm revealed that the predictors of AUR were prostate volume, serum prostate-​ specific antigen (PSA) levels, and symptom severity.12 Subsequent analysis by both Emberton and Roehrborn has added further understanding to this issue with greater clarity of the risk factors for LUTS/​benign prostatic hyperplasia (BPH) progression and the increasing risk of retention, including PSA >1.4 and non-​response to medical treatments.11,13 Marberger in particular showed in an analysis of the placebo arms of three finasteride randomized controlled trials (RCTs) that benign prostatic enlargement (BPE) patients with larger prostate volumes and higher PSA levels have an increased risk of developing AUR. He suggested therefore that they might derive the greatest benefit from the risk reduction seen with finasteride therapy.14 He showed that PSA had an even greater predictive value than prostate volume in calculating the risk of retention. In addition, dynamic variables such as worsening symptoms and increasing post-​void residual volumes in untreated men serve as good predictors of AUR in men with LUTS.15 Also non-​response to medical treatment (IPSS stable or worsening and increasing bother) predicts a greater risk of AUR, or needing prostate surgery.16 One retrospective cohort study in the Netherlands of 56,958 males showed that the incidence rate of AUR overall was very low at 2.2/​1,000 man-​years. However, AUR was the first symptom of

urinary retention in men

LUTS in half (49%) of the 149 AUR cases that occurred. The risk of AUR was 11-​fold higher in patients newly diagnosed with LUTS (RR 11.5; 95% CI: 8.4–​15.6) with an overall incidence rate of 18.3/​ 1,000 man-​years (95% CI: 14.5–​22.8).17 The incidence of retention has changed over time and one study using data from the Hospital Episode Statistics (HES) database of the Department of Health in England from 1998 and 2003, based on the ICD10 coding system analysed data from 165,527 men who were identified to have been hospitalized with AUR in the study period.18 The incidence of primary AUR was 3.06/​1,000 men yearly. It was spontaneous in 65.3% of cases. The incidence of AUR decreased from 3.17/​1,000 men yearly in 1998 to 2.96/​1,000 yearly in 2003. Surgical treatment following spontaneous AUR decreased by 20% from 32% in 1998 to 26% in 2003. This trend coincided with a 20% increase in the rate of recurrent acute urinary retention.18 These authors suggested that the slight decrease in the incidence of AUR may be due to the increased use of oral drug treatments, and the subsequent move away from initial surgical treatments for LUTS has not resulted in an increase in AUR. However, they suggest that the increase in recurrent AUR indicates that the observed decrease in surgery after AUR may have put more men at risk for AUR recurrence.18 The 2010 HES for England alone recorded 18,000 admissions with AUR. Interestingly, urinary retention appears to be significantly more common in the colder winter months than the warmer months;19 and in one community-​based study, men who currently smoke may be at a modestly reduced risk of AUR.20 Inflammation has also been shown to be an important putative risk factor for retention. In a subgroup analysis of the MTOPS study, not a single patient who did not have inflammation on their baseline biopsies developed AUR in the four years of the study.21 Further support for this hypothesis came from an epidemiological study in men with rheumatoid arthritis, where a group that needed to take daily non-​steroidal anti-​inflammatory drugs (NSAIDs) were compared with a control group who did not. The rate of LUTS, poor flow and even the risk of an enlarged prostate were all significantly lower in the arthritis group taking regular NSAIDs.22 The use of NSAIDs therefore may reduce the risk of AUR, although properly constructed RCTs are required to test this hypothesis. Overall, it was calculated by Roehrborn that a 60-​year-​old man would have a 23% probability of experiencing AUR if he were to reach the age of 80.13 Retention is over ten times more common in men than in women and AUR is rare in male children and is then usually associated with infection, with or without phimosis, or occurs postoperatively.23,24 More recently, the resistive index of the prostate capsular arteries measured by colour Doppler transrectal ultrasound has been shown to be both a good predictor of retention and to correlate very accurately with urodynamic obstruction. This may become a good predictor of risk in certain patient subgroups.25,26 There is, however, the potential for bias when the placebo arms of clinical trials are used to characterize the natural history of the LUTS disease compared with the outcomes in community-​dwelling men. One study comparing the Olmsted County data with the placebo data from the MTOPS study showed that the rates of AUR and those for symptom progression were, perhaps surprisingly, higher in the community patients than the placebo-​treated patients, while the likelihood of any surgical intervention was almost double in the clinical trial group.27 In the Olmsted County study, incidence

415

416

416

Section 5  

benign prostatic hyperplasia

rates per 1,000 person-​years were 8.5 (95% CI, 6.4–​11.2) for AUR; 97.1 (95% CI, 88.7–​106.0) for symptom progression, 6.6 (95% CI, 4.8–​9.0) for any surgery; and 105.1 (95% CI, 96.4–​114.4) for any outcomes for all men. For the smaller cohort who would have met the MTOPS trial inclusion criteria, incidence rates were higher at 18.3, 86.5, 16.8, and 109.4, respectively. By comparison, incidence rates per 1,000 person-​years for the placebo arm of the MTOPS study were 6 for AUR, 36 for symptom progression, and 45 for any outcome. Extrapolation therefore from one study to another must be done with care.27

Aetiology Aetiology is the understanding of why things occur—​the factors that come together to cause the abnormality or illness. It is derived from the Greek αἰτιολογία, aitiologia. Essentially most causes of retention are due to delayed voiding from a variety of causes, leading to overdistension of the bladder thereby reducing the ability of the bladder to contract normally, resulting in retention. Overdistension may lead to detrusor decompensation if it is prolonged. This was suggested a long time ago and is frequently forgotten.28

Acute retention Acute urinary retention is usually characterized by the sudden, painful inability to void; painless AUR is rare and when it occurs is often associated with neurological abnormalities. AUR may be further subdivided into precipitated or spontaneous retention.1,3,6 Precipitated AUR follows a triggering event such as anaesthesia, surgery, or the use of drugs with a sympathomimetic effect (see Box 5.2.2). All other AUR events with no prior triggering event should be classified as spontaneous. Spontaneous retention is most frequently associated with LUTS and BPE, and is regarded as a sign of disease progression. Urinary retention has been described with the use of drugs with anticholinergic activity (e.g. antipsychotic drugs, antidepressant agents, and anticholinergic respiratory agents), opioids and anaesthetic agents, alpha-​adrenoceptor agonists, benzodiazepines, NSAIDs, detrusor relaxants, and calcium channel antagonists. The differentiation between precipitated and spontaneous retention is clinically important because prostate surgery is less commonly needed in patients with precipitated AUR; as they are more likely to have a successful trial without catheter (TWOC). Box 5.2.2  Factors that can trigger precipitated acute urinary retention

Precipitated acute urinary retention may be triggered by: ◆ Bladder overdistension ◆ Surgery with either general or regional anaesthesia ◆ Excessive fluid intake ◆ Alcohol consumption ◆ Urinary tract infections ◆ Prostatic inflammation ◆ Use of drugs with sympathomimetic, anticholinergic, or antihistamine effects

In addition, the likelihood of recurrent AUR is more likely in the spontaneous group. The exact initiating cause of the retention may be unclear in many cases but the following mechanisms have been suggested: (i) Increased resistance to flow of urine (obstructive); either mechanical (e.g. urethral stricture, clot retention) or dynamic obstruction (e.g. increased α-​adrenergic activity, prostatic inflammation) (ii) Bladder overdistension (myogenic); (immobility, constipation, drugs inhibiting bladder contractility) (iii) Neuropathic causes in the sensory input or the motor output of the detrusor muscle (e.g. spinal disease, diabetic cystopathy)

Postoperative retention Although this could be seen as just one of the many causes of AUR or sometimes CUR, it merits consideration separately as well. Its rate is highly variable.29 It is more common after pelvic surgery; for example, anorectal, gynaecological, or urological, as well as after perineal and anal surgery, and of course after surgery of the lower urinary tract, particularly with traumatic instrumentation. Many factors can contribute to this risk, including30,31: ◆

major laparotomy especially if the period of anaesthesia is greater than 60 minutes;

◆ muscle

paralysis and ventilation and cases that were reversed by atropine and neostigmine;

◆ opiate

analgesia, particularly if used intravenously;

◆ excessive

intravenous fluids resulting in bladder distension;

◆ diminished ◆ pre-​existing

awareness of bladder sensation; increased bladder outlet resistance;

◆ postoperative ◆ prolonged

pain (nociceptive inhibitory reflex);

immobilization in the postoperative period.

Patient age and sex may be less important, other factors being equal. Perhaps one of the greatest tragedies is post-​partum retention. Once again, bladder distension secondary to decreased awareness of bladder sensation may be more important than local pain or anxiety.

Chronic retention The aetiology of chronic retention (CUR) is more complex but can usefully be divided into high-​pressure chronic retention (HPCR) and low-​pressure chronic retention (LPCR).32–​34 The terms ‘high’ and ‘low’ refer to the subtracted detrusor pressure, during urodynamic studies, at the end of micturition (i.e. at the start of the next filling phase).33,34 Bladder outlet obstruction usually exists in HPCR and the voiding detrusor pressure is high, but is associated with poor urinary flow rates. The persistently high bladder pressure in HPCR during both the storage and voiding phases of micturition results in retrograde pressure on the upper tract and leads to bilateral hydronephrosis and varying degrees of renal dysfunction. However, other patients may have large-​volume retention in a very compliant floppy bladder with no evidence of hydronephrosis and normal renal function, and these are said to have LPCR. Pressure flow studies in these men with LPCR reveal poor flow rates, low detrusor pressures, and very large residual volumes. The LUTS in both types of CUR, however, are usually mild especially in the

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Chapter 5.2 

early stages of their condition, until typically the onset of nocturnal enuresis, resulting from the drop in urethral resistance during sleep, which is overcome by the maintained high bladder pressure causing incontinence—​sometimes inappropriately called overflow incontinence.33,34 Some authors like to break the causes of retention into anatomical, myogenic, pharmacological, functional, and psychogenic, but in practice the cause is usually multifactorial and therefore this is not always of much benefit in real life practice. In young male adults in particular, the use of psychoactive substances, such as stimulants like MDMA (ecstasy) and amphetamine should not be overlooked. The condition of paruresis or shy bladder syndrome, where there is the inability to urinate in the presence of others (such as public toilets), should not be forgotten.35,36

Pathogenesis The pathogenesis of a condition or disease is the description of the underlying mechanism that causes the disease. It comes from the Greek for pathos, ‘disease’, and genesis, ‘creation’. The evidence base for pathogenesis is less robust than that for the aetiology.

urinary retention in men

colleagues reported an increased incidence of prostatic inflammation in men with AUR compared with men with LUTS.41 More recently in another study, chronic inflammation was more commonly found in the prostate from resections for AUR than in those specimens from men operated upon for LUTS alone.42 This is further supported by evidence suggesting that prostatic inflammation may be a predictor of BPH progression.43,44 In a British study of TURP, 374 patients were studied regarding the finding of acute or chronic inflammation in the resection specimens. Seventy per cent (70%) of men undergoing TURP for retention against only 45% of men undergoing TURP for LUTS alone were found to have inflammation.45 Regarding logistic regression, the pathological factors associated with TURP for acute retention compared to that for LUTS were more powerful for the presence of acute or chronic inflammation than for prostate volume, using increasing resection weight as a proxy for prostate volume.45

Increased α-​adrenergic activity

(iv) Decrease in the stromal: epithelial ratio

Some cases of AUR are associated with a rise in the prostatic intraurethral pressure through an increase in α-​adrenergic stimulation (e.g. stress, cold weather, sympathomimetic agents used in cold remedies, and so on). Prostatic infarction or prostatitis may contribute to this process. Bladder overdistension also leads to increased sympathetic adrenergic tone.46 The overdistension can lead to ischaemic injury of the detrusor muscle. Prolonged bladder overdistension leads to a temporary neurogenic detrusor dysfunction, which is associated with decreased or absent bladder sensation; therefore patients do not complain, and management is delayed.

(v) Neurotransmitter modulation

A decrease in the stromal: epithelial ratio

Pathology and pathogenesis Five factors have been implicated in pathogenesis: (i) Prostatic infarction (ii) Prostatic inflammation (iii) Increased α-​adrenergic activity

Prostatic infarction The finding of prostatic infarction caused by infection, instrumentation, and thrombosis, is far more common in prostatectomy specimens after AUR than in TURP specimens for LUTS alone. This has been suggested in many studies as an underlying cause of retention. In a study of 100 patients, Spiro and colleagues found evidence for infarction in 85% of prostates removed for AUR, compared with only 3% in prostates of men having surgery for LUTS alone.37 They suggested that the infarction resulted from distortion of the prostatic intraglandular blood supply. Other possible causes would include infection stasis, thrombosis, atherosclerosis, and embolization.23,38 This may develop because of the accumulation of activated lymphocytes and up-​regulation of pro-​inflammatory cytokines resulting in tissue destruction and subsequent tissue rebuilding perhaps contributing to these prostatic infarcts.23,39 A newer hypothesis is that the prostatic infarction may also lead to neurogenic disturbance in the prostatic urethra, preventing relaxation of the prostatic urethra, leading to a rise in urethral pressure and subsequent AUR.23 This finding appears to be more common in spontaneous than in precipitated AUR.

Prostatic inflammation Much of the pathophysiology of BPH development involves an underlying inflammatory disorder with a strong association with non-​insulin dependant diabetes and metabolic syndrome.39 There is a statistically significant association between inflammation and both BPH severity and progression to AUR. Kramer and Marberger also reported that inflammation was associated with larger prostates, higher PSA levels, and a greater risk of AUR.40 Truncel and

This has been noted in AUR. This may in part explain the effect of the agents finasteride and dutasteride, which are known to act mainly on the epithelial component of the prostate, thereby increasing the stromal:epithelial ratio and may explain how they are able to reduce the risk of retention. Choong and Emberton suggested that it was feasible to bring these three mechanisms together by postulating that changes in epithelial/​stromal growth in BPH may result in prostate infarction through changes in the prostatic blood flow. This in turn leads to a rise in urethral pressure indirectly increasing adrenergic tone resulting in increasing obstruction.23

Neurotransmitter modulation Alterations in the non-​adrenergic, noncholinergic transmitters (e.g. vasoactive polypeptide (VIP), neuropeptide Y (NPY), substance P) has been postulated as another underlying cause. These may act by influencing the release of acetylcholine and noradrenalin, and will also impact on bladder wall blood flow.47 In conclusion, bladder outlet obstruction if present leads to hypertrophy of detrusor smooth muscle cells, leading to detrusor wall thickening and increase in bladder mass, increased collagen synthesis, and deposition. In parallel, the bladder overdistension leads to high intravesical pressures that cause detrusor ischaemia, this leads to the release of neurotransmitters like ATP, NO, and prostaglandin from the urothelium. The obstruction may also lead to partial denervation of the detrusor, supersensitivity of muscarinic receptors to acetylcholine,48 reorganization of the spinal micturition reflex, neurotramsmitter imbalance, and changes in the electrical properties of detrusor smooth muscle cells. Consequently, this leads to deterioration of bladder contractility

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and reduced compliance. This multiplicity of factors will decide whether changes are reversible or irreversible.46,49–​51

Presentation, initial assessment, and investigation Acute retention The most common presentation is a patient with lower abdominal pain, an inability to pass urine (or passing only very small amounts of urine), and a palpable mass arising from the pelvis, which is dull to percussion. Although it is usually stated that patients with AUR did not have previous LUTS, it is more likely that many of these patients had not recognized or complained of these symptoms before. That is, they may have either not recognized their significance or assumed them to be an inevitable consequence of ageing. Examination should include a digital rectal examination noting the size and texture of prostate, anal tone, and the presence or absence of constipation. Although AUR is primarily a clinical diagnosis, a bladder volume scan (if available) will further confirm the diagnosis before catheterization. The volume drained is usually less than 1 L. If the volume drained is 1 L or more, this can be used as a distinction between acute and acute-​on-​chronic retention, particularly if associated with less pain (a finding that is more typical of CUR.24

retention may also occur secondary to any of the above conditions; it is therefore important for the patient to be re-​examined soon after catheterization to confirm that the symptoms and signs have resolved. In addition, any patient with an abdominal mass should be considered for catheterization to exclude a distended bladder prior to further examination or investigation. Occasionally, an obese patient with renal failure may be mistaken for a case of AUR.

Management Acute retention The treatment of acute retention is urgent catheterization. This may be urethral or suprapubic catheterization, and this decision is usually based on a combination of factors. Whether patients are catheterized at home by a GP or district/​practice nurse, in an accident and emergency department, or in a surgical/​urology ward depends mainly on local circumstances, as does the decision to admit or send the patient home after catheterization. If patients are kept in hospital awaiting definitive treatment, this results in an overall longer total hospital stay.6 The initial urine volume, typically drained in the first 10–​15 minutes following catheterization, must be accurately recorded in the patient’s notes, to enable a distinction between acute and

Chronic retention CUR occurs when patients retain a substantial amount of urine in the bladder after each void. As already stated, a defined volume for CUR is difficult and the finding of persistent residual volumes of >300 mL (some authors suggest >500 mL) after voiding is often used as evidence of chronic retention; some patients however may present with many litres in their bladders. Patients may be asymptomatic or describe low volume micturition, increased frequency, or difficulty initiating and maintaining micturition. Other features of CUR include nocturnal incontinence, a palpable but painless bladder, and signs of chronic renal failure. LUTS are less common and generally less bothersome.

Acute retention

Catheterize Urethral, suprapubic or CIC

Measure & record volume

Assessment In both types of retention, urinalysis should always be performed and a catheter specimen of urine sent if there are signs of infection:  urinary infection should be treated. Urea, creatinine and electrolytes, and an eGFR should be checked; this is especially important in (high pressure) CUR. Renal ultrasound is indicated in patients with high-​volume retention and in patients with abnormal renal function. Prostate-​specific antigen testing is best avoided during the acute episode, since retention and any instrumentation of the prostate leads to a spurious rise in PSA.52,53 Bladder volume per se will not separate LPCR from the more serious HPCR. In the author’s unit within the last three months, two contrasting men with chronic retention were admitted. One had 1.3 L in the bladder, a creatinine of over 900 and bilateral hydronephrosis; and another patient a few days later with 6.5 L in the bladder and a normal creatinine, and only the slightest degree of hydronephrosis.

Test urine & consider renal function tests

Start alpha blocker & after 2 doses

TWOC

Successful TWOC

Unsuccessful TWOC

Monitor LUTS & review medication

Re-TWOC, TURP, ISC or LTC

Differential diagnosis This is not usually difficult, but diverticulitis or a diverticular abscess, perforated or ischaemic bowel, or an abdominal aortic aneurysm are all recognized as potentially more serious conditions that can be referred into hospital as ‘acute retention’. Urinary

Fig. 5.2.1  Acute retention.

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Chapter 5.2 

acute-​on-​chronic retention to be made. This has important clinical implications (Fig. 5.2.1).

Chronic retention The management of CUR is more complex. Catheterization is less urgent as the condition is generally less painful or painless. Early catheterization is indicated if there is renal dysfunction or upper tract dilatation; both signs of HPCR. These patients with HPCR must be monitored for a postobstructive diuresis. They may pass many litres of urine in the first few days following catheterization (Fig. 5.2.2). The diuresis is due to: ◆

off-​loading of retained salt and water (retained in the weeks prior to the episode of retention);

◆ loss

of the corticomedullary concentration gradient. This is caused by reduced urinary flow through the chronically obstructed kidney;

◆ osmotic

diuresis caused by the high urea level.

urinary retention in men

In about 10% of cases, the diuresis is excessive and could require careful fluid balance and replacement. Daily weighing can be an accurate way of monitoring fluid output. After the first 24 hours, fluid replacement should not religiously follow the output, which would simply perpetuate the diuresis. Potassium levels, which are often high, should be monitored and will usually (but not always) fall with the diuresis. Catheterization is often followed by haematuria; this is caused by renal tract decompression and not usually by the catheter itself. If patients present with chronic retention electively through the outpatient department, the indications for catheterization before TURP in cases of CUR are again renal impairment and water and salt retention; otherwise it is best to avoid catheterization to avoid infection and bladder shrinkage before TURP, but the patients should be listed for early surgery once their renal function is stable. Many patients with LPCR do poorly after TURP, frequently failing to void completely after surgery, even after prolonged periods of catheterization; this is primarily due to detrusor decompensation.32,54,55 Intermittent self-​catheterization should be considered in this group.

Chronic retention

Measure renal function and scan kidneys

Abnormal renal function or hydronephrosis [HPCR]

Normal renal function and kidneys [LPCR]

Catheterize

Consider catheter only if symptomatic

Measure & record volume

If fit

If unfit

Monitor renal function & electrolytes

Consider TWOC, TURP or ISC

Monitor LUTS & renal function +/– catheter

Consider TURP, ISC or LTC

Monitor LUTS, renal function & review

Fig. 5.2.2  Chronic retention.

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What should be the speed of bladder emptying? Rapid emptying of an extended bladder in urinary retention is often considered dangerous because of the risk of haematuria or circulatory collapse. Therefore, many papers and textbooks advise the use of gradual drainage of the bladder. A recent German RCT of rapid or gradual emptying of 260 men has been performed to address this issue.56 Haematuria occurred in similar numbers in each group (11%), only half of whom required further treatment for this reason. There were no cases of circulatory collapse in this study. Reduction in blood pressure and pulse rate were not clinically significant in either group. In conclusion, the practice of slow decompression is unnecessary and haematuria usually settles after 48–​72 hours.56

A trial without catheter The increased morbidity and mortality associated with emergency surgery, particularly when performed shortly after AUR, and the potential morbidity associated with prolonged catheterization (bacteriuria, fever, urosepsis) has led to an increasing use of a TWOC. It is now considered a standard of care in most countries around the world and is utilized in most patients with acute retention, and in a significant number of patients with LPCR.6,55 The catheter is usually removed after one to three days, allowing the patient to successfully void in approximately half of cases. This enables these patients to go home without the morbidities associated with an in situ catheter. In addition, this allows surgery to be delayed to an elective setting if significant symptoms persist or may prevent the need for surgery in some1,57. Factors leading to a higher probability of successful TWOC include1,57: ◆ Lower

age (1 L

◆ previous LUTS

◆ voiding

detrusor 10 mm

However, even if an initial TWOC is successful, half of these men will experience recurrent AUR over the next year and a third will require surgery within the following six months. Patients with PVR>500 mL, no precipitating factor for AUR, and maximum flow rate 10 mm.60 Also in the Olmsted County study, IPP correlated significantly with greater prostate volume, lower peak flows, and higher obstructive symptoms, thereby suggesting that it may have clinical usefulness in predicting the need for treatment.61 In another study of IPP in 100 men with AUR, only 33% of men with an IPP greater than 10  mm had a successful TWOC, while 64% of men with IPP from 1 to 5 mm had a successful one,62 and in a recent presentation at the ICS meeting in Beijing, a 10-​fold difference in the rate of AUR (20% vs. 2%) with an IPP either side of 10 mm was reported.63

Should patients with high-​pressure chronic retention undergo trial without catheter? If there is evidence of renal failure, which settles with catheterization, the patient should not undergo a TWOC before a definitive procedure has been considered. Even though they might void again after TWOC, the risk of ongoing renal dysfunction is too great and definitive treatment is required.

The use of alpha blockers before trial without catheter The use of an alpha blocker, taking typically two or more doses before TWOC, increases the likelihood of a successful outcome. In a study of 360 men with a first episode of spontaneous AUR randomly assigned to receive 10 mg alfuzosin or placebo, successful TWOC was recorded in 61.9% of the 236 patients treated with alfuzosin vs. 47.9% of the 121 receiving placebo (p = 0.012).59 Elderly patients (65 years or older) and patients with a drained volume of 1,000 mL or greater had significantly greater chances of TWOC failure. Even in the presence of these two factors, 10 mg alfuzosin once daily almost doubled the likelihood of successful TWOC (OR 1.98, 95% CI 1,226 to 3,217). In the second phase of the study, all patients with successful TWOC were randomized to alfuzosin or placebo for six months.64 The need for BPH surgery (primary end point) was assessed after one, three, and six months of treatment. In this phase, 14 (17.1%) of the 82 alfuzosin-​treated patients versus 20 (24.1%) of the 83 placebo-​treated patients required BPH surgery, 5 (36%) of 14 versus 13 (65%) of 20 within one month, and 8 (57%) of 14 versus 17 (85%) of 20 within three months of treatment. Higher PSA values and larger post-​TWOC residual urine volumes significantly increased the risk of AUR relapse and subsequent outflow surgery. Similar work by Lucas and colleagues with tamsulosin confirmed these findings.65 They showed that 48% of their patients taking tamsulosin versus 26% of men taking placebo did not require recatheterization (p = 0.011; odds ratio 2.47).

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Chapter 5.2 

Five randomized clinical trials of alpha blockers before TWOC were reviewed in a Cochrane systematic review in 2009.66 Four trials used alfuzosin and one tamsulosin. In four, the alpha blocker was used for 24–​72 hours before TWOC and in one study for eight days. Overall rates of successful TWOC favoured alpha blockers over placebo (RR 1.39, 95% CI 1.18–​1.64) irrespective of the alpha blocker used (alfuzosin: RR 1.31, 95% CI 1.10–​1.56; tamsulosin: RR 1.86, 95% CI 1.17–​2.97).66 In real life practice, the Reten-​World survey revealed that 82% of patients received an α1-​blocker before catheter removal; TWOC success was greater in those receiving α-​ blockers, regardless of age.57 This policy allows more patients to return home without a catheter in situ, thereby perhaps reducing the subsequent perioperative complications of prostate surgery. This should contribute to decrease the morbidity and mortality associated with emergency surgery and avoids the discomfort and potential morbidity associated with an in situ catheter.

Increased mortality in retention patients Mortality is increased after retention. The rate within the year following an AUR episode is significantly higher than in the general population, especially in younger patients. Mortality in men admitted to hospital with AUR is strongly correlated with age and co-​morbidity. Men with AUR have a high risk of developing complications and a greater risk of death after prostatectomy than men having surgery for LUTS alone.67 In a study of one hundred thousand men who presented with spontaneous AUR,68 Armitage and colleagues reported that the one-​year mortality was 4.1% in men aged 45–​54 and 32.8% in those aged 85 and over. In another 75,979 men with precipitated AUR, mortality was higher at 9.5% and 45.4%, respectively. One-​year mortality was considerably higher in those patients (aged 75–​84) with co-​morbidities. Meanwhile, in men with spontaneous AUR it was 12.5% in men without co-​ morbidity and 28.8% in men with co-​morbidity and 18.1% and 40.5%, respectively, in those with precipitated retention. Compared with the general population however, the highest relative increase in mortality was in men aged 45–​54 (standardized mortality ratio 10.0 for spontaneous and 23.6 for precipitated acute urinary retention) and the lowest for men aged 85 years and over (1.7 and 2.4, respectively). The mortality was higher in patients with precipitated rather than spontaneous retention, perhaps because precipitated retention occurs after a triggering event that is unrelated to the prostate, and therefore a further indication of co-​morbidity. It was suggested therefore that patients would benefit from a multidisciplinary approach to identify and treat co-​morbid conditions before surgery. The current main morbidities include diabetes, hypertension, cardiovascular disease, and metabolic syndrome. It was also shown by the UK National Prostatectomy Audit that immediate surgery after AUR was associated with a greater perioperative morbidity and death rate after surgery at 30  days (RR 26.6) and 90 days (RR 4.4) when compared with elective prostatectomy for symptoms alone.67 In a more recent study of over 400 men in Taiwan, the rates of recatheterization, septicaemia, and shock were highly significantly more common in the TURP after AUR group, than in those having TURP for symptoms alone.69 The AUR group also had more UTIs.

Hospitalize versus send home The decision regarding whether to admit patients to hospital or send them home from accident and emergency or a surgical

urinary retention in men

assessment unit is based more on local resources and preferences than any evidence-​based protocol. A UK survey found that most urologists (65.5%) preferred to admit their patients, with only 1 in 5 urologists admitting only in the presence of abnormal renal function.70 Admission is essential if the patient is:  unwell with urosepsis; has abnormal renal function needing investigation and fluid monitoring; has acute neurological problems; or cannot take care of the catheter.53 A recent publication from China showed that the establishment of an ambulatory care programme for patients presenting to their emergency department with AUR reduced the hospital admission rate and reduced cost without jeopardizing the TWOC success rate and patient safety.71

Urethral versus suprapubic catheterization Apart from specific indications, such as after urethral trauma and for long-​term catheterization for bladder dysfunction, suprapubic catheterization (SPC) has perceived advantages for the management of retention. The principal advantages of SPC are reduction in UTIs, less stricture formation, and the fact that it permits TWOC without catheter removal.72–​74 Patients therefore frequently express a preference for SPC because of its increased comfort, and the ability to maintain active sexual function is important to some patients. As a significant number of patients will fail their TWOC, patients will often have to undergo repeat catheterization with all the consequent discomfort. Many studies have shown the benefits of SPC in AUR. It could therefore be regarded as the preferred route of catheterization. However, the suprapubic approach is often overlooked when deciding on the mode of catheterization. In the Reten-​World survey, it was reported that a majority of urologists performed urethral catheterization (>80%) with suprapubic catheters inserted for urethral catheter failures.57 This survey also reported similar complication rates for both types of catheter. Surprisingly, there was no difference in asymptomatic bacteriuria, lower urinary tract infection, or urosepsis between the two catheter types. This may have been due to the fact that this was not an RCT, but rather a study of real life practice, and the indications for the type of catheterization were not standardized. Urethral catheters however were associated with an increased incidence of urinary leakage. Disadvantages associated with SPC insertion are that it is a more complex procedure, which not all health professionals are adequately skilled to perform. Serious complications, such as bowel perforation, posterior bladder wall injury, and peritonitis have been reported.74,75 SPC safety will have reduced with the introduction of the safer Seldinger technique SPC catheter, which replaces the traditional blind insertion of the trocar and cannula with SPC insertion over a guidewire.75–​77 Wherever possible this should be performed under ultrasound guidance,75,78 as per the recommended advice of the British Association of Urological Surgeons’ (BAUS) guideline.78 This technique has been shown in a small study to be associated with increased patient satisfaction and clinician confidence.77 This, together with the use of simulation and models, should in the future support the training of junior doctors, thereby allowing the use of SPC insertion in the emergency setting to become more widespread.79

The role of clean intermittent self-​catheterization Clean intermittent self-​catheterization (CISC) is a viable alternative to an indwelling catheter. It is a safe, simple, and generally well-​ accepted technique by patients that results in fewer infections than indwelling urethral catheterization. Without any external devices,

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maintenance of sexual activity is possible. It may also increase the rate of subsequent successful spontaneous voiding. CISC can be used either instead of an indwelling catheter after an episode of AUR or CUR, or in patients who fail to void following a prostatectomy. This is can be particularly valuable in patients with neurological bladder dysfunction. A  period of CISC prior to TURP may be useful in patients with low-​pressure CUR, as it may allow recovery of bladder contractility. A retrospective analysis of over 500 patients showed that in-​out catheterization for the treatment of AUR was as effective as indwelling catheterization and was likely to be particularly successful for younger men and those with lower residual volumes.80 In a randomized study of men with CUR and preoperative urodynamics before TURP, a low detrusor voiding pressure was associated with a poor TURP outcome.81 Preoperative CISC rather than indwelling urethral catheterization was associated with a significant improvement in voiding and end-​filling pressures, indicating some recovery of bladder function. The authors concluded that a preliminary period of CISC before TURP for men with CUR and low voiding pressure might be valuable.81

Prevention of acute urinary retention If one considers the pain and discomfort from AUR, the considerable healthcare costs involved, and the increased mortality from both presentation with retention and the increased risk from prostatic surgery, then the case for primary prevention of AUR should be clear. The benefits however are only accrued by the at-​risk group. The risk factors for AUR have already been listed in the epidemiology section (Box 5.2.1). The more of these risk factors that are present the greater the benefit, and the more cost-​effective the treatment.82,83

The 5-​alpha reductase inhibitors The PLESS, MTOPS, and the CombAT studies were designed to look at the risk reduction of AUR with 5-​alpha reductase inhibitor (5-​ARI) medical therapy.10,12,84 The first two studied finasteride and the third dutasteride. The PLESS was a four-​year study of finasteride versus placebo in over 3,000 men.12 The overall risk of AUR was 6.6% on placebo and 2.8% on finasteride—​a risk reduction of 57%. The risk reduction for both spontaneous and precipitated AUR from finasteride treatment varied by both serum PSA and prostate volume at baseline. Stratified by PSA tertiles, the reduction ranges from 7% to 77% for spontaneous and from 35% to 66% for both types of AUR, compared with the placebo-​treated patients.85 The MTOPS study evaluated doxazosin, finasteride, and combination therapy in 3,047 men followed for a mean of 4.5 years.10 Combination therapy decreased the risk for AUR by 81% versus placebo (p 4, a 50% rise in serum creatinine, AUR, recurrent UTIs or incontinence, or BPH surgery rates). MTOPS showed that a combination of doxazosin and finasteride resulted in improvements in symptom scores and peak flow rates and reduced disease progression (primarily as symptom scores) as compared to placebo or monotherapy. CombAT showed that combination therapy with tamsulosin and dutasteride was more effective at reducing BPH progression and improved symptom scores than monotherapy alone. This latter study also showed that combination therapy was superior to tamsulosin monotherapy only at reducing the relative

risk of AUR or surgery. This latter aspect has also been highlighted previously in the SMART study,57 which showed that the use of an alpha blocker and a 5-​α reductase inhibitor can be used to provide rapid symptom relief and then subsequent cessation of the alpha blocker after six months allows ongoing symptom control. Further analysis of these studies has led to guideline proposals38,58 that long-​term combination therapy should be offered to men with moderate to severe LUTS with prostates >40 mL, PSA >1.4 ng/​nl, and reduced maximum peak flow rates.

Phosphodiesterase type 5 inhibitors There is a link between erectile dysfunction and LUTS; both occur as men age and an early report highlighted an improvement in LUTS in men treated with Viagra.59 Hypotheses for mechanism of improvement in LUTS include changes to pelvic atherosclerosis, autonomic hyperactivity, interaction with the Rho-​kinase pathway and alterations to nitric oxide levels. Randomized studies60–​62 show no improvement in peak flow rates despite improvements in LUTS (in both storage and obstructive scores) which suggest that improvements occur because of changes to bladder function rather than changes to the prostate or BPH. Despite FDA approval for a phosphodiesterase inhibitor to be used for LUTS (although confusingly referred to as BPH or an enlarged prostate), it is unknown what are the long-​term effects of once daily use of this class of drug.

Phytotherapy Plant extracts, from roots, seeds, bark or fruits, are used to improve LUTS. These compounds consist of a variety of chemicals (such as phytosterols, plant oils, trepenoids) and various production techniques, and therefore careful scientific appraisal and comparison is difficult. Potential mechanisms of action include anti-​ inflammatory, hormonal, and growth factor pathways. Popular and common agents include Serenoa repens (saw palmetto berry extract) and Pygeum Africanum (from African Plum). Until further clarity is obtained from higher quality studies,63 the current body of evidence64,65 does not favour treatment with these compounds.

Surgical therapy for benign prostatic hyperplasia Prostate stents The type and indication for intraprostatic stents is constantly evolving. Early stents were utilized for medically unfit patients instead of a urinary catheter and can be fitted under a local anaesthetic. However, they remain problematic and may be difficult to reposition or remove. Complications are high with haematuria, perineal pain, encrustation, migration, breakage, stress incontinence, and UTIs. Spiral stents can be self-​retaining (Prosta coil) or malleable and heat-​expandable (Memokath). Using the latter, IPSS reduction can be maintained up to seven years’ follow-​up66,67 but there was high rate of repositioning and removal. Epithelial hyperplasia and ingrowth can be problematic. A variety of polyurethane stents are available and have been used as temporary measures to keep the prostatic lumen open during the heating effects of thermotherapy treatment for the prostate, and to prevent post thermotherapy retention. Equally, biodegradable stents have been used as a temporary relieving stent following laser ablative techniques on the prostate. Finally, permanent stents have been tried to treat

 435

Chapter 5.3 

BPH in medically unfit patients. UroLume is a metallic stent that allows epithelialization over the stent. It has been used with success in unfit patients who have presented with AUR,68,69 or as an alternative to TURP.70 Further complications encountered include irritative LUTS and painful ejaculation. One study showed that at up to 12 years’ follow-​up, 47% had to be removed.71 Memotherm is an another thermoexpandable metal stent that is reportedly easy to remove, as traction unravels the single wire. Again, complication rates remain high with a significant incidence of urinary symptoms, UTI, and urethral stricture disease. Overall, prostatic stents are infrequently used in clinical practice.

Minimally invasive therapy Transurethral microwave thermotherapy (TUMT) is also undergoing evolution and higher energy techniques have been used. In theory, by producing heat variation in the periurethral prostatic tissue, and by causing resultant coagulative necrosis, nerve degeneration, and inducing apoptosis, improvements are observed in LUTS. The prostate is heated using microwave energy with simultaneous cooling of the urethra. Despite lack of improvement in objective parameters such as peak flow rates, considerable improvements in IPSS can be observed. Equally important however is the large number of unpredictable non-​responders, even in the higher energy studies. As results are less favourable to TURP over the long term,72 currently this technique is considered experimental. Transurethral needle ablation of the prostate (TUNA) also delivers heat to the prostate, via radiofrequency energy delivered by needles placed into the prostate, with resultant necrosis to prostatic tissue. There may also be a neuromodulatory effect. As the needles are placed within the prostate, the prostatic urethra is spared. Treatment efficacy is less comparable to TURP, with very little data on follow-​up at greater than one year.73 Complication rates are low, with the most common adverse events being bleeding (30%), temporary AUR (up to 40%), UTI (7%), and urethral stricture disease (2%). TUNA results in less sexual dysfunction than TURP. As above, this is not a recommended standard technique for BPH management. The technique is associated with a high reoperation rate (14–​20% within two years). Heat delivery between the above methods differ slightly. With microwaves, heat is applied more broadly and deeply than with TUNA. The central temperature is therefore kept lower to protect the capsule and surrounding tissues; as such, treatment takes longer with TUMT. With TUNA, heat generation is faster and hotter, but to a smaller area. Similarities are that both can be done in an outpatient setting with minimal sedation and hence maybe suitable for unfit patients. Both procedures result in marked postoperative irritative urinary symptoms because of postoperative necrosis and subsequent sloughing of prostatic tissue over a number of weeks. Heat delivery has also been tried with high-​intensity focused ultrasound (HIFU). This procedure is a low morbid option with a resultant improvement in symptoms scores.74–​76 However due to complications of AUR and even rectourethral fistula, and a very high rate of early reoperation with TURP (up to 44%), this technique has been abandoned. Hot water-​induced thermotherapy involves an extracorporeal heat source and a proprietary closed-​ loop catheter system. Water, heated to 60°C, is circulated through the catheter to a treatment balloon, which conducts thermal energy to targeted prostatic tissue. Catheters are left in for a minimum of one week. Symptom scores are improved following treatment,77–79

benign prostatic hyperplasia

but due to complications of dysuria, bleeding, AUR, and high retreatment rates, this technique is no longer used. Transurethral ethanol ablation (TEAP) involves endoscopic injection of up to 13 mL dehydrated ethanol (98% concentration) at four to eight sites in the prostate either transurethrally (most common), transperineally, or transrectally. This results in coagulative necrosis and subsequent prostate gland volume reduction. Symptom scores and flow rates do improve but again, a high reintervention rate is observed. Single-​centre series with short follow-​up only have been described.80–​82 A further option evaluated in medically unfit patients is injection of botulinum toxin into the prostate. Following transperineal ultrasound guided injection (transurethral and transrectal routes have also been described), short-​term improvement is observed in symptom scores in medically unfit patients.83–​86 It is unclear how the toxin exerts its effects (either locally or centrally, via muscle relaxation, or by prostate apoptosis and longer term volume reduction); it is also unclear what are the potential adverse effects of the need for repeated injection into prostate tissue; hence, currently this therapy is experimental. In an early investigational study, radiofrequency energy has also been used clinically for BPH using a pulsed electromagnetic field87 with promising early results.

Transurethral Prostatectomy (TURP) Monopolar TURP remains the gold standard treatment for the surgical management of BPH and BOO. This is despite the lack of randomized controlled trial (RCT) evidence to support its introduction. TURP rates have declined over the past two decades. This is primarily related to the beneficial effects of medical therapy of BPH and to a lesser extent on the evaluation of alternative surgical techniques. Indications for TURP include: ◆ Moderate

to severe LUTS (either not controlled with medical therapy or by patient choice)

◆ AUR ◆ Recurrent UTI ◆ Recurrent

haematuria

◆ Obstructive

uropathy

It is of value to remind the reader that BOO can only be diagnosed by urodynamic studies; symptoms, flow rates, post-​void residual urine measurements, and cystoscopic findings can only infer BOO by BPH. Surgical resection of the prostate can occur by monopolar (standard) or more recently, by bipolar resection. The resection involves a step-​wise approach to resect the three lobes of the prostate by resecting the prostatic tissue in small slices and washing out the prostate chips; haemostasis is completed using rollerball diathermy (see Fig. 5.3.9). The urinary catheter may or may not be irrigated and can be removed after 24–​48 hours. The reduction in symptoms score and improvement in QoL scores remain high after this operation and currently has not been bettered by any endoscopic technique. The large national prostatectomy audit88 outlined that that most men underwent TURP because of one of the indications above, rather than for symptoms, and that TURP was effective in reducing symptoms and symptom bother (although not all men experienced a good reduction in symptoms; 4% were worse, 10% were the same, and a quarter experienced only slight improvement). Six per cent (6%) had problematic incontinence (this is less than 2% in contemporary series), two-​thirds had retrograde ejaculation, and

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benign prostatic hyperplasia (A)

(B)

Fig. 5.3.9  (A) Endoscopic view during transurethral resection of prostate (TURP) resection; (B) diathermy.

a third reported erectile dysfunction (it is important to stress that the natural history of impotence in elderly men remains unknown). Mortality risk is low with this operation.89 Results remain durable with published data up to 22  years.90 Reoperation, usually with another TURP, is around 1–​2% per year. The risk of transurethral resection (TUR) syndrome (dilutional hyponatraemia from fluid absorption) has dramatically decreased (better awareness, reduced operating times, and better perioperative assessment and care) and is less than 1%. Risk factors associated with TUR syndrome are excessive bleeding and an open venous sinus, prolonged operation time, large prostates, and smoking. Postoperative transfusion rates remain low at 2%. Younger men with BOO may benefit from an incision at the bladder neck (BNI or transurethral incision of the prostate, TUIP), usually at the 5 and 7 o’clock positions91 rather than undergoing a complete TURP. To improve haemostasis, length of catheterization, and reduce TUR syndrome, bipolar TURP has become popular. The technique uses a specialized resectoscope loop, which contains both the active and return electrodes and allows resection during saline irrigation. Prostate tissue is heated indirectly by the heat from the ignition of the spark that occurs between the electrode loops. The move to this resection technique has occurred, despite the lack of long-​term evidence. Studies to date would point to a trend in lower rates of clot retention, catheterization, operating time, irrigation and TUR syndrome with other surgical outcomes (IPSS scores, reoperation rates, and so on) comparable to monopolar TURP in short-​term follow-​up.92 At up to five years, results appear to be durable and comparable to monopolar TURP.93 Prostate enucleation has also been described using bipolar energy.94 Transurethral vaporization of the prostate (TUVP) involves vaporization by steam at high heat at the leading edge of the probe and subsequent desiccation to dry out the prostatic tissue at the trailing edge of the probe with resultant coagulation (see Fig. 5.3.10). Generators need to be effective at altering power in response to resistance of the prostatic tissue, which varies depending on the level of hydration. This is a bipolar technique allowing surgery with saline irrigation. There are many electrode designs available; for example, a rollerball, rollerbar, and various loop configurations. At one year, complication rates are similar to TURP, but catheterization, haematuria, and transfusion rates are lower with TUVP95–​97 albeit with longer operating times for the procedure. Similar to TURP, vaporization-​resection of the prostate has also been described.

Fig. 5.3.10  Endoscopic view of transurethral vaporization of the prostate (TUVP). Reproduced courtesy of Dr Bogdon Geavlete, Assistant Professor, “Saint John” Emergency Clinical Hospital, Department of Urology, Bucharest, Romania.

Laser surgery There are currently four groups of lasers used for BPH surgery by either coagulating, vaporizing, or enucleating the prostate: ◆ Potassium

titanyl phosphate (KTP); neodymium yttrium aluminium garnet (Nd-YAG); and lithium borate (LBO)

◆ Diode lasers ◆ Holmium ◆ Thulium

(Ho): YAG (HoLEP)

(Tm): YAG (ThuLEP or ThuVEP)

KTP lasers have been used for photoselective vaporization of the prostate (PVP). Initially 60 W lasers were used,98 subsequently 80 W lasers and then more recently the 120 W laser is being used. Two RCTs comparing TURP and PVP with 80 W KTP have been published. One showed equivalent results to TURP at one-​year follow-​ up99; the second showed superior flow rate results with TURP at 6 months’ follow-​up.100 KTP PVP with 80 W has also shown comparative results with open prostatectomy.101 LBO PVP has shown similar short-​term equivalence to TURP and appears to be quicker than KTP PVP. Both KTP and LBO emit green light and have been shown to reduce intraoperative blood loss and have reduced postoperative blood transfusion rates as compared to TURP. Stricture, retrograde ejaculation, and retreatment rates appear similar to TURP. Much of the data on diode lasers refer to the 980-​mn laser diode. These prospective studies with follow-​up to one year show

 437

Chapter 5.3 

(A)

benign prostatic hyperplasia

(B)

(C)

Fig. 5.3.11  (A) Endoscopic views during holmium (Ho): YAG (HoLEP) laser surgery, prostatic incision; (B) just prior to prostate lobe detachment and; (C) during morcellation. Reproduced courtesy of Mr Tev Aho, Consultant Urologist, Cambridge, UK.

improvement in flow rates and a reduction in PVRs and PSA.102,103 Worryingly, this technique is associated with higher rates of bladder neck stricture or obstruction from necrotic tissue and as such, this type of BOO surgery is not recommended. In HoLEP, high temperatures generated by the holmium laser create bubbles of steam which tears tissue apart with excellent haemostasis (see Fig. 5.3.11). Initially holmium lasers were used to vaporize or ablate the prostate (HoLAP), which resulted in urodynamic improvements similar to TURP but with a smaller reduction in prostate volume at short-​term follow-​up. Holmium was then used to resect the prostate (HoLRP), much like TURP. This technique has now progressed onto HoLEP with enucleation of the entire lobes, which are then pushed into the bladder and then morcellated (see Fig. 5.3.9).104 There have been six RCTS comparing HoLEP with TURP and one comparing HoLEP with open prostatectomy. Essentially there is no statistically significant difference between HoLEP and TURP in improving symptom scores and quality of life scores at up to seven years.105–​107 HoLEP showed greater improvement in flow rates at one year but not at seven years. Less blood loss and transfusion rates have been observed with HoLEP.108 HoLEP has a significantly longer operating time than TURP but this may be offset by shorter catheterization or hospital stay in some centres. At five years’ follow-​up, HoLEP is also comparable to open prostatectomy.109 Thulium laser allows better tissue vaporization than holmium. Similar to the evolution of the technique with holmium lasers, thulium lasers have been used to treat BPH by vaporization,

vaporesection (ThuVARP), vapoenucleation and laser enucleation (ThuVEP). At one-​year follow-​up, there seems to be no difference in outcome or complication rates between TURP and ThuVARP.110 Equally there seems to be no difference between HoLEP and ThuVEP111 or ThuLEP.112 Laser techniques for treating BPH appear to have equivalent results to TURP. They are superior to TURP in anticoagulated patients with lower risks of bleeding and the need for postoperative blood transfusion.113,114 As with bipolar TURP, saline irrigation can be used and this limits the development of hyponatraemia (this is still possible following use of large volumes of irrigant, inappropriate post-​op fluid management, and inappropriate SIADH release). Shorter periods of catheterization and length of stay need to offset the higher operating costs (in terms of equipment and operating time); as such, TURP remains a cost-​effective modality for BPH surgery.115

Open prostatectomy Open prostatectomy is still relevant in today’s medicine; it involves enucleation of the hyperplastic prostatic adenoma. It was first performed for many centuries via a perineal approach. Later descriptions include Freyer’s suprapubic transvesical approach,116 Millin’s retropubic transcapsular prostatectomy,117 and more recently laparoscopic118 and robotic-​assisted119 approaches. Prostatectomy still holds a strong place in many developing countries where resources, endourological equipment, and expertise may be lacking. It is clear that simple prostatectomy provides good functional

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outcome with excellent long-​term improvements in flow rates, post-​void residuals, and symptom scores.27,120,121 This has to be weighed up against a longer operating time, hospital stay and recovery, the need for a lower midline incision, and higher postoperative bleeding potential. The common view is that this approach should be reserved for larger prostates. In these patients, HoLEP is a reasonable endourological alternative allowing a minimally invasive alternative to prostate enucleation; functional outcome and complication rates appear the same.109 However, the open approach should be considered in men with prior urethral disease (e.g. following hypospadius repair and/​or ongoing stricture disease), in the presence of large bladder calculi, or in men with fixed hips that do not allow flexion.

Novel therapies A number of novel therapies have been investigated recently. The Urolift procedure involves placing tiny implants that stretch the prostatic urethra open. The delivery system allows the implant to be placed and tensioned, and usually requires an average of four implants per person. The improvements in symptom score and flow rate are far superior to those seen with medical therapy, but not as good as those seen with conventional surgery. There is no associated sexual dysfunction and although recovery time is superior to that from conventional surgery, long-term outcomes are unknown. NICE approval was granted in 2014 for this procedure. Other novel therapies currently under investigation include prostate artery embolization (PAE) and aquablation of the prostate. During PAE, an interventional radiologist, using a percutaneous transfemoral approach, performs super-selective catheterization of small prostatic arteries and embolizes them by introducing microparticles of polyvinyl alcohol or gelatin sponge. Aquablation involves using image-guided high-velocity waterjet technology to resect and remove prostate tissue.

Bladder outlet obstruction surgery Although there seems to be clear indications for BOO surgery, many questions remain in this area.122 We do not know what specific elements of BOO result in damage to the urinary tract (e.g. bladder pressure at rest or during voiding, the role of compliance in BOO), or to what extent BPH contributes to BOO and to what extent should PV be reduced by surgery to reduce BOO and its complications.123 It is however clear that in the long term, the bladder plays a central role in the symptoms of men with BPH. BOO surgery is more successful in men who suffer from confirmed BOO.124 However, untreated BOO does not result in long-​term loss of bladder function or greatly alter LUTS.125 In addition, BOO surgery in men provides no advantage to bladder function or symptoms as compared to surveillance if they suffer from detrusor underactivity.126 Finally, those with underactivity prior to surgery continue to suffer from long-​term underactivity33 despite surgical deobstruction. The effect of BOO surgery on erectile dysfunction is unclear. Large scale trials would suggest a detrimental effect on ejaculatory function and potency, regardless of technique.127,128 However, more detailed examination confirms a high rate of sexual inactivity prior to BOO surgery, and no detrimental (and in some cases a positive) effect of BOO surgery on those men that were sexually active prior to surgery.129

Conclusions BPH affects many men, is very common, and with an ageing population, is a worldwide problem. BPH and BOO are one of many causes of LUTS. The natural history of BPH would suggest that complications from BOO, including haematuria, UTIs, and AUR, occur infrequently. Simple evaluation of treatment of male LUTS is encouraged in primary care. Following GP assessment, medical therapy can be commenced. Secondary care assessment allows accurate definition of BOO (by urodynamic studies). The ongoing development of medical therapy for obstructive LUTS has led to a reduction in surgical therapy for BPH. Following clinical effectiveness observed in the use of alpha blockade within the prostate, there is ongoing development of superselective alpha blockers (e.g. silodosin and naftopidil). 5-​α reductase inhibitors, finasteride, and dutasteride, have shown clinical utility in improving symptoms and reducing prostate volume. Combination therapy with α–​blockers and 5-​α reductase inhibitors have shown not only improvement in flow rates and symptoms scores, but also a reduction in BPH progression events over four years. Recently, there is mounting evidence for the causal association of BPH and ED with the subsequent licensing approval of a PDE​5i for the treatment of BPH. Open prostatectomy results in long-​term durable effectiveness for BOO surgery. This has largely been replaced by TURP, which has equally shown to produce excellent long-​term results in symptom scores and flow rates. There are ongoing attempts to improve on the results of TURP, largely by laser techniques which are undergoing constant evolution with higher energy delivery to allow faster prostate volume reduction with lowered catheterization and hospital stay. Many options remain intuitively as good as or better than TURP, but because of difficulties in recruiting to and performing high quality randomized controlled trials in surgery, TURP remains the gold standard deobstructing procedure. The choice of treatment of BPH will remain under the influence of several factors; this includes findings at assessment in primary and secondary care, treatment choice, and expectations of the patient for onset of symptom control, efficacy, side effects, and disease progression. As patients age, BPH increases, and medical therapy is often superseded by surgical treatment of BPH.

Further reading Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132(3):474–9. Bruskewitz R, Girman CJ, Fowler J, et al. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology 1999; 54(4):670–8. Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 2009; 104(3):352–60. European Association of Urology. EAU Guideline on Male LUTS, including BPO, 2012. Available at: https://uroweb.org/wp-content/uploads/12_ Male_LUTS_LR-May-9th-2012.pdf [Online]. Herrmann TR, Liatsikos EN, Nagele U, Traxer O, Merseburger AS. EAU guidelines on laser technologies. Eur Urol 2012; 61(4):783–95. Homma Y, Gotoh M, Takei M, Kawabe K, Yamaguchi T. Predictability of conventional tests for the assessment of bladder outlet obstruction in benign prostatic hyperplasia. Int J Urol 1998; 5(1):61–6. Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract

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symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50(6):1306–14; discussion 14–5. Lee KL, Peehl DM. Molecular and cellular pathogenesis of benign prostatic hyperplasia. J Urol 2004; 172(5 Pt 1):1784–91. Marker PC, Donjacour AA, Dahiya R, Cunha GR. Hormonal, cellular, and molecular control of prostatic development. Dev Biol 2003; 253(2):165–74. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349(25):2387–98. McNeill SA, Hargreave TB, Roehrborn CG. Alfuzosin 10 mg once daily in the management of acute urinary retention: results of a double-blind placebo-ontrolled study. Urology 2005;65(1):83–9; discussion 9–90. National Institute of Clinical Health and Excellence. Clinical guideline [CG97] Lower urinary tract symptoms in men: management, 2010. Available at: https://www.nice.org.uk/guidance/cg97 [Online]. Oelke M, Burger M, Castro-Diaz D, et al. Diagnosis and medical treatment of lower urinary tract symptoms in adult men: applying specialist guidelines in clinical practice. BJU Int 2012; 110(5):710–18. Reich O, Gratzke C, Stief CG. Techniques and long-term results of surgical procedures for BPH. Eur Urol 2006; 49(6):970–8; discussion 8. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol 2010; 57(1):123–31.

References 1. De Marzo AM, Nelson WG, Meeker AK, Coffey DS. Stem cell features of benign and malignant prostate epithelial cells. J Urol 1998; 160(6 Pt 2):2381–​92. 2. Lepor H, Tang R, Meretyk S, Shapiro E. Alpha 1 adrenoceptor subtypes in the human prostate. J Urol 1993; 149(3):640–​2. 3. Silver RI, Wiley EL, Davis DL, Thigpen AE, Russell DW, McConnell JD. Expression and regulation of steroid 5 alpha-​reductase 2 in prostate disease. J Urol 1994; 152(2 Pt 1):433–​7. 4. Marker PC, Donjacour AA, Dahiya R, Cunha GR. Hormonal, cellular, and molecular control of prostatic development. Dev Biol 2003; 253(2):165–​74. 5. Barrack ER, Berry SJ. DNA synthesis in the canine prostate: effects of androgen and estrogen treatment. Prostate 1987; 10(1):45–​56. 6. Lee KL, Peehl DM. Molecular and cellular pathogenesis of benign prostatic hyperplasia. J Urol 2004; 172(5 Pt 1):1784–​91. 7. Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol 2007; 51(5):1202–​16. 8. Sanda MG, Beaty TH, Stutzman RE, Childs B, Walsh PC. Genetic susceptibility of benign prostatic hyperplasia. J Urol 1994; 152(1):115–​9. 9. McNeal JE. The zonal anatomy of the prostate. Prostate 1981; 2(1):35–​49. 10. Shapiro E, Becich MJ, Hartanto V, Lepor H. The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 1992; 147(5):1293–​7. 11. Srinivasan D, Kosaka AH, Daniels DV, Ford AP, Bhattacharya A. Pharmacological and functional characterization of bradykinin B2 receptor in human prostate. Eur J Pharmacol 2004; 504(3):155–​67. 12. Waldkirch E, Uckert S, Sigl K, et al. Expression of cAMP-​dependent protein kinase isoforms in the human prostate: functional significance and relation to PDE4. Urology 2010; 76(2):515 e8–​14. 13. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132(3):474–​9. 14. Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int 2009; 104(3):352–​60.

benign prostatic hyperplasia

15. Chute CG, Panser LA, Girman CJ, et al. The prevalence of prostatism: a population-​based survey of urinary symptoms. J Urol 1993; 150(1):85–​9. 16. Meigs JB, Barry MJ, Giovannucci E, Rimm EB, Stampfer MJ, Kawachi I. Incidence rates and risk factors for acute urinary retention: the health professionals followup study. J Urol 1999; 162(2):376–​82. 17. Bruskewitz R, Girman CJ, Fowler J, et al. Effect of finasteride on bother and other health-​related quality of life aspects associated with benign prostatic hyperplasia. PLESS Study Group. Proscar Long-​term Efficacy and Safety Study. Urology 1999; 54(4):670–​8. 18. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-​term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349(25):2387–​98. 19. Roehrborn CG. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: results of a 2-​year placebo-​controlled study. BJU Int 2006; 97(4):734–​41. 20. Irwin DE, Milsom I, Hunskaar S, et al. Population-​based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50(6):1306–​14; discussion 14–​5. 21. Kupelian V, Wei JT, O’Leary MP, et al. Prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) Survey. Arch Int Med 2006; 166(21):2381–​7. 22. Fukuta F, Masumori N, Mori M, Tsukamoto T. Natural history of lower urinary tract symptoms in Japanese men from a 15-​year longitudinal community-​based study. BJU Int 2012; 110(7):1023–​9. 23. Lieber MM, Rhodes T, Jacobson DJ, et al. Natural history of benign prostatic enlargement: long-​term longitudinal population-​based study of prostate volume doubling times. BJU Int 2010; 105(2):214–​9. 24. Coyne KS, Kaplan SA, Chapple CR, et al. Risk factors and comorbid conditions associated with lower urinary tract symptoms: EpiLUTS. BJU Int 2009; 103(Suppl 3):24–​32. 25. Kupelian V, McVary KT, Kaplan SA, et al. Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston Area Community Health Survey. J Urol 2009; 182(2):616–​24; discussion 24–​5. 26. Hammarsten J, Hogstedt B, Holthuis N, Mellstrom D. Components of the metabolic syndrome-​risk factors for the development of benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1998; 1(3):157–​62. 27. Gratzke C, Schlenker B, Seitz M, et al. Complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. J Urol 2007; 177(4):1419–​22. 28. Levin RM, Haugaard N, O’Connor L, et al. Obstructive response of human bladder to BPH vs. rabbit bladder response to partial outlet obstruction: a direct comparison. Neurourol Urodyn 2000; 19(5):609–​29. 29. Abrams PH, Farrar DJ, Turner-​Warwick RT, Whiteside CG, Feneley RC. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979; 121(5):640–​2. 30. Grosse H. [Frequency, localization and associated disorders in urinary calculi. Analysis of 1671 autopsies in urolithiasis]. Zeitschrift fur Urologie und Nephrologie 1990; 83(9):469–​74. Frequenz, Lokalisation und Begleiterkrankungen der Harnsteine. Analyse von 1671 Urolithiasis-​Obduktionen. 31. Millan-​Rodriguez F, Izquierdo-​Latorre F, Montlleo-​Gonzalez M, Rousaud-​Baron F, Rousaud-​Baron A, Villavicencio-​Mavrich H. Treatment of bladder stones without associated prostate surgery: results of a prospective study. Urology 2005; 66(3):505–​9. 32. Flanigan RC, Reda DJ, Wasson JH, Anderson RJ, Abdellatif M, Bruskewitz RC. 5-​year outcome of surgical resection and watchful waiting for men with moderately symptomatic benign prostatic hyperplasia: a Department of Veterans Affairs cooperative study. J Urol 1998; 160(1):12–​6; discussion 6–​7.

439

40

440

Section 5  

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33. Al-​Hayek S, Thomas A, Abrams P. Natural history of detrusor contractility—​minimum ten-​year urodynamic follow-​up in men with bladder outlet obstruction and those with detrusor. Scand J Urol Nephrol Suppl 2004; (215):101–​8. 34. Donohue JF, Hayne D, Karnik U, Thomas DR, Foster MC. Randomized, placebo-​controlled trial showing that finasteride reduces prostatic vascularity rapidly within 2 weeks. BJU Int 2005; 96(9):1319–​22. 35. Roehrborn CG, Bruskewitz R, Nickel GC, et al. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37(5):528–​36. 36. Rosen RC, Wei JT, Althof SE, Seftel AD, Miner M, Perelman MA. Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: results from the BPH Registry. Urology 2009; 73(3):562–​6. 37. Vallancien G, Emberton M, Harving N, van Moorselaar RJ. Sexual dysfunction in 1,274 European men suffering from lower urinary tract symptoms. J Urol 2003; 169(6):2257–​61. 38. National Institute of Clinical Health and Excellence. Clinical guideline [CG97] Lower urinary tract symptoms in men: management, 2010. Available at: https://​www.nice.org.uk/​guidance/​cg97 [Online]. 39. Homma Y, Gotoh M, Takei M, Kawabe K, Yamaguchi T. Predictability of conventional tests for the assessment of bladder outlet obstruction in benign prostatic hyperplasia. Int J Urol 1998; 5(1):61–​6. 40. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-​ specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999; 53(3):581–​9. 41. Ball AJ, Feneley RC, Abrams PH. The natural history of untreated “prostatism”. Br J Urol 1981; 53(6):613–​6. 42. Brown CT, Yap T, Cromwell DA, et al. Self management for men with lower urinary tract symptoms: randomised controlled trial. BMJ 2007; 334(7583):25. 43. Wasson JH, Bubolz TA, Lu-​Yao GL, Walker-​Corkery E, Hammond CS, Barry MJ. Transurethral resection of the prostate among medicare beneficiaries: 1984 to 1997. For the patient outcomes research team for prostatic diseases. J Urol 2000; 164(4):1212–​5. 44. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975; 47(2):193–​202. 45. Hieble JP, Caine M, Zalaznik E. In vitro characterization of the alpha-​adrenoceptors in human prostate. Eur J Pharmacol 1985; 107(2):111–​7. 46. Shapiro E, Hartanto V, Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate 1992; 21(4):297–​307. 47. Kortmann BB, Floratos DL, Kiemeney LA, Wijkstra H, de la Rosette JJ. Urodynamic effects of alpha-​adrenoceptor blockers: a review of clinical trials. Urology 2003; 62(1):1–​9. 48. McNeill SA, Hargreave TB, Roehrborn CG. Alfuzosin 10 mg once daily in the management of acute urinary retention: results of a double-​blind placebo-​ontrolled study. Urology 2005; 65(1):83–​9; discussion 9–​90. 49. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. New Engl J Med 1992; 327(17):1185–​91. 50. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-​Term Efficacy and Safety Study Group. New Engl J Med 1998; 338(9):557–​63. 51. Roehrborn CG, Marks LS, Fenter T, et al. Efficacy and safety of dutasteride in the four-​year treatment of men with benign prostatic hyperplasia. Urology 2004; 63(4):709–​15. 52. Donohue JF, Sharma H, Abraham R, Natalwala S, Thomas DR, Foster MC. Transurethral prostate resection and bleeding: a randomized, placebo controlled trial of role of finasteride for decreasing operative blood loss. J Urol 2002; 168(5):2024–​6.

53. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. New Engl J Med 1996; 335(8):533–​9. 54. Debruyne FM, Jardin A, Colloi D, et al. Sustained-​release alfuzosin, finasteride and the combination of both in the treatment of benign prostatic hyperplasia. European ALFIN Study Group. Eur Urol 1998; 34(3):169–​75. 55. Kirby RS, Roehrborn C, Boyle P, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 2003; 61(1):119–​26. 56. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-​year results from the CombAT study. Eur Urol 2010; 57(1):123–​31. 57. Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S, van Vierssen Trip OB. Alpha-​blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-​ reductase inhibitor dutasteride. Eur Urol 2003; 44(4):461–​6. 58. European Association of Urology. EAU Guideline on Male LUTS, including BPO, 2012. Available at: https://​uroweb.org/​wp-​content/​ uploads/​12_​Male_​LUTS_​LR-​May-​9th-​2012.pdf [Online]. 59. Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, Hanbury DC. Sildenafil influences lower urinary tract symptoms. BJU Int 2002; 90(9):836–​9. 60. McVary KT, Monnig W, Camps JL Jr, Young JM, Tseng LJ, van den Ende G. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-​blind trial. J Urol 2007; 177(3):1071–​7. 61. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2007; 177(4):1401–​7. 62. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E. A randomised, placebo-​controlled study to assess the efficacy of twice-​daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 2008; 53(6):1236–​44. 63. Lee JY, Foster HE Jr, McVary KT, et al. Recruitment of participants to a clinical trial of botanical therapy for benign prostatic hyperplasia. J Altern Complement Med 2011; 17(5):469–​72. 64. MacDonald R, Tacklind JW, Rutks I, Wilt TJ. Serenoa repens monotherapy for benign prostatic hyperplasia (BPH): an updated Cochrane systematic review. BJU Int 2012; 109(12):1756–​61. 65. Barry MJ, Meleth S, Lee JY, et al. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA 2011; 306(12):1344–​51. 66. Perry MJ, Roodhouse AJ, Gidlow AB, Spicer TG, Ellis BW. Thermo-​ expandable intraprostatic stents in bladder outlet obstruction: an 8-year study. BJU Int 2002; 90(3):216–​23. 67. Armitage JN, Rashidian A, Cathcart PJ, Emberton M, van der Meulen JH. The thermo-​expandable metallic stent for managing benign prostatic hyperplasia: a systematic review. BJU Int 2006; 98(4):806–​10. 68. Chapple CR, Milroy EJ, Rickards D. Permanently implanted urethral stent for prostatic obstruction in the unfit patient. Preliminary report. Br J Urol 1990; 66(1):58–​65. 69. McLoughlin J, Jager R, Abel PD, el Din A, Adam A, Williams G. The use of prostatic stents in patients with urinary retention who are unfit for surgery. An interim report. Br J Urol 1990; 66(1):66–​70. 70. Bajoria S, Agarwal SA, White R, Zafar F, Williams G. Experience with the second generation UroLume prostatic stent. Br J Urol 1995; 75(3):325–​7. 71. Masood S, Djaladat H, Kouriefs C, Keen M, Palmer JH. The 12-​year outcome analysis of an endourethral wallstent for treating benign prostatic hyperplasia. BJU Int 2004; 94(9):1271–​4.

 41

Chapter 5.3 

72. Hoffman RM, Monga M, Elliot SP, Macdonald R, Wilt TJ. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2007; (4):CD004135. 73. Bouza C, Lopez T, Magro A, Navalpotro L, Amate JM. Systematic review and meta-​analysis of Transurethral Needle Ablation in symptomatic Benign Prostatic Hyperplasia. BMC Urol 2006; 6:14. 74. Sullivan L, Casey RW, Pommerville PJ, Marich KW. Canadian experience with high intensity focused ultrasound for the treatment of BPH. Can J Urol 1999; 6(3):799–​805. 75. Lu J, Hu W, Wang W. Sonablate-​500 transrectal high-​intensity focused ultrasound (HIFU) for benign prostatic hyperplasia patients. J Huazhong Univ Sci Technolog Med Sci 2007; 27(6):671–​4. 76. Madersbacher S, Schatzl G, Djavan B, Stulnig T, Marberger M. Long-​term outcome of transrectal high-​intensity focused ultrasound therapy for benign prostatic hyperplasia. Eur Urol 2000; 37(6):687–​94. 77. Muschter R. Conductive heat: hot water-​induced thermotherapy for ablation of prostatic tissue. J Endourol 2003; 17(8):609–​16. 78. Corica FA, Cheng L, Ramnani D, et al. Transurethral hot-​water balloon thermoablation for benign prostatic hyperplasia: patient tolerance and pathologic findings. Urology 2000; 56(1):76–​80; discussion 1. 79. Corica AG, Qian J, Ma J, Sagaz AA, Corica AP, Bostwick DG. Fast liquid ablation system for prostatic hyperplasia: a new minimally invasive thermal treatment. J Urol 2003; 170(3):874–​8. 80. Magno C, Mucciardi G, Gali A, Anastasi G, Inferrera A, Morgia G. Transurethral ethanol ablation of the prostate (TEAP): an effective minimally invasive treatment alternative to traditional surgery for symptomatic benign prostatic hyperplasia (BPH) in high-​risk comorbidity patients. Int Urol Nephrol 2008; 40(4):941–​6. 81. Sakr M, Eid A, Shoukry M, Fayed A. Transurethral ethanol injection therapy of benign prostatic hyperplasia: four-​year follow-​up. Int J Urol 2009; 16(2):196–​201. 82. El-​Husseiny T, Buchholz N. Transurethral ethanol ablation of the prostate for symptomatic benign prostatic hyperplasia: long-​term follow-​up. J Endourol 2011; 25(3):477–​80. 83. Chuang YC, Chiang PH, Yoshimura N, De Miguel F, Chancellor MB. Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia. BJU Int 2006; 98(5):1033–​7; discussion 337. 84. Brisinda G, Cadeddu F, Vanella S, Mazzeo P, Marniga G, Maria G. Relief by botulinum toxin of lower urinary tract symptoms owing to benign prostatic hyperplasia: early and long-​term results. Urology 2009; 73(1):90–​4. 85. Sacco E, Bientinesi R, Marangi F, et al. Patient-​reported outcomes in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with intraprostatic OnabotulinumtoxinA: 3-​month results of a prospective single-​armed cohort study. BJU Int 2012; 110(11 Pt C):E837–​44. 86. Hamidi Madani A, Enshaei A, et al. Transurethral intraprostatic Botulinum toxin-​A injection: a novel treatment for BPH refractory to current medical therapy in poor surgical candidates. World J Urol 2013; 31(1):235–​9. 87. Giannakopoulos XK, Giotis C, Karkabounas S, et al. Effects of pulsed electromagnetic fields on benign prostate hyperplasia. Int Urol Nephrol 2011; 43(4):955–​60. 88. Emberton M, Neal DE, Black N, et al. The National Prostatectomy Audit: the clinical management of patients during hospital admission. Br J Urol 1995; 75(3):301–​16. 89. Holman CD, Wisniewski ZS, Semmens JB, Rouse IL, Bass AJ. Mortality and prostate cancer risk in 19,598 men after surgery for benign prostatic hyperplasia. BJU Int 1999; 84(1):37–​42. 90. Reich O, Gratzke C, Stief CG. Techniques and long-​term results of surgical procedures for BPH. Eur Urol 2006; 49(6):970–​8; discussion 8. 91. Orandi A. Transurethral incision of prostate. Seven-​year follow-​up. Urology 1978; 12(2):187–​9.

benign prostatic hyperplasia

92. Mamoulakis C, Ubbink DT, de la Rosette JJ. Bipolar versus monopolar transurethral resection of the prostate: a systematic review and meta-​analysis of randomized controlled trials. Eur Urol 2009; 56(5):798–​809. 93. Xie CY, Zhu GB, Wang XH, Liu XB. Five-​year follow-​up results of a randomized controlled trial comparing bipolar plasmakinetic and monopolar transurethral resection of the prostate. Yonsei Med J 2012; 53(4):734–​41. 94. Liao N, Yu J. A study comparing plasmakinetic enucleation with bipolar plasmakinetic resection of the prostate for benign prostatic hyperplasia. J Endourol 2012; 26(7):884–​8. 95. Patel A, Fuchs GJ, Gutierrez-​Aceves J, Andrade-​Perez F. Transurethral electrovaporization and vapour-​resection of the prostate: an appraisal of possible electrosurgical alternatives to regular loop resection. BJU Int 2000; 85(2):202–​10. 96. Poulakis V, Dahm P, Witzsch U, Sutton AJ, Becht E. Transurethral electrovaporization vs transurethral resection for symptomatic prostatic obstruction: a meta-​analysis. BJU Int 2004; 94(1):89–​95. 97. Nuhoglu B, Balci MB, Aydin M, et al. The role of bipolar transurethral vaporization in the management of benign prostatic hyperplasia. Urologia Int 2011; 87(4):400–​4. 98. Malek RS, Barrett DM, Kuntzman RS. High-​power potassium-​titanyl-​ phosphate (KTP/​532) laser vaporization prostatectomy: 24 hours later. Urology 1998; 51(2):254–​6. 99. Bouchier-​Hayes DM, Anderson P, Van Appledorn S, Bugeja P, Costello AJ. KTP laser versus transurethral resection: early results of a randomized trial. J Endourol 2006; 20(8):580–​5. 100. Horasanli K, Silay MS, Altay B, Tanriverdi O, Sarica K, Miroglu C. Photoselective potassium titanyl phosphate (KTP) laser vaporization versus transurethral resection of the prostate for prostates larger than 70 mL: a short-​term prospective randomized trial. Urology 2008; 71(2):247–​51. 101. Skolarikos A, Papachristou C, Athanasiadis G, Chalikopoulos D, Deliveliotis C, Alivizatos G. Eighteen-​month results of a randomized prospective study comparing transurethral photoselective vaporization with transvesical open enucleation for prostatic adenomas greater than 80 cc. J Endourol 2008; 22(10):2333–​40. 102. Chen CH, Chiang PH, Chuang YC, Lee WC, Chen YT. Preliminary results of prostate vaporization in the treatment of benign prostatic hyperplasia by using a 200-​W high-​intensity diode laser. Urology 2010; 75(3):658–​63. 103. Ruszat R, Seitz M, Wyler SF, et al. Prospective single-​centre comparison of 120-​W diode-​pumped solid-​state high-​intensity system laser vaporization of the prostate and 200-​W high-​intensive diode-​laser ablation of the prostate for treating benign prostatic hyperplasia. BJU Int 2009; 104(6):820–​5. 104. Fraundorfer MR, Gilling PJ. Holmium:YAG laser enucleation of the prostate combined with mechanical morcellation: preliminary results. Eur Urol 1998; 33(1):69–​72. 105. Tan A, Liao C, Mo Z, Cao Y. Meta-​analysis of holmium laser enucleation versus transurethral resection of the prostate for symptomatic prostatic obstruction. Br J Surg 2007; 94(10):1201–​8. 106. Lourenco T, Pickard R, Vale L, et al. Minimally invasive treatments for benign prostatic enlargement: systematic review of randomised controlled trials. BMJ 2008; 337:a1662. 107. Gilling PJ, Wilson LC, King CJ, Westenberg AM, Frampton CM, Fraundorfer MR. Long-​term results of a randomized trial comparing holmium laser enucleation of the prostate and transurethral resection of the prostate: results at 7 years. BJU Int 2012; 109(3):408–​11. 108. Martin AD, Nunez RN, Humphreys MR. Bleeding after holmium laser enucleation of the prostate: lessons learned the hard way. BJU Int 2011; 107(3):433–​7. 109. Kuntz RM, Lehrich K, Ahyai SA. Holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-​year follow-​up results of a randomised clinical trial. Eur Urol 2008; 53(1):160–​6.

441

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benign prostatic hyperplasia

110. Xia SJ, Zhuo J, Sun XW, Han BM, Shao Y, Zhang YN. Thulium laser versus standard transurethral resection of the prostate: a randomized prospective trial. Eur Urol 2008; 53(2):382–​89. 111. Bach T, Xia SJ, Yang Y, et al. Thulium: YAG 2 mum cw laser prostatectomy: where do we stand? World J Urol 2010; 28(2):163–​8. 112. Zhang F, Shao Q, Herrmann TR, Tian Y, Zhang Y. Thulium laser versus holmium laser transurethral enucleation of the prostate: 18-​month follow-​up data of a single center. Urology 2012; 79(4):869–​74. 113. Hauser S, Rogenhofer S, Ellinger J, Strunk T, Muller SC, Fechner G. Thulium laser (revolix) vapoenucleation of the prostate is a safe procedure in patients with an increased risk of hemorrhage. Urol Int 2012; 88(4):390–​4. 114. Tyson MD, Lerner LB. Safety of holmium laser enucleation of the prostate in anticoagulated patients. J Endourol 2009; 23(8):1343–​6. 115. Lourenco T, Armstrong N, N’Dow J, et al. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement. Health Technol Assess 2008; 12(35):iii, ix–​x, 1–​146:69–​515. 116. Freyer PJ. Total enucleation of the prostate: A further series of 550 cases of the operation. BMJ 1919; 1(3031):121–​0 2. 117. Millin T. Retropubic prostatectomy; a new extravesical technique; report of 20 cases. Lancet 1945; 2(6380):693–​6. 118. Mariano MB, Tefilli MV, Graziottin TM, Morales CM, Goldraich IH. Laparoscopic prostatectomy for benign prostatic hyperplasia—​a six-​ year experience. Eur Urol 2006; 49(1):127–​31; discussion 31–​2. 119. Sotelo R, Clavijo R, Carmona O, et al. Robotic simple prostatectomy. J Urol 2008; 179(2):513–​5. 120. Tubaro A, Carter S, Hind A, Vicentini C, Miano L. A prospective study of the safety and efficacy of suprapubic transvesical prostatectomy in patients with benign prostatic hyperplasia. J Urol 2001; 166(1):172–​6.

121. Varkarakis I, Kyriakakis Z, Delis A, Protogerou V, Deliveliotis C. Long-​term results of open transvesical prostatectomy from a contemporary series of patients. Urology 2004; 64(2):306–​10. 122. Oelke M, Kirschner-​Hermanns R, Thiruchelvam N, Heesakkers J. Can we identify men who will have complications from benign prostatic obstruction (BPO)? ICI-​RS 2011. Neurourol Urodyn 2012; 31(3):322–​6. 123. Abidi SS, Feroz I, Aslam M, Fawad A. Elective hemi transurethral resection of prostate: a safe and effective method of treating huge benign prostatic hyperplasia. J Coll Physicians Surg Pak 2012; 22(1):35–​40. 124. Thomas AW, Cannon A, Bartlett E, Ellis-​Jones J, Abrams P. The natural history of lower urinary tract dysfunction in men: minimum 10-​year urodynamic followup of transurethral resection of prostate for bladder outlet obstruction. J Urol 2005; 174(5):1887–​91. 125. Thomas AW, Cannon A, Bartlett E, Ellis-​Jones J, Abrams P. The natural history of lower urinary tract dysfunction in men: minimum 10-​year urodynamic follow-​up of untreated bladder outlet obstruction. BJU Int 2005; 96(9):1301–​6. 126. Thomas AW, Cannon A, Bartlett E, Ellis-​Jones J, Abrams P. The natural history of lower urinary tract dysfunction in men: the influence of detrusor underactivity on the outcome after transurethral resection of the prostate with a minimum 10-​year urodynamic follow-​ up. BJU Int 2004; 93(6):745–​50. 127. Zong HT, Peng XX, Yang CC, Zhang Y. The impact of transurethral procedures for benign prostate hyperplasia on male sexual function: a meta-​analysis. J Androl 2012; 33(3):427–​34. 128. Frieben RW, Lin HC, Hinh PP, Berardinelli F, Canfield SE, Wang R. The impact of minimally invasive surgeries for the treatment of symptomatic benign prostatic hyperplasia on male sexual function: a systematic review. Asian J Androl 2010; 12(4):500–​8. 129. Mishriki SF, Grimsley SJ, Lam T, Nabi G, Cohen NP. TURP and sex: patient and partner prospective 12 years follow-​up study. BJU Int 2012; 109(5):745–​50.

 43

SECTION 6

Oncology

Section editor: James W.F. Catto

6.1 Epidemiology of prostate cancer  445 Alison J. Price and Timothy J. Key 6.2 Molecular biology of prostate cancer  455 Ines Teles Alves, Jan Trapman, and Guido Jenster 6.3 Prostate cancer: Pathology  463 Rodolfo Montironi, Liang Cheng, Antonio Lopez-Beltran, Roberta Mazzucchelli, Matteo Santoni, and Marina Scarpelli 6.4 Prostate-specific antigen and biomarkers for prostate cancer  474 Sven Wenske and Hans Lilja 6.5 Screening for prostate cancer  483 Fritz H. Schröder 6.6 Clinical features, assessment, and imaging of prostate cancer  493 Anders Bjartell and David Ulmert 6.7 Prostate cancer: Treatment of localized disease  501 Matthew Cooperberg and Peter Carroll 6.8 Focal therapy for prostate cancer  512 Hashim Uddin Ahmed, Louise Dickinson, and Mark Emberton 6.9 High-risk prostate cancer  521 Steven Joniau, Siska Van Bruwaene, R. Jeffrey Karnes, Gert De Meerleer, Paolo Gontero, Martin Spahn, and Alberto Briganti 6.10 Technology and prostatectomy  538 Giacomo Novara, Alexander Mottrie, Filiberto Zattoni, and Vincenzo Ficarra 6.11 Metastatic disease in prostate cancer  551 Noel W. Clarke

6.12 Novel therapies and emerging strategies for the treatment of patients with castration-resistant prostate cancer  561 Deborah Mukherji, Aurelius Omlin, Carmel Pezaro, and Johann De Bono 6.13 Bladder and upper urinary tract cancer  569 Maria E. Goossens, Frank Buntinx, and Maurice P. Zeegers 6.14 Molecular biology of bladder cancer  579 Neveen Said and Dan Theodorescu 6.15 Pathology of bladder and upper urinary tract tumours  592 Simone Bertz and Arndt Hartmann 6.16 Screening for bladder cancer  603 Maree Brinkman and Maurice Zeegars 6.17 General overview of bladder cancer  615 Richard J. Bryant and James W.F. Catto 6.18 The investigation of haematuria  620 Richard J. Bryant and James W.F. Catto 6.19 Low and intermediate risk non-muscle-invasive bladder cancer  625 Aditya Bagrodia and Yair Lotan 6.20 Bladder cancer: High-grade non-muscle-invasive disease  638 Richard P. Meijer, Alexandre R. Zlotta, and Bas W.G. van Rhijn 6.21 Muscle-invasive bladder cancer  644 Pascal Zehnder and George N. Thalmann 6.22 Treatment of metastatic bladder cancer  657 Fabio Calabrò and Cora N. Sternberg 6.23 Squamous cell bladder cancer  669 Roman Mayr and Maximilian Burger

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6.24 Adenocarcinoma of the bladder  675 Roy Mano and Ofer Yossepowitch 6.25 Urothelial carcinomas of the upper urinary tract  683 Tarek P. Ghoneim, Pierre Colin, and Morgan Rouprêt 6.26 The aetiology, epidemiology, clinical features, and investigation of kidney cancer  696 Nilay Patel, David Cranston, and Mark Sullivan 6.27 Genetics and molecular biology of renal cancer  710 Mariam Jafri and Eamonn R. Maher 6.28 Pathology of renal cancer and other tumours affecting the kidney  719 Antonio Lopez-Beltran, Rodolfo Montironi, and Liang Cheng 6.29 Treatment of localized renal cell cancer  732 Ashraf Almatar and Michael A.S. Jewett 6.30 Ablative technologies for renal cancer  743 Stephen Faddegon, Ephrem O. Olweny, and Jeffrey A. Cadeddu

6.31 Kidney cancer: Treatment of locally advanced and low volume metastatic disease  752 Tim O’Brien and Amit Patel 6.32 Treatment of metastatic renal cancer  757 Han Hsi Wong, Basma Greef, and Tim Eisen 6.33 Testicular cancer  776 Christian Winter and Peter Albers 6.34 Pathology of testicular tumours  786 John Goepel 6.35 Testis cancer: Treatment  793 Axel Heidenreich 6.36 Penile cancer  810 Rosa Djajadiningrat and Simon Horenblas 6.37 Adrenocortical cancer  822 Steve Ball and Sajid Kalathil 6.38 Treatment of adrenal tumours  829 Atul Bagul and Saba Balasubramanian

 45

CHAPTER 6.1

Epidemiology of prostate cancer Alison J. Price and Timothy J. Key Introduction to the epidemiology of prostate cancer Prostate cancer is the second most common malignancy and the sixth most common cause of cancer death for men worldwide.1 Aside from age, ethnicity, and family history of disease, the risk factors are not well understood. This chapter aims to give a description of the geographical and temporal trends in prostate cancer incidence and mortality, and an outline of the risk factors possibly involved in the aetiology of the disease, with an emphasis on the role of hormonal and dietary factors.

The nature of the evidence Much of the literature pertaining to the aetiology of prostate cancer is derived from epidemiological investigations, both observational (ecological, case–​control, and cohort studies) and interventional (randomized controlled trials), of associations between biological, physical, and chemical exposures, and risk for prostate cancer diagnosis or death. Studies of animal models and cell cultures are used to explore findings at a mechanistic and functional level, but these will not be discussed here. The natural history of prostate cancer is complex as it can take many years to present clinically and, while some men develop an aggressive, lethal form of the disease, many men develop cancer that remains small and undetected, and ultimately these men die with the disease, rather than from it.2 Differentiating non-​aggressive from aggressive disease is known to be crucial for determining the best treatment approach (and preventing men undergoing invasive treatments for cancers that may never become life-­threatening), and it may also be important for determining possible aetiological differences. However, determining if identified risk factors are associated more with malignant transformation or tumour progression is difficult, because the duration between onset of asymptomatic disease and clinical symptoms has been estimated to be up to 12 years3), and some men will develop a form of disease that has little impact on health even in the absence of treatment.4 Indeed, autopsy studies have shown microscopic, well-​differentiated tumours of the prostate gland in 10–​14% of men between the age of 40 and 50 years5) and 30–​40% of men aged over 50 years.2 By 80 years of age, it is estimated that 80% of all men have asymptomatic prostatic carcinoma.6 A further complication for understanding the aetiology of prostate cancer is the increased use of prostate-​specific antigen (PSA) testing in some populations, as it has led to much earlier detection of asymptomatic disease (by as much as 10 years in men aged

55  years7), decreased numbers of advanced cancers, and a concomitant increase in the proportion of early localized cancers (of which many may never progress to clinical disease).8 While future research may identify diagnostic and prognostic biomarkers of prostate cancer that provide a clear differentiation between aggressive and non-​aggressive disease, there are currently no such validated biomarkers in general use, and so disease aggressiveness is determined by stage and grade. The prostate cancer tumour staging system (TNM)9 and the Gleason score,10 devised over 40 years ago, are the standard benchmarks for determining the clinical and pathological stages and the histological grade of prostate cancer. However, diagnostic practices and criteria have evolved during this time with implications for the interpretation of stage and grade information. In years, ultrasound-​guided needle biopsy tissue (collected at diagnosis) has become widely used for grading disease, whereas previously this information was derived mostly from tissue collected during radical prostatectomy or from transurethral resection of the prostate. A change in pathologists’ interpretation of biopsy specimens over time has also been evident, with a trend toward allocation of higher grades to cancers that would have previously been classified as less aggressive forms of the disease.9,11,12 To accommodate heterogeneous patterns of early disease (detected by PSA testing) that were not apparent when the Gleason criteria were first devised, scoring recommendations have also been updated.13 In the original system the two predominant Gleason scores were used to grade prostate cancers; however, the current recommendation can be based on the most predominant score and the tertiary score, thereby contributing further to the upward trend in grade allocation over time.12 An important consequence of changes in diagnostic practices that alter disease classification during the follow-​up period of longitudinal studies is partial misclassification of the outcome. This may obscure aetiological relations between exposures and risk for disease. To address this issue, some prospective observational studies and clinical trials have standardized prostate cancer grade14 and stage15 data and collected detailed information on a participant’s PSA screening history.16 However, this may not be feasible for large, international and/​or multicentre studies. Furthermore, for studies without information on prostate cancer screening, it becomes difficult to ascertain the likely lead time associated with an individual’s diagnosis and to account for this in the analytical methodology. In summary, the complex natural history of prostate cancer and the use of PSA testing means that incident prostate cancer represents a heterogeneous group of cancers which may impede aetiological investigations. While information on stage and grade of disease may help to differentiate risk factors for disease initiation

46

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Section 6  Oncology

and progression, this remains a relatively imprecise tool. The totality of the evidence from epidemiological research of risk factors for prostate cancer should be interpreted with these caveats in mind.

cancer incidence rates and trends is in part due to the substantial differences worldwide in the diagnosis of latent cancers through PSA testing of asymptomatic individuals, as well as during prostate surgery. In comparison with the very wide variation in incidence of prostate cancer between economically developed and developing countries, there is less variation in mortality rates, although this is still substantial (Fig. 6.1.2). Age-standardized mortality rates for prostate cancer are highest in the Caribbean and sub-​Saharan Africa (more than 24 per 100,000 men per year), and moderately high in Western countries (between 9 and 15 per 100,000 men per year).1 The lowest age standardized mortality rates are experienced in parts of Asia, especially South-Central Asia, with less than three prostate cancer deaths per 100,000 men per year.1 Mortality rates are less sensitive than incidence rates to diagnostic practices, and so provide a more accurate reflection of the true underlying variation in rates of prostate cancer between countries. For example, despite a nearly 30% higher incidence rate among white men in the United States compared with the United Kingdom, 2012 age-​ adjusted mortality rates in these two countries show a higher mortality rate in the United Kingdom than the United States with 13.1 and 9.8 deaths per 100,000 men per year, respectively.

Prostate cancer incidence and mortality Geographic trends Prostate cancer is the second most common malignancy and the sixth leading cause of cancer death among men worldwide. There were an estimated 1,111,700 new cases and 307,500 new deaths in 2008.1 The worldwide prostate cancer burden is expected to grow to 1.7 million new cases and 499,000 new deaths by 2030 simply due to the growth and ageing of the global population.1 Although prostate cancer is the most common type of cancer diagnosed in men in most Western countries,1 there are large differences between countries in the age standardized incidence rate of the disease (Fig. 6.1.1). The highest age standardized incidence rates of prostate cancer are reported in Western Europe, North America, and Australia, with rates per 100,000 men ranging from 85 to 112 per year, while the lowest rates, between 4.5 and 11.2 per 100,000 men per year, are reported in Northern Africa and South-​Central, Eastern, and Southeastern Asia.17 It is important to acknowledge that although incidence rates can provide useful information about the distribution and frequency of cancer, a reliable calculation requires adequate health infrastructure, including a sophisticated healthcare system, universal access to a diagnosis, good health records, and consistent and timely reporting of new cases to a population-​based cancer registry. Differences in healthcare delivery or uptake and reporting of cancers, either between populations or over time, distort temporal and population comparisons, and the wide variation in international prostate South Central Asia

Temporal trends Much of the observed geographic variation in prostate cancer incidence may be due to differences in screening practices and the prevalence of PSA testing, which increases early detection of tumours and latent disease.18 Following the introduction of widespread PSA testing in the United States in the late 1980s, prostate cancer incidence increased by 100% over a seven-​year period, reaching a peak incidence in 1992 (in excess of 100 cases

4.5

Eastern Asia

10.5

Northern Africa

10.6

South Eastern Asia

11.2

Eastern Africa

23.3

Western Africa

25.1

Middle Africa

27

Western Asia

28

Central America

28.4

Central and Eastern Europe

31.3

Southern Europe

58.6

Micronesia

60

Southern America

60.1

Southern Africa

61.7

Caribbean

79.8

Polynesia

81.9

Northern Europe

85

Western Europe

85.8

Northern America

97.2

Australia/New Zealand

111.6 0

20

40

60

80

100

120

Age standardized (world) prostate cancer incidence rates per 100,000 men

Fig. 6.1.1  Age standardized prostate cancer incidence rates by world area. Source: data from GLOBOCAN 2012 Estimated Cancer Incidence, Mortality and Prevalence Worldwide, International Agency for Research on Cancer (IARC) Cancer. Lyon, France, Copyright © 2017 IARC.

 47

Chapter 6.1 

South Central Asia

2.9

Eastern Asia

3.1

South Eastern Asia

epidemiology of prostate cancer

6.7

Northern Africa

7

Southern Europe

9.1

Northern America

9.8

Western Europe

10.7

Central and Eastern Europe

11.6

Micronesia

11.9

Central America

12.1

Australia/New Zealand

12.9

Western Asia

13.1

Northern Europe

14.5

Polynesia

15.1

Southern America

16.6

Eastern Africa

18.7

Western Africa

21.2

Middle Africa

24.2

Southern Africa

24.4

Caribbean

29.3 0

20 40 60 80 100 Age standardized (world) prostate cancer mortality rates per 100,000 men

120

Fig. 6.1.2  Age standardized prostate cancer mortality rates by world area. Source: data from GLOBOCAN 2012 Estimated Cancer Incidence, Mortality and Prevalence Worldwide, International Agency for Research on Cancer (IARC) Cancer. Lyon, France, Copyright © 2017 IARC.

200

Rate per 100,000 men

180 160 140 120 100 80 60 1985

1990

1995

2000

2005

2010

2015

Year of diagnosis

Fig. 6.1.3  European age standardized incidence rates per 100,000 men in the United Kingdom. Source: data from Cancer Research UK, available from http://​www.cancerresearchuk.org/​health-​professional/​cancer-​statistics

per 100,000 population per year19) and subsequently declined to 85 cases per 100,000 population per year in 2008, as the proportion of prevalent cases diminished.17 Similar incidence trends have been observed in countries with high uptake of PSA testing, such as Australia and Canada. In the United Kingdom, incidence rates increased more gradually between 1993 and 2009, which may reflect the lower prevalence of PSA testing, with only 6% of men aged 45–​84 years tested in 200220 compared with 57% in

the United States,21 and 34% in Canada22 in 2001 (see Fig. 6.1.3 for the temporal trend in prostate cancer incidence in the United Kingdom). Prostate cancer mortality in most developed countries has been decreasing over the past 10 years,1 as illustrated for the United Kingdom in Figure 6.1.4. The reasons for this decrease are not well understood, and may include general improvements in treatment and medical care, as well as earlier diagnosis of disease. The

447

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65 60

Rate per 100,000 men

448

55 50 45 40 35 30 1985

1990

1995

2000

2005

2010

2015

Year of death

Fig. 6.1.4  European age standardized mortality rates per 100,000 men in the United Kingdom. Source: data from Cancer Research UK, available from http://​www.cancerresearchuk.org/​health-​professional/​cancer-​statistics

role of PSA testing in mortality reduction has been contentious; a European trial23,24 reported a 20% reduced rate of death from prostate cancer in the arm screened with PSA, which was maintained after extended follow-​up. In contrast, a large randomized controlled trial in the United States25 reported no reduction in mortality with PSA testing after 10 years of follow-​up, but had low power to detect an effect of organized screening because of high rates of PSA testing in the control arm of the trial. In contrast to the downward trend observed in Northern America, Western and Northern Europe, and Australia, mortality appears to be increasing in Eastern Europe and several Asian countries, including Japan.26 This increase may be related to changes in exposure to environmental risk factors, such as the increasing adoption of a Western lifestyle and corresponding changes in dietary habits which may influence the progression of prostate cancer. While some of the variation in incidence and mortality rates between countries and over time is attributable to differences in screening and diagnostic practices,27,28 access to healthcare, treatment practices, and death certificate reporting,29,30 the magnitude of the difference (with a more than a fivefold variation in mortality rates between high-​and low-​risk countries) suggests that exposures to either lifestyle, environmental, and/​or genetic factors must play an important part in the development of prostate cancer to a clinical and ultimately fatal form.

Risk factors Established risk factors for prostate cancer Advanced age,31 African ethnic origin,32,33 a family history of disease,34–​41 and genetic factors42 are the only well-​established risk factors for prostate cancer. Nonetheless, there is much interest in the role of endogenous hormones, diet, and other lifestyle factors in relation to prostate cancer risk.

Age Worldwide, very few cases of prostate cancer occur in men aged less than 50  years, but incidence and mortality rates increase

exponentially with age. In 2008, worldwide age-​specific rates per 100,000 population per year were 1.2 in men aged 40–​44 but rose to 4.9, 19.1, 51.8, 114.6, 204.6, 293.2 for each successive five-​ year age group, with the highest rate of 392.1 in men 75 years or older.43

Ethnicity The incidence of prostate cancer in American black men is 50–​60% greater than that for American white men.44 Between 2002 and 2006, the prostate cancer incidence was 146.3 and 231.9 cases per 100,000 population in whites and blacks, respectively,45 although this may be an underestimate of the difference because PSA testing uptake is lower in black men.46 Incidence rates of prostate cancer in black men living in the Caribbean are lower than those observed in American black men—​but the extent to which this difference reflects a true lower risk or less case ascertainment via PSA testing is difficult to determine. Data on prostate cancer incidence are available for parts of Africa and vary substantially, with generally higher rates in western and southern Africa than in northern and eastern Africa. In a study conducted in the United Kingdom, higher rates of prostate cancer were observed in black (166; 95% CI 151–​180 per 100,000 population per year) than in white men (56.4; 95% CI 53.3–​59.5 per 100,000 population per year) and the higher risk in black men compared with white men was more apparent in younger age groups (p heterogeneity 100 ng/ml 575 (8.3%) had missing data

13,917 died from any cause 299 (0.4%) died from prostate cancer 189 died in yr 1–9 110 died in yr 10 or late

89,352 were assigned to the control group

Prostate cancer cases 5396 (6.0%) had prostate cancer 4044 had prostate cancer in yr 1–9 1352 had prostate cancer in yr 10 or late Risk-group distribution 2249 (41.7%) were at low risk 1442 (26.7%) were at intermediate risk 673 (12.5%) were at high risk 424 (7.9%) had M1 or PSA >100 ng/ml 608 (11.3%) had missing data

17,256 died from any cause 462 (0.5%) died from prostate cancer 274 died in yr 1–9 188 died in yr 10 or late

Fig. 6.5.2  Enrollment and outcomes in the ERSPC study. From The New England Journal of Medicine, Fritz H. Schröder et al, ‘Prostate-​Cancer Mortality at 11 Years of Follow-​up’, Volume 366, Issue 11, pp. 981–​90, Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

gain of 73 years or 8.4 years per prostate cancer death avoided was calculated. The number of quality of life adjusted life years gained was 56, a reduction of 23% from the 73 life years. This information will be important for healthcare providers and public health authorities in judging on the value of prostate cancer screening.

Definitions of screening In this chapter, we follow the criteria of screening defined by Wilson and Jungner16 in 1968. These criteria seem old but have survived and are still used in the critical assessment of cancer screening trials. These experts define screening as ‘the presumptive identification of unrecognized disease or defect by the application of tests, examinations of other procedures which can be applied rapidly’. The authors then state that screening tests differentiate apparently well persons from those who probably have a disease. A screening test is not intended to be diagnostic. Furthermore, because all screening trials select for men at certain age groups, the definition of ‘selective screening’ applies. As the term is used for selection of high-​risk populations, it may be applied to population-​based screening. These procedures are strictly differentiated from ‘case finding’ of which the main object is ‘to detect disease and bring patients to treatment, in contrast to epidemiological surveys’. The criteria of Wilson and Jungner will be used to structure the present chapter. The criteria are given in Box 6.5.1.16

Quality requirements for screening trials, population screening, and case finding This chapter will provide a step-​by-​step discussion of the ten pre-​ requirements for population-​based screening. In doing so, most information will be used to judge whether the requirements are presently met for prostate cancer screening trials and what the future perspectives may be.

 485

32,298 men in Gotebrog on Dec 31, 1994, aged 50–64 years

20,000 randomized in a 1:1 ratio

48 excluded 19 deceased or emigrated before randomization date 29 men with prevalent prostate cancer

9,552 invited every 2 years for PSA testing 1995–2008 (screening group)

48 excluded 21 deceased or emigrated before randomization date 27 men with prevalent prostate cancer

9,552 not invited (control group)

7,578 attendees

2,374 non-attendees

1,046 with PC 27 died from PC

92 with PC 17 died from PC

718 with PC 78 died from PC

Fig. 6.5.3  Trial profile, ERSPC Göteborg. Reprinted from The Lancet Oncology, Volume 11, Issue 8, Jonas Hugosson et al., ‘Mortality results from the Göteborg randomised population-​based prostate-​cancer screening trial’, pp. 725–​732, Copyright © 2010 Elsevier Ltd., with permission from Elsevier, http://​www.sciencedirect.com/​science/​journal/​14702045

150

Cumulative number of deaths

125

100

75

50

25 Study arm Control Intervention

0 0

1

2

3

4

5

7

6

8

9

11

10

12

13

Study year of death Cumulative deaths – I Cumulative PY – I Cumulative deaths – C Cumulative PY – C

3 38,217 1 38,223

6 12 16 26 36 51 61 80 98 118 140 158 * 76,112 113,629 150,725 187,382 223,541 259,118 294,052 328, 048 359,768 387,164 409,535 426,977 * 4

11

18

23

33

44

59

69

85

108

133

145

*

76,132 113,635 150,689 187,278 223,329 258,811 293,631 327,455 358,904 386,109 408,262 425,439 *

Fig. 6.5.4  Nelson–​Aalen curves of PLCO, ERSPC, and the Göteborg trial. PLCO: Cumulative deaths from prostate cancer in the intervention and control arms from year 1 to 13; C: control arm; I: intervention arm; PY: person years. Reproduced from Gerald L. Andriole et al., ‘Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-​ up’, Journal of the National Cancer Institute, Volume 104, Issue 2, pp. 125–​32, Copyright © 2012, by permission of Oxford University Press.

486

Section 6  Oncology

0.014

Cumulative hazard of death from prostate cancer

0.012 0.010 Control group

0.008 0.006 0.004

Screening group

0.002 0.000

0

2

4

6

8

10

12

14

Years since randomization

Fig. 6.5.5  Cumulative hazard of death from prostate cancer among men 55–​69 years of age in the ERSPC study. From The New England Journal of Medicine, Fritz H. Schröder et al, ‘Prostate-​Cancer Mortality at 11 Years of Follow-​up’, Volume 366, Issue 11, pp. 981–​90, Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

0.010 Nelson–Aalen cumulative hazard estimates

486

0.008

0.006

0.004

0.002

0

Number at risk Screening group Control group

Screening group Control group

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Time from randomization (years) 9,952 9,952

9,333 9,345

8,585 8,580

7,746 7,755

Fig. 6.5.6  ERSPC Göteborg—​cumulative risk of death from prostate cancer using Nelson–​Aalen cumulative hazard estimates. Reprinted from The Lancet Oncology, Volume 11, Issue 8, Jonas Hugosson et al., ‘Mortality results from the Göteborg randomised population-​based prostate-​cancer screening trial’, pp. 725–​732, Copyright © 2010 Elsevier Ltd., with permission from Elsevier, http://​www.sciencedirect.com/​science/​journal/​14702045

‘The condition sought should be an important health problem’ This section leans on variations in prostate cancer incidence and mortality worldwide (this article17 is recommended reading). As seen in Figure 6.5.7,17 incidence and mortality vary considerably with geographic location. In most Western countries, prostate cancer is the most frequently diagnosed cancer and the second or third most frequent cause of cancer related deaths in men. The reasons for strong geographic variations are not entirely understood, but are likely to involve PSA testing. Classical examples include the rise of prostate cancer incidence in the United States between 1983 and 199318 following PSA use advocacy, compared to a country where PSA use for early detection of prostate cancer has been strongly discouraged by

the government (e.g. in Denmark the incidence did not rise in the late 1990s). The rise of PSA-​driven incidence due to screening is considered undesirable and so no single country in the world at this moment recommends screening for prostate cancer using the PSA test. The incidence is due to so called ‘opportunistic screening’, which may be patient and physician driven. The uncertainty about screening is the result of lacking evidence that damage and potential benefits of screening are in an acceptable balance.13 Prostate cancer mortality has shown trends to decrease in many countries around the world, often in line with an increased use of early diagnostic testing. Again, the most typical example is the United States. It is estimated17 that between 1996 and 2005 prostate cancer mortality has decreased at an annual rate of 4.3%, a total decrease of 43%. Obviously, this mortality decrease, which in trend is seen in many other countries, can not be

 487

Chapter 6.5 

Box 6.5.1  Pre-​requirements for the application of screening 1. The condition sought should be an important health problem. 2. There should be an accepted treatment for patients with recognized disease. 3. Facilities for diagnosis and treatment should be available. 4. There should be a recognizable latent or early symptomatic stage. 5. The natural history of the condition, including development from latent to declared disease, should be adequately understood. 6. There should be an agreed policy on whom to treat as patients. 7. There should be a suitable test or examination. 8. The test should be acceptable to the population. 9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. 10. Case finding should be a continuing process and not a ‘once and for all’ project. Reproduced with permission from Wilson JMG and Jungner G., Principles and practice of screening for disease, pp. 26–​27, World Health Organization, Geneva, Switzerland, Copyright © World Health Organization 1968.

United States

conclusively explained at this present time. In a two-​centre modelling experiment, Etzioni et al.19 suggest that 45–​70% of the mortality decrease may be due to opportunistic screening. The remaining change in mortality is attributed to improvement in treatment, mainly by radical prostatectomy, radiotherapy, and maybe most importantly, radiotherapy combined with endocrine treatment in locally advanced disease.20,21 An increase in incidence is also seen in some of the traditional low-​risk countries of East Asia such as Japan. An unusual example is Korea, where incidence rise is accompanied with a rise in mortality. The best possible explanation for this may be the change of dietary habits in Korea, which in the past may have been the reason for the low incidence and mortality of this disease. Considering the available data, there is little doubt that the first requirement is met and that prostate cancer can be considered an important health problem.

‘There should be an accepted treatment for patients with recognized disease and facilities for diagnoses and treatment should be available’ Significant progress in treatment of locally confined, locally advanced, and metastatic prostate cancer has been made in years. Technical improvements of radical prostatectomy led to improvements of functional and oncological outcomes.22,23 A  large Scandinavian study compared radical prostatectomy to watchful waiting in 679 men randomized with a follow-​up of 12.8 years.24 The study recruited selected clinical participants and very few screen-​detected cancers. The study group found an absolute risk Italy

The Netherlands

200

200

200

100

100

100

10

10

10

1

5

8 19

90 95 000 2 19 19

8

0 20

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5

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90 95 000 2 19 19

Denmark

8

0 20

1

85

19

200

100

100

90 995 000 2 1

19

08

20

Republic of Korea

Japan

200

screening for prostate cancer

200 100

100 10

10

1

1

5

8 19

90 95 000 2 19 19

8

0 20

1

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8 19

90 95 000 005 009 2 2 2 19 19

0.1

85

19

90 995 000 005 009 2 2 2 1

19

Fig. 6.5.7  Join point regression of incidence and mortality in six selected areas. Reprinted from European Urology, Volume 61, Issue 6, Melissa M. Center et al., ‘International Variation in Prostate Cancer Incidence and Mortality Rates’, pp. 1079–​1092, Copyright © 2012 European Association of Urology, with permission from Elsevier, http://​www.sciencedirect.com/​science/​journal/​03022838

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reduction of death from prostate cancer of 6.1% and a 38% relative reduction. Overall survival improved in a similar fashion. In a study of 415 patients with locally advanced disease treated by either radiotherapy alone or androgen suppression for a period of three years post-​treatment, a study group of the European Organization for Research and Treatment of Cancer (EORTC) found with a 9.1-​year follow-​up significant improvements in prostate cancer specific and overall survival in the range of 25%.20 After this keynote study, the question of whether hormone therapy might have the same effect remained open. This question was addressed by the Scandinavian Prostate Cancer Group in a study randomizing men with lymph node positive disease between endocrine treatment alone and endocrine treatment plus radiotherapy. The study found a significant advantage of the combination treatment. After this, for locally advanced disease radiotherapy plus endocrine treatment for a period of three years can be considered standard management. The period of post-​radiotherapy treatment was subject to another EORTC study, which confirmed an advantage of the three-​year treatment.25 Metastatic disease is rarely diagnosed through screening. If so, standard forms of endocrine treatment are applied. In most countries, facilities for diagnosis and treatment of prostate cancer are readily available. If anything, as indicated in the previous section, there may be an overutilization of the available diagnostic tests, including PSA and subsequent biopsies. The large differences between incidence and mortality seen in Figure 6.5.7 are also confirmed in the available randomized studies and overdiagnosis has been quantified to be in the range of 50%.14 To curb opportunistic screening and the rates of overdiagnosis and overtreatment is one of the key issues to be dealt with in urological research in the nearby future. The performance characteristics of PSA were unknown for many years, until the placebo control arm of the Prostate Cancer Prevention Trial (PCPT) could be carried out. In more than 5,000 men who initially presented with PSA values below 3.0 ng/​mL (low risk), sextant prostate biopsies were carried out after a follow-​up of seven years irrespective of PSA values or findings at rectal examination. The data are summarized in Table 6.5.1 and derived from

Table 6.5.1  Performance characteristics of prostate-​specific antigen Any PCa vs. no PCa PSA level

Gleason ≥7 vs. 50 ng/​mL and/​or PSA-​DT or = 20 ng/​ml undergoing radical prostatectomy. Eur Urol 2007; 52(4):1058–​65. 54. Magheli A, Rais-​Bahrami S, Peck HJ, et al. Importance of tumor location in patients with high preoperative prostate specific antigen levels (greater than 20 ng/​ml) treated with radical prostatectomy. J Urol 2007; 178(4 Pt 1):1311–​15. 55. Gontero P, Spahn M, Tombal B, et al. Is there a prostate-​specific antigen upper limit for radical prostatectomy? BJU Int 2011; 108(7):1093–​100. 56. Abdolah F, Sun M, Thuret R, et al. Lymph node count threshold for optimal pelvic lymph node staging in prostate cancer. Int J Urol 2012; 19(7):645–​51. 57. Briganti A, Blute ML, Eastham JH, et al. Pelvic lymph node dissection in prostate cancer. Eur Urol 2009; 55(6):1251–​65. 58. Briganti A, Suardi N, Gallina A, Abdollah F, Montorsi F. Pelvic lymph node dissection in prostate cancer: the mistery is taking shape. Eur Urol 2013; 63(3):459–​61. 59. Briganti A, Suardi N, Capgrosso P, et al. Lymphatic spread of nodal metastases in high-​risk prostate cancer: The ascending pathway from the pelvis to the retroperitoneum. Prostate 2012; 72(2):186–​92. 60. Schreiber D, Rineer J, Sura S, et al. Radical prostatectomy for cT3–​4 disease: an evaluation of the pathological outcomes and patterns of care for adjuvant radiation in a national cohort. BJU Int 2011; 108(3):360–​5. 61. Johnstone PA, Ward KC, Goodman M, Assikis V, Petros JA. Radical prostatectomy for clinical T4 prostate cancer. Cancer 2006; 106(12):2603–​9. 62. Joniau S, Hsu CY, Gontero P, Spahn M, Van Poppel H. Radical prostatectomy in very high-​risk localized prostate cancer: long-​ term outcomes and outcome predictors. Scand J Urol Neprol 2012; 46(3):164–​71. 63. Schumacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Good outcome for patients with few lymph node metastases after radical retropubic prostatectomy. Eur Urol 2008; 54(2):344–​52. 64. Da Pozzo LF, Cozzarini C, Briganti A, et al. Long-​term follow-​up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur Urol 2009; 55(5):1003–​11. 65. Engel J, Bastian PJ, Baur H, et al. Survival benefit of radical prostatectomy in lymph node-​positive patients with prostate cancer. Eur Urol 2010; 57(5):754–​61. 66. Steuber T, Budäus L, Walz J, et al. Radical prostatectomy improves progression-​free and cancer-​specific survival in men with lymph node positive prostate cancer in the prostate-​specific antigen era: a confirmatory study. BJU Int 2011; 107(11):1755–​61. 67. Briganti A, Karnes RJ, Da Pozzo LF, et al. Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2–​4 pN+ prostate cancer: results of a matched analysis. Eur Urol 2011; 59(5):832–​40. 68. Schröder FH, Kurth KH, Fosså SD, et al. Members of the European Organisation for the Research and Treatment of Cancer Genito-​ urinary Group. Early versus delayed endocrine treatment of pN1–​3 M0 prostate cancer without local treatment of the primary tumor: results

69.

70.

71. 72.

73. 74. 75. 76.

77.

78. 79.

80.

81.

82. 83.

84.

of European Organisation for the Research and Treatment of Cancer 30846-​-​a phase III study. J Urol 2004; 172(3):923–​7. Messing EM, Manola J, Yao J, et al. Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-​positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006; 7(6):472–​9. Briganti A, Karnes JR, Da Pozzo LF, et al. Two positive nodes represent a significant cut-​off value for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a two-​ institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur Urol 2009; 55(2):261–​70. Van Poppel H, Joniau S. An analysis of radical prostatectomy in advanced stage and high-​grade prostate cancer. Eur Urol 2008; 53(2):253–​9. Gontero P, Marchioro G, Pisani R, et al. Is radical prostatectomy feasible in all cases of locally advanced non-​bone metastatic prostate cancer? Results of a single-​institution study. Eur Urol 2007; 51(4):922–​9. Lerner SE, Blute ML, Zincke H. Extended experience with radical prostatectomy for clinical stage T3 prostate cancer: outcome and contemporary morbidity. J Urol 1995; 154(4),1447–​52. Joniau S, Van Baelen A, Hsu CY, Van Poppel H. Complications and functional results of surgery for locally advanced prostate cancer. Adv Urol 2012; 2012:706309. Daly T, Hickey BE, Lehman M, Francis DP, See AM. Adjuvant radiotherapy following radical prostatectomy for prostate cancer. Cochrane Database Syst Rev 2011; (12):CD007234. Morgan SC, Walker-​Dilks C, Goldman B, et al. Does the benefit of adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-​positive prostate cancer extend to all pathologic subgroups? A meta-​analysis of the randomised trials. Int J Radiat Oncol Biol Phys 2010; 78(3):S29–​30. Zakeri K, Rose BS, Gulaya S, D’Amico AV, Mell LK. Competing event risk stratification may improve the design and efficiency of clinical trials: Secondary analysis of SWOG 8794. Contemp Clin Trials 2013; 34(1):74–​9. Thompson IM Jr, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006; 296(19):2329–​35. Bolla M, Van Poppel H, Tombal B, et al. European Organisation for Research and Treatment of Cancer, Radiation Oncology and Genito-​Urinary Groups. Postoperative radiotherapy after radical prostatectomy for high risk prostate cancer: long-​term results of a randomized controlled trial (EORTC trial 22911). Lancet 2012; 380(9858):2018–​27. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-​specific antigen: ARO 96–​02/​AUO AP 09/​95. J Clin Oncol 2009; 27(18):2924–​30. Swanson GP, Hussey MA, Tangen CM, et al.; SWOG 8794. Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007; 25(16):2225–​9. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007; 25(15):2035–​41. Ost P, De Troyer B, Fonteyne V, Oosterlink W, De Meerleer G. A matched control analysis of adjuvant and salvage high-​dose postoperative intensity-​modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2011; 80(5):1316–​22. Trabulsi EJ, Valicenti RK, Hanlon AL, et al. A multi-​institutional matched-​control analysis of adjuvant and salvage postoperative radiation therapy for pT3–​4N0 prostate cancer. Urology 2008; 72(6):1298–​302.

 53

Chapter 6.9 

85. Briganti A, Wiegel T, Joniau S, et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-​controlled multi-​institutional analysis. Eur Urol 2012; 62(3):472–​87. 86. Viani GA, Stefano EJ, Afonso SL. Higher-​than-​conventional radiation doses in localized prostate cancer treatment: a meta-​analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009; 74(5):1405–​18. 87. Coen JJ, Zietman AL, Thakral H, Shipley WU. Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases. J Clin Oncol 2002; 20(15):3199–​205. 88. Zelefsky MJ, Yamada Y, Fuks Z, et al. Long-​term results of conformal radiotherapy for prostate cancer: impact of dose escalation on biochemical tumor control and distant metastases-​free survival outcomes. Int J Radiat Oncol Biol Phys 2008; 71(4):1028–​33. 89. Ost P, Fonteyne V, Villeirs G, Lumen N, Oosterlinck W, De Meerleer G. Adjuvant high-​dose intensity-​modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients. Eur Urol 2009; 56(4):669–​75. 90. King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys 2008; 71(2):346–​50. 91. Bernard JR Jr, Buskirk SJ, Heckman MG, et al. Salvage radiotherapy for rising prostate-​specific antigen levels after radical prostatectomy for prostate cancer: dose-​response analysis. Int J Radiat Oncol Biol Phys 2010; 76(3):735–​40. 92. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006; 97(2):247–​54. 93. Wirth MP, Weissbach L, Marx FJ, et al. Prospective randomized trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for locally advanced, lymph node-​negative prostate cancer. Eur Urol 2004; 45(3):267–​70. 94. Dorff TB, Flaig TW, Tangen CM, et al. Adjuvant androgen deprivation for high-​risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol 2011; 29(15):2040–​5. 95. Schubert M, Joniau S, Gontero P, et al. The role of adjuvant hormonal treatment after surgery for localized high-​risk prostate cancer: results of a matched multiinstitutional analysis. Adv Urol 2012; 2012:612707. 96. Isbarn H, Boccon-​Gibod L, Carroll PR, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 2009; 55(1):62–​75. 97. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node-​positive prostate cancer. J Clin Oncol 2009; 27(1):100–​5. 98. Boorjian SA, Thompson RH, Siddiqui S, et al. Long-​term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol 2007; 178:864–​70. 99. Shelley MD, Kumar S, Wilt T, Staffurth J, Coles B, Mason MD. A systematic review and meta-​analysis of randomised trials of neo-​ adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev 2009; 35(1):9–​17. 100. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-​adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006; (4):CD006019. 101. Mostaghel EA, Nelson P, Lange PH, et al. Neoadjuvant androgen pathway suppression prior to prostatectomy. J Clin Oncol 2012; 30(15 Suppl):282s (abs.4520). 102. Taplin ME, Montgomery RB, Logothetis C, et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-​risk prostate cancer (LHRPC): Results of a randomized phase II study. J Clin Oncol 2012; 30(15 Suppl):282s (abs.4521).

high-risk prostate cancer

103. Efstathiou E, Davis JW, Troncoso P, et al. Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-​risk prostate cancer (PCa): Preliminary results of a randomized preoperative study. J Clin Oncol 2012; 30(15 Suppl):291s (abs.4556). 104. Ryan CJ, Tindall DJ. Androgen receptor rediscovered: the new biology and targeting the androgen receptor therapeutically. J Clin Oncol 2011; 29(27):3651–​8. 105. Briganti A, Karnes RJ, Da Pozzo LF, et al. Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2–​4 pN+ prostate cancer: results of a matched analysis. Eur Urol 2011; 59(5):832–​40. 106. Ost P, Cozzarini C, De Meerleer G, et al. High-​dose adjuvant radiotherapy after radical prostatectomy with or without androgen deprivation therapy. Int J Radiat Oncol Biol Phys 2012; 83(3):960–​5. 107. Shipley WU, Hunt D, Lukka H, et al. Initial report of RTOG 9601: A phase III trial in prostate cancer: Anti-​androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) improves freedom from progression and reduces the incidence of metastatic disease in patients following radical prostatectomy (RP) with pT2–​3, N0 disease, and elevated PSA levels. Int J Radiat Oncol Biol Phys 2010; 78:S27 (abs.58). 108. Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) trial 86–​10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 50(5):1243–​52. 109. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85–​31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 49(4):937–​46. 110. Viani GA, Stefano EJ, Afonso SL. Higher-​than-​conventional radiation doses in localized prostate cancer treatment: a meta-​analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009; 74(5):1405–​18. 111. Pieters BR, de Back DZ, Koning CCE, Zwinderman AH. Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: a systematic review. Radiother Oncol 2009; 93(2):168–​73. 112. Hoskin PJ, Rojas AM, Bownes PJ, Lowe GJ, Ostler PJ, Bryant L. Randomised trial of external beam radiotherapy alone or combined with high-​dose-​rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103(2):217–​22. 113. Arcangeli G, Saracino B, Gomellini S, et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-​risk prostate cancer. Int J Radiat Oncol Biol Phys 2010; 78(1):11–​18. 114. Shelley MD, Kumar S, Wilt T, Staffurth J, Coles B, Mason MD. A systematic review and meta-​analysis of randomised trials of neo-​ adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev 2009; 35(1):9–​17. 115. Bria E, Cuppone F, Giannarelli D, et al. Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?: meta-​analysis of randomized trials. Cancer 2009; 115(15):3446–​56. 116. Shelley MD, Kumar S, Coles B, Wilt T, Staffurth J, Mason MD. Adjuvant hormone therapy for localised and locally advanced prostate carcinoma: a systematic review and meta-​analysis of randomised trials. Cancer Treat Rev 2009; 35(7):540–​6. 117. Verhagen PC, Schröder FH, Collette L, Bangma CH. Does local treatment of the prostate in advanced and/​or lymph node metastatic disease improve efficacy of androgen-​deprivation therapy? A systematic review. Eur Urol 2010; 58(2):261–​9. 118. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-​ adjuvant and adjuvant hormone therapy for localised and locally

535

536

536

Section 6  Oncology

119.

120. 121. 122.

123. 124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

advanced prostate cancer. Cochrane Database Syst Rev 2006 Oct 18;(4):CD006019. Nanda A, Chen MH, Braccioforte MH, Moran BJ, D’Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-​induced congestive heart failure or myocardial infarction. JAMA 2009; 302(8):866–​73. D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008; 299(3):289–​95. Bolla M, de Reijke TM, van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009; 360(24):2516–​27. Horwitz EM, Bae K, Hanks GE, et al. Ten-​year follow-​up of radiation therapy oncology group protocol 92–​02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008; 26(15):2497–​504. Harmenberg U, Hamdy FC, Widmark A, Lennernas B, Nilsson S. Curative radiation therapy in prostate cancer. Acta Oncol 2011; 50(Suppl 1):98–​103. Zelefsky MJ, Pei X, Chou JF, et al. Dose escalation for prostate cancer radiotherapy: predictors of long-​term biochemical tumor control and distant metastases-​free survival outcomes. Eur Urol 2011; 60(6):1133–​9. Denham JW, Steigler A, Lamb DS, et al. Short-​term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-​Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 2005; 6(11):841–​50. Denham JW, Steigler A, Lamb DS, et al. Short-​term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-​year data from the TROG 96.01 randomised trial. Lancet Oncol 2011; 12(5):451–​9. Roach M, Bae K, Speight J, et al. Short-​term neoadjuvant androgen deprivation therapy and external-​beam radiotherapy for locally advanced prostate cancer: long-​term results of RTOG 8610. J Clin Oncol 2008; 26(4):585–​91. Bolla M, Collette L, Blank L, et al. Long-​term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360(9327):103–​6. Bolla M, Collette L, Van Tienhoven G, et al. Ten year results of long term adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: a phase III EORTC study. Int J Radiat Oncol Biol Phys 2008; 72:S30–​1. (abs. 65). Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma-​-​long-​term results of phase III RTOG 85–​31. Int J Radiat Oncol Biol Phys 2005; 61(5):1285–​90. See WA, Tyrrell CJ. The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer. J Cancer Res Clin Oncol 2006; 132(Suppl 1):S7–​S16. Laverdière J, Nabid A, De Bedoya LD, Ebacher A, Fortin A, Wang CS, Harel F. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-​T3 prostate cancer. J Urol 2004; 171(3):1137–​40. Roach M, DeSilvio M, Lawton C, et al. Phase III trial comparing whole-​pelvic versus prostate-​only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003; 21(10):1904–​11. Lawton CA, DeSilvio M, Roach M, et al. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94–​13, with emphasis on unexpected hormone/​radiation interactions. Int J Radiat Oncol Biol Phys 2007; 69(3):646–​55.

135. Pommier P, Chabaud S, Lagrange JL, et al. Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-​01. J Clin Oncol 2007; 25(34):5366–​73. 136. Nguyen PL, D’Amico AV. Targeting pelvic lymph nodes in men with intermediate-​and high-​risk prostate cancer despite two negative randomized trials. J Clin Oncol 2008; 26(12):2055–​6. 137. Roach M. Targeting pelvic lymph nodes in men with intermediate-​ and high-​risk prostate cancer, and confusion about the results of the randomized trials. J Clin Oncol 2008; 26(22):3816–​17. 138. Abdollah F, Cozzarini C, Suardi N, et al. Indications for pelvic nodal treatment in prostate cancer should change. Validation of the Roach formula in a large extended nodal dissection series. Int J Radiat Oncol Biol Phys 2012; 83(2):624–​9. 139. Wang-​Chesebro A, Xia P, Coleman J, Akazawa C, Roach M. Intensity-​ modulated radiotherapy improves lymph node coverage and dose to critical structures compared with three-​dimensional conformal radiation therapy in clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2006; 66(3):654–​62. 140. Bastian PJ, Boorjian SA, Bossi A, et al. High-​risk prostate cancer: from definition to contemporary management. Eur Urol 2012; 61(6):1096–​106. 141. Zelefsky MJ, Eastham JA, Cronin AM, et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol 2010; 28(9):1508–​13. 142. Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-​adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-​deprivation therapy for localized prostate cancer. Cancer 2010; 116(22):5226–​34. 143. Arcangeli G, Strigari L, Arcangeli S, et al. Retrospective comparison of external beam radiotherapy and radical prostatectomy in high-​risk, clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2009; 75(4):975–​82. 144. Abdollah F, Sun M, Thuret R, et al. A competing-​risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988–​2006. Eur Urol 2011; 59(1):88–​95. 145. Boorjian SA, Karnes RJ, Viterbo R, Rangel LJ, Bergstralh, Horwitz EM. Long-​term survival after radical prostatectomy versus external-​ beam radiotherapy for patients with high-​risk prostate cancer. Cancer 2011; 117(13):2883–​91. 146. Parikh R, Sher DJ. Primary radiotherapy versus radical prostatectomy for high-​risk prostate cancer: a decision analysis. Cancer 2012; 118(1):258–​67. 147. Giordano SH, Kuo YF, Duan Z, Hortobagyi GN, Freeman J, Goodwin JS. Limits of observational data in determining outcomes from cancer therapy. Cancer 2008; 112(11):2456–​66. 148. Huggins C, Stevens R, Hodges CV. Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941; 43(2):209–​23. 149. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293–​7. 150. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-​7/​ SFUO-​3): an open randomised phase III trial. Lancet 2009; 373(9660):301–​8. 151. de la Taille A. Circumstances of prescription of hormone therapy for patients with prostate cancer. Prog Urol 2009; 19(5):313–​20. 152. Lu-​Yao GL, Albertsen PC, Moore DF, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 2008; 300(2):173–​81. 153. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006; 97(2):247–​54.

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154. Schulman CC, Irani J, Morote J. Androgen-​deprivation therapy in prostate cancer: a European expert panel review. Eur Urol 2010; 9(7):675–​91. 155. Hu JC, Williams SB, O’Malley AJ, Smith MR, Nguyen PL, Keating NL. Androgen-​deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol 2012; 61(6):1119–​28. 156. Studer UE, Collette L, Whelan P, et al. Using PSA to guide timing of androgen deprivation in patients with T0-​4 N0-​2 M0 prostate cancer

high-risk prostate cancer

not suitable for local curative treatment (EORTC 30891). Eur Urol 2008; 53(5):941–​9. 157. Flaig TW, Tangen CM, Hussain MHA, Stadler WM, Raghavan D, Crawford ED, Glodé LM. Randomization reveals unexpected acute leukemias in Southwest Oncology Group prostate cancer trial. J Clin Oncol 2008; 26(9):1532–​6. 158. Rosenthal SA, Sandler HM. Treatment strategies for high-​risk locally advanced prostate cancer. Nat Rev Urol 2010; 7(1):31–​8.

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CHAPTER 6.10

Technology and prostatectomy Giacomo Novara, Alexander Mottrie, Filiberto Zattoni, and Vincenzo Ficarra Introduction to technology and prostatectomy Radical prostatectomy (RP) is the gold standard surgical treatment for patients with clinically localized prostate cancer (PCa) and life expectancy more than 10 years.1 RP allows excellent local control of PCa and confers cancer-​specific survival benefit over watchful waiting. Moreover, long-​term oncological data after RP showed 25-​year biochemical recurrence (BCR)-​free survival and cancer-​ specific survival as high as and 55% and 80%, respectively.2 In the last decades, the desire to reduce the invasiveness of open retropubic RP (RRP) produced an increasing interest towards laparoscopic techniques. The shift from open to laparoscopic surgery represents a completely new experience for the surgeon, who must learn a new surgical anatomy, new operative procedures, and deal with new surgical tools. More specifically, the reduction of the range of motion (only 4 degrees of freedom (df)), two-​dimensional vision (two-​dimensional camera and display), the impaired eye–​ hand coordination (disorientation between real and visible movements), and the reduced haptic sense (minimal tactile feedback) are the main restrictions associated with a steep learning curve.3 For surgeons with no experience with laparoscopy, the learning period could amount to hundreds of cases, extending over several years, which limited the application of laparoscopy to complex procedures such RP. Robotic platforms have been introduced in an attempt to reduce the difficulty in performing complex laparoscopic procedures, particularly for non-​laparoscopic surgeons. The first system, with a surgeon’s console and remotely controlled telemanipulators, was developed with funding from the US Department of Defense in 1991 and came to be called the Stanford Research Institute Green Telepresence Surgery System after Phil Green, PhD.3 That early system had only 4 df, similar to standard laparoscopic instruments. In 1995, Fredrick Moll licensed the commercial rights to the SRI Green Telepresence Surgery System and used this acquisition to found Intuitive Surgical Systems. After further development, a renovated master–​slave clinical system was released in April 1997 in prototype form as the da Vinci surgical system, which received US Food and Drug Administration approval in July 2000. The da Vinci robot includes a true three-​dimensional imaging system that provides magnification up to ×12. This system also incorporates the patented EndoWrist technology, which duplicates the dexterity of the surgeon’s forearm and wrist at the operative site, thus providing 7 df.3 Although the acceptance of traditional laparoscopic radical prostatectomy (LRP) was limited primarily by the steep learning

curve of the procedure, robotic-​assisted laparoscopic radical prostatectomy (RARP) had a rapid and wide diffusion in the world. Today, in the United States, more than 75% of the radical prostatectomy are performed using Intuitive Surgical’s da Vinci platform and the procedure is largely adopted in several countries in the Western world.

Surgical technique According to Pasadena recommendations, RARP has the same indications accepted for RRP and LRP procedures. Specifically, patients with low-​and intermediate-​risk localized prostate cancer and a life expectancy >10 yr are the best candidates for RARP.4 Moreover, the procedure can be performed in patients with stage T1a disease and a life expectancy >15 yr or Gleason score 7; in selected patients with low volume high-​risk localized PCa and in highly selected patients with very high-​risk localized PCa (cT3b–​T4 N0 or any T N1) in the context of multimodal treatment. According to the most important international guidelines, in patients with high or very high-​risk disease the procedure must be anticipated from extended pelvic lymphadenectomy. This last category of patients together with those who are obese (BMI >30), with large prostate (prostate volume >70 gr), median lobe or receiving previous transurethral resection of prostate (TURP) or other procedure for benign prostatic hyperplasia (BPH) should be avoided in the learning curve step and reserved only for experienced surgeons. Similarly, patients requiring salvage RARP after radiation failure should be treated by very experienced surgeons. The majority of robotic surgeons perform RARP using a transperitoneal, antegrade (from bladder neck to the apex) approach. The patient is placed in supine position with the legs in a semi-​ lithotomy position with compression stockings and sequential compression device for deep vein thrombosis prophylaxis, using well-​padded Allen stirrups. The preferred primary access for pneumoperitoneum is represented by the Hasson technique, and only few surgeons still use the Verres needle. Usually, a longitudinal camera port incision is performed. However, Beck et al. proposed to use a transverse camera port incision to reduce the risk of camera port site hernia due to specimen extraction, particularly in obese patients and/​or patients with large prostates.5 After the insertion of the primary port, the abdomen is insufflated to a pressure of 15 mmHg. Then, the remaining ports are placed under direct camera supervision. Figure 6.10.1 shows the most used trocars placement. The definitive degree of Trendelenburg inclination is not standardized, and a wide range (between 10 and 40 degrees) is reported in the literature. The minimum possible degree of

 539

Chapter 6.10 

Fig. 6.10.1  Two 8 mm instrument trocars are placed approximately 7–​10 cm (one hand breadth) lateral of the umbilicus in the direction of the anterior superior iliac spine. A third 8 mm robotic port (for the fourth arm) is placed 7–​10 cm lateral to the left robotic port 2 cm above and anteriorly to the anterior superior iliac spine. Finally, a 5 mm assistant port is placed lateral to the camera port and superior to the right robotic port. A second 12 mm assistant port is placed 7–​10 cm directly lateral to the right robotic port.

Trendelenburg inclination should be performed to minimize the potential anesthesiology issues and to reduce the traction during the urethrovesical anastomosis step. After complete mobilization of the bladder, the periprostatic fat is removed from the endopelvic fascia and from the prostate. The majority of surgeons prefer opening the endopelvic fascia to gain access to the lateral surface of the prostate gland. Different techniques were described to show a clear outline of the prostatovesical junction. Then, the bladder neck is incised in the midline and deepened until the anterior muscular layer of the Denonvilliers’ fascia is encountered. The majority of robotic surgeons perform a bladder neck preservation to increase the continence rate and to improve the quality of the urethrovesical anastomosis. A transverse incision is made on anterior Denonvilliers’ fascia close to the prostate. Most of the robotic surgeons suggest an athermal dissection or a minimal use of cautery in the area of the seminal vesicles, in order to avoid injury to cavernous nerves. Vas deferens are divided and the seminal vesicles are completely dissected using a sharp dissection. Some surgeons spare the seminal vesicle tip in low-​risk patients in order to minimize the injury at level of cavernous nerves. Moreover, in low-​risk patients where nerve preservation is feasible, the posterior layer of Denonvilliers fascia can be left on the rectum while in high-​risk patients it should be included with the specimen. The Denonvillier’s fascia incision is made few millimetres below the base of the prostate. Once incised, the perirectal fat is visible covering the fascia propria of rectum and the incision is continued on Denonvillier’s fascia laterally along the entire width of prostate. The rectum can be separated from the prostate using scissors, under direct vision. The plane between rectum and prostate is defined by blunt and sharp dissection, continuing distally. The fascial space is dissected down all the way to the apex and laterally over the neurovascular bundles. Anatomical studies showed multiple compartments, which could be developed from the levator fascia to the prostate capsule

technology and prostatectomy

by entering different fascial planes during surgery. According to the wide variability and subjectivity among surgeons regarding these facets of the procedure, Pasadena Panel suggested using the newer concept of nerve-​sparing procedures instead of old interfascial or intrafascial definitions. In detail, the first consensus conference on best practices in RARP proposed the following new definitions:  (i)  maximum preservation of cavernous nerves (full nerve-​sparing), which is obtained by following the plane between the prostatic capsule and the multilayer tissue of the prostatic fascia; (ii) the less extended nerve-​sparing technique (partial nerve-​ sparing) within the multilayer tissue of prostatic fascia; and (iii) the minimal nerve-​sparing procedure preserving only the fibres running posterolaterally. After the antegrade release of the lateral cavernous nerves, the prostatic vascular pedicles are dissected so that large Hem-​o-​lock clips can be placed to secure them. The cavernous nerves can be damaged by direct mechanical trauma, traction, or thermal energy. Most of robotic surgeons support the cautery-​free dissection to avoid thermal injury of cavernous nerves. In high-​risk patients, after ligation and division of prostatic pedicles, the prostatectomy is continued anteriorly with an extrafascial technique, with resection of the prostatic fascia and of the neurovascular bundles up to the apex. Then the puboprostatic ligaments and the dorsal vein complex are dissected to isolate the prostatic apex. Different surgical techniques can be used to realize this step of the procedure. The anterior urethral wall is opened just below the apical limit, exposing the Foley catheter. The posterior wall and the underlying rectourethralis muscle are then divided close to the prostate. The division of the rectourethralis muscle completely frees the specimen, which is placed in an Endobag sac. During the reconstructive steps of the procedure, some robotic surgeons perform posterior muscolo-​fascial plate reconstruction with the aim of shortening the time to the recovery of urinary continence recovery and to reduce the risk of bleeding and anastomosis leakage. Several techniques were proposed to perform this step of the procedure and no comparative studies showed what is the best one. Recent systematic reviews showed only a minimal advantage in favour of posterior musculofascial reconstruction in terms of urinary continence recovery within 1 month of RP. The urethrovesical anastomosis is the last step of the procedure. Most robotic surgeons prefer to use running sutures. Therefore, the use of interrupted stitches representing the gold standard in the era of open surgery has been abandoned. An 18 Ch catheter is placed into the bladder and usually removed after four to six days.

Perioperative outcomes and complication rates RARP can be performed routinely in a reasonably short operative time, with low risk of blood loss and low transfusion rates. Specifically, a systematic review of the literature demonstrated overall mean operative time was 152 min (range:  90–291  min), mean blood loss of 166 ml (range: 69–​534 mL), mean transfusion rate as low as 2% (range:  0.5–​5%), mean catheterization time of 6.3 d (range: 5–​8.6 d), and mean in-​hospital stay as low as 1.9 d (range: 1–​6 d)6 (Table 6.10.1). Some patient characteristics such as high BMI, large prostate volume, prior abdominal surgery, prior BPH surgery, or presence of median lobe may make the surgical procedure more difficult, possibly increasing operative time,

539

540

Table 6.10.1  Perioperative outcomes in a robotic-​assisted laparoscopic radical prostatectomy (RARP) series of studies Author

Institution

Cases

Study design

Median/​Mean operative time (min.)

Median/​Mean blood loss (ml)

Transfusion rate (%)

Catheterization­ duration (days)

In-​hospital stay (days)

Patel (2008)7

Global robotic institute, Celebration, FL, US

1,500

Prospective case series

105 (55–​300)

111 (50–​500)

0.4%

6.3 (4–​28)

1

Tewari (2008)8

Weill Cornell Medical College, NY, US

215

Prospective case series

120–​240

150 ± 195

3%

7 (4–​14)

—​

Carlucci (2009)9

Mount Sinai Medical Center, NY, US

700

Prospective case series

124 (48–​266)

69 (5—​400)

0

7 (4–​30)

1

Greco (2009)10

Northwesterm Univ, Chicago, IL, US

180

Prospective case series

291

359

—​

—​

1.8

Jaffe (2009)11

Montsuris, Paris, France

293

Prospective case series

158 ± 51

534 ± 416

8.6 ± 3.5

5 ± 2.6

Martin (2009)12

Mayo Clinic Arizona, Phoenix, AZ, US

509

Retrospective case series

190 ± 50

155 ± 212

1.2%

—​

—​

Murphy (2009)13

Melbourne, Australia

400

Prospective case series

186 ± 49

—​

2.5%

8.2 ± 3.1

3.1 ± 1.4

Coelho (2010)14

Global robotic institute, Celebration, FL, US

2,500

Prospective case series

90 (75–​100)

100 (100–​150)

0.5%

5 (4–​6)

1

Davis (2010)15

University of Texas MD Anderson Cancer Center, Houston, TX, US

178

Prospective case series

246 (126–​378)

200 (35–​850)

0.5%

—​

1.8

Jeong (2010)16

Robert Wood Johnson Medical School, NJ, US

200

Retrospective case series

212 (110–​540)

189 (50–​800)

0

Lasser (2010)17

Warren Alpert Medical School at Brown University, Providence, RI, US

239

Prospective case series

231.9 (125–​537)

—​

4%

—​

2.37 (1–​23)

Lee (2010)18

Yonsei University College of Medicine, Seoul, South Korea

307

Unclear

210 ± 46

337 ± 287

2%

11.4 ± 4

5.1 ± 3

Novara (2010)19

Univ. of Padua, Italy

415

Prospective case series

184 ± 56

300 (150–​400)

5%

5 (4–​7)

6 (5–​7)

Ploussard (2010)20 Creteil, Paris, France

206

Prospective case series

160

504

3%

8.2

4.3

Bolenz (2011)21

University of Texas Southwestern Medical Center, Dallas, TX, US

264

Retrospective case series

235 (209–​270)

—​

5%

—​

1 (1–​2)

Heldt (2011)22

Loma Linda University, US

418

Retrospective case series

291.1 ± 6.9

154.6 ± 10.3

—​

—​

1.7 ± 0.2

Jayram (2011)23

Univ. of Chicago, IL, US

Prospective case series

—​

150 (25–​1,000)

3%

6 (5–​8)

—​

148 D’amico high risk

1.13

Adapted from European Urology, Volume 62, Issue 3, Novara G et al., ‘Systematic review and meta-​analysis of perioperative outcomes and complications after robot-​assisted radical prostatectomy’, pp. 431–​52, Copyright © 2012, with permission from Elsevier, http://​www.sciencedirect.com/​science/​journal/​03022838

 541

Chapter 6.10 

blood loss, or catheterization time. Similarly, surgeon experience (i.e. number of cases performed, achieving a fellowship training in RARP) are associated with better perioperative outcomes. Postoperative complications are relatively uncommon, with overall mean rate around 10%. High-​g rade severe complications are very uncommon following RARP. Specifically, the mean complication rate is as low as 9% (range:  3–​2 6%), with grade 1 complications being as prevalent as 4% (range:  2–​ 11.5%); grade 2, 3% (range: 2–9%); grade 3, 2% (range: 0.5–​7%); grade 4, 0.4% (range: 0–​1.5%); grade 5, 0.02% (range: 0–​0.5%) (6). Lymphocele or lymphorrea (mean 3.1%; range 1.2–​2 9%), urinary leak (mean 1.8%; range 0.1–6.7%) and reoperation (mean 1.6%; range 0.5–​7 %) were the commonest surgical complications.6 Several studies have compared perioperative outcomes and complications in RRP, LRP, and RARP (Table 6.10.2). With regard to RARP and RRP, a systematic review and meta-​analysis showed statistically significant differences in terms of rates for blood loss (weight mean difference [WMD]: 582.77; 95% CI, 435.25–​ 730.29; p 5% risk of developing Wilms tumour should undergo ultrasound screening at three-​monthly intervals until they reach five to seven years of age. Screening should be undertaken under the guidance of a clinical geneticist.13 The genetic basis of WT is of particular scientific interest because, like retinoblastoma, the statistical comparison between unilateral and bilateral cases led to a step change in our understanding of cancer genetics.14 At the time of presentation the main differential diagnosis lies between Wilms tumour and the other major abdominal tumour of childhood, neuroblastoma. But whereas children with Wilms tumour generally appear healthy, those with neuroblastoma are often overtly unwell as a result of metastatic spread. Examination of a child with an abdominal mass must always include blood pressure measurement since both these tumours can cause hypertension. In cases of Wilms tumour hypertension is generally caused by renin secretion,15,16 while in neuroblastoma it is due to catecholamine secretion. The initial investigation of an abdominal mass in a child is by ultrasound. If the ultrasound appearances are suggestive of a renal tumour the following further investigations are then recommended: ◆ Urinary

catecholamine metabolites (raised in neuroblastoma)

◆ Serum

alpha-fetoprotein (AFP) measurement (raised in hepatoblastoma and teratoma)

◆ Computed

tomography (CT) or MR scan of the abdomen and pelvis (to characterize the primary tumour, identify bilateral tumours, look for intravascular spread and intra-​abdominal metastases) (Figs 8.13.1)

◆ CT

scan of the chest (screen for lung metastases)

The standard staging for Wilms tumour [Table 8.13.1] is informed by the initial investigations, but also requires information derived from surgical resection. In the United Kingdom children are treated in accordance with international protocols published by SIOP (International Society of Paediatric Oncology), which currently include pre-​surgical (neoadjuvant) chemotherapy in all cases presenting in children over six months of age.17 In localized (stage I–​III) tumours, neoadjuvant chemotherapy was initially given to shrink the tumour with the aim of reducing surgical morbidity.18,19 This has been the subject of an important UK study (UKW3)with randomization between immediate and delayed resection. The results of this study confirmed that neoadjuvant chemotherapy reduces surgical complications and also downgrades some stage III tumours—​thus allowing the subsequent burden of chemotherapy to be reduced.20,21 However, the routine use of neoadjuvant chemotherapy for all children with localized tumours may result in some low risk tumours being overtreated. For this reason the protocols from the Children’s Oncology Group in the USA continue to recommend immediate primary resection of localized tumours.22 Protocols from the USA only recommend pre-​resection chemotherapy for children with metastases, intravascular extension, or tumour in the contralateral kidney. In the UK, histological confirmation of diagnosis is recommended before treatment is started. This entails an ultrasound-​ guided needle-​core biopsy via a retroperitoneal approach.23 The advantages of tumour biopsy lie in excluding rare non-​malignant renal masses and in identifying histological subgroups that may require alternative chemotherapy regimens. This biopsy technique does not alter the tumour stage whereas a transperitoneal or incisional biopsy automatically upgrades the tumour to stage III. Wilms tumour is a very chemo-​and radio-​sensitive malignancy, and multimodal therapy regimes have been refined over many clinical trials, initiated by the National Wilms Tumor Study (NWTS) in the United States.24–29 Outcomes are now very good, with overall long-​term survival of >70% for all tumours and a survival rate of >90% for low risk localized tumours with favourable histology.30

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Section 8  Paediatrics

(A)

(B)

Fig. 8.13.1  (A) Axial image from a contrast computed tomography (CT) scan of a three-​year-​old boy who presented with an asymptomatic abdominal mass. The scan shows a very large Wilms tumour replacing most of the right kidney. Note the crescent of renal parenchyma splayed around the posterior margin of the tumour, showing that the tumour arises from the kidney. (B) A coronal reconstruction from the same CT scan, showing displacement of the inferior vena cava, but no evidence of intravascular spread. The CT scan is also important to exclude tumour in the contralateral kidney, to look for enlarged (and possibly involved) para-​aortic lymph nodes, and to visualize other sites of potential intra-​abdominal metastases.

Risk stratification is based upon histological classification, and is used to guide intensity of adjuvant therapy.31 Protocols are being developed which are aimed at intensifying treatment for high risk tumours, while decreasing therapy for low risk tumours and thus reducing adverse effects at the same time as maintaining the excellent outcomes. Bilateral tumours and tumours with intracaval or intra-​atrial extension present a particular surgical challenge. Following neoadjuvant chemotherapy it is usually possible to carry out nephron-​ sparing surgery on in stage V tumours, occasionally using bench surgery.32,33 Although the use of neoadjuvant chemotherapy has reduced the number of cases with intravascular tumour extension, there are still occasions when cardiopulmonary bypass is required to achieve complete tumour resection.34 In stage IV disease,

metastases usually respond well to chemotherapy but there can be a role for metastatectomy to treat residual lesions.

Table 8.13.1  Staging system for Wilms tumour

Nephroblastomatosis

Stage

Definition

I

Tumour confined to kidney and completely excised

II

Tumour extending beyond kidney into perinephric fat, adjacent organs, vena cava; completely excised

III

Incomplete excision of tumour; or complete excision with abdominal lymph node involvement; or preoperative/​ intraoperative tumour rupture; or peritoneal tumour deposits; or tumour thrombi present at resection margins of vessels or ureter

IV

Haematogenous metastases; or lymph node metastases outside abdomen/​pelvis

V

Bilateral renal tumours

Reproduced with permission from National Wilms Tumor Study (NTWS), Copyright © NWTS, http://​www.nwtsg.org

Mesoblastic nephroma In infants under six months of age the differential diagnosis of renal tumours includes mesoblastic nephroma. Although it can be locally infiltrative, this renal tumour is usually benign.35 Mesoblastic nephroma commonly presents as an incidental flank mass in early infancy, but can also present perinatally with associated features including; polyhydramnios, hydrops foetalis, and hypercalcaemia.36,37 Treatment consists of total nephrectomy. The kidney is removed en bloc with surrounding perinephric fat to prevent recurrence.38 No adjuvant treatment is required. Because of the difficulty in distinguishing mesoblastic nephroma from Wilms tumour on diagnostic imaging, immediate nephrectomy is recommended for renal tumours in this age group. The presence of foci of embryonal nephrogenic tissue may be observed in association with Wilms tumour, and these are considered to be potential precursors of nephroblastoma.39 Some children present with benign aggregations or ‘rests’ of nephrogenic tissue and the appearances of these lesions on MR imaging may be sufficiently distinctive to permit observation rather than surgical intervention.40

Other renal tumours Two rare malignancies, clear cell sarcoma and rhabdoid tumours, were previously classified as forms of Wilms tumour. However, their histological features and poorer outcomes distinguish them from other forms of Wilms tumour and their management entails more intensified adjuvant treatment.41 Surgical management, however, is the same as for Wilms tumour.

 1021

Chapter 8.13 

Renal cell carcinoma occurs rarely in older children, and is treated as in adults.

Malignant tumours of the bladder Rhabdomyosarcoma The dominant bladder/​prostate malignancy in children is rhabdomyosarcoma (RMS). This highly malignant tumour arises from primitive mesenchymal cells which are committed to differentiation into striated muscle. The incidence of bladder/​prostate RMS is bimodal with most cases presenting between two and five years of age, and a second, smaller group presenting in adolescence.42 Bladder/​prostate RMS typically presents with either with haematuria or bladder outlet obstruction. The tumour mass is usually readily visualized on ultrasound examination. A full histological and cytogenetic diagnosis is mandatory to distinguish embryonal and alveolar rhabdomyosarcoma since these two sub types require different therapeutic approaches and have markedly different outcomes.43–45 Alveolar RMS is characterized by the cytogenetic translocation t2,13 and is associated with a worse prognosis.46 Treatment usually starts with chemotherapy, preceded by tumour biopsy. Primary tumour resection should only be considered in those cases where it seems feasible to completely excise a tumour in the bladder dome without risk to bladder function. Bladder tumours are easily biopsied endoscopically, whereas biopsying a prostatic RMS may need a perineal or transrectal needle-​ core approach. Treatment of RMS is risk-​stratified, based upon pathological grading, site of disease, ease of resection, age at presentation, size of primary tumour, and lymph node involvement.47,48 The aim of treatment is to achieve cure with the minimal amount of morbidity, particularly with regard to bladder function.49,50 Unfavourable alveolar histology tends to be associated with other parameters of higher risk.51 The bladder outlet and prostatic region are unfavourable sites and for this reason bladder/​prostate tumours are classified as high risk. Such tumours are likely to require aggressive neoadjuvant chemotherapy, attempted surgical resection, and adjuvant radiotherapy. A  recently reported approach which combines resection of the tumour with prostatic brachytherapy is encouraging, since it may offer a higher chance of conserving the bladder.52 Younger children with embryonal tumours are at intermediate risk, but still require multimodal therapy, albeit with a lower intensity. Even seemingly localized RMS is presumed to be micrometastatic, and so all children with RMS receive some chemotherapy.

Urothelial tumours Urothelial tumours are exceedingly rare in childhood. Transitional cell carcinoma can very occasionally occur in older adolescents, and its treatment is the same as in adults. Outcomes in children are reported to be better than in adults. Urothelial neoplasms of low malignant potential (PUNLMP) can also occur in older adolescents,53 and are treated according to adult guidelines.

Testicular tumours Although the management of testicular masses in childhood generally mirrors their management in adults there are some important

urological malignancies in children

distinctions. Most malignant tumours of the testis in children present with an enlarging mass but, importantly, some present with a hydrocele.54 Examination of a child with a hydrocele should therefore include careful palpation of the scrotal contents to ensure that the underlying testis is normal. If this is in any doubt ultrasound should be performed.55 Blood tests for tumour markers (AFP and βHCG) are then performed prior to surgical exploration and orchidectomy via an inguinal approach. In order of frequency, the testicular tumours encountered in children are; mature teratoma, malignant germ cell tumour (yolk sac tumour) and paratesticular rhabdomyosarcoma.56 In principle, testicular sparing surgery can be considered for a mature teratoma, but in reality these tumours usually exceed the volume of the small prepubertal testis, and so there is no alternative to orchidectomy. For a discreet lump within an otherwise normal testis preoperative ultrasound can be very valuable,in identifying benign masses such as an epidermoid cyst which can be enucleated. Nevertheless intraoperative frozen section is a recommended precaution in such cases. Subsequent management, including imaging for metastases, is guided by the histological diagnosis—​with adjuvant treatment depending on the stage and grade of tumour.57 Lymph node involvement is generally identified on imaging rather than on biopsy.58 Malignant germ cell tumours and paratesticular RMS both respond very well to treatment and have excellent outcomes.59,60 In the perinatal period an enlarged testis is most likely to be a consequence of intrauterine (‘neonatal’) testicular torsion, and is invariably beyond salvage. Since atrophy is the inevitable outcome, conservative management has been widely adopted in preference to surgical exploration.61 Poorly controlled congenital adrenal hyperplasia in adolescents may be associated with the development of hyperplastic nodules on both testes—​with histological features resembling Leydig Cell tumours.62 Surgical intervention is not required.

Conclusions Urological malignancies are rare in childhood. Survival rates for Wilms tumour have improved dramatically over recent decades and the challenge is now to devise protocols which offer comparable outcomes with lower treatment-​related morbidity. Rhabdomyosarcoma remains a challenging tumour to treat—​both because of the tumour biology and the unfavourable anatomical location in many cases. Multimodal treatment is necessary to provide a reasonable prospect of cure with preservation of bladder function. The presentation and management of testicular tumours in children broadly mirrors that in adults. Management consists of radical orchidectomy with chemotherapy when this is indicated by tumour histology and staging. Childhood cancers of the urinary tract should be managed by multidisciplinary teams in specialist centres.

Further reading D’Angio GJ. The treatment of Wilms’ tumor. Results of the National Wilms’ Tumor Study. Cancer 1976; 38:633–46. Dasgupta R, Rodeberg DA. Update on rhabdomyosarcoma. Sem Pediatr Surg 2012; 21:68–78. Hamilton TE, Shamberger RC. Wilms tumor: recent advances in clinical care and biology. Sem Pediatr Surg 2012; 21:15–20.

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Knudson AG, Strong LC. Mutation and cancer: a model for Wilms’ tumor of the kidney. J Natl Cancer Inst 1972; 48(2):313–24. Metcalfe PD, Farivar-Mohseni H, Farhat W, McLorie G, Khoury A, Bagli DJ. Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol 2003; 170:2412–5. Pritchard-Jones K. Controversies and advances in the management of Wilms’ tumour. Arch Dis Child 2002; 87:241–4. Rescorla FJ. Pediatric germ cell tumors. Sem Pediatr Surg 2012; 21:51–60.

References 1. Stiller CA, Parkin DM. International variations in the incidence of childhood renal tumours. Br J Cancer 1990; 62:1026–​30. 2. D’Angio GJ. The treatment of Wilms’ tumor. Results of the National Wilms’ Tumor Study. Cancer 1976; 38:633–​46. 3. Wilms M. Die Mischgeswulste der niere. Leipzig, Germany: Verlag von Arthur Georgi. 1899. 4. Coppes-​Zantinga AR, Coppes MJ. Max Wilms and “Die Mischgeswulste der Niere”. CMAJ 1999; 160:1196. 5. Miller RW, Fraumeni JF Jr, Manning MD. Association of Wilm’s tumor with aniridia, Hemihypertrophy, and other congenital malformations. N Eng J Med 1964; 270:922–​7. 6. Olshan AF, Breslow NE, Falletta JM, et al. Risk factors for Wilms tumor. Report from the National Wilms Tumor Study. Cancer 1993; 72:938–​44. 7. Fischbach BV, Trout KL, Lewis J, Luis CA, Sika M. WAGR syndrome: a clinical review of 54 cases. Pediatrics 2005; 116:984–​8. 8. Wiedemann HR. Familial malformation complex with umbilical hernia and macroglossia—​a “new syndrome”? (in French). J génétique humaine 1964; 13:223–​32. 9. Beckwith J. Macroglossia, omphalocoele, adrenal cytomegaly, gigantism and hyperplastic visceromegaly. Birth Defects 1969; 5:188. 10. Porteus MH, Narkool P, Neuberg D, et al. Characteristics and outcome of children with Beckwith-​Wiedemann syndrome and Wilms’ tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2000; 18:2026–​31. 11. Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W. Association of an anatomo-​pathological syndrome of male pseudohermaphroditism, Wilms’ tumor, parenchymatous nephropathy and XX/​XY mosaicism (in French). Arch Fr Pediatr 1967; 24:729–​39. 12. Drash A, Sherman F, Hartmann WH, Blizzard RM. A syndrome of pseudohermaphroditism, Wilms’ tumor, hypertension, and degenerative renal disease. J Pediatr 1970; 76:585–​93. 13. Choyke PL, Siegel MJ, Craft AW, Green DM, DeBaun MR. Screening for Wilms tumor in children with Beckwith-​Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol 1999; 32:196–​200. 14. Knudson AG, Strong LC. Mutation and cancer: a model for Wilms’ tumor of the kidney. J Natl Cancer Inst 1972; 48(2):313–​24. 15. Mitchell JD, Baxter TJ, Blair-​West JR, McCredie DA. Renin levels in nephroblastoma (Wilms’ tumour). Arch Dis Child 1970; 45:376–​84. 16. Leckie BJ, Birnie G, Carachi R. Renin in Wilms’ tumour: prorenin as an indicator. J Clin Endocrinol Metab 1994; 76:1742–​6. 17. Pritchard-​Jones K. Controversies and advances in the management of Wilms’ tumour. Arch Dis Child 2002; 87:241–​4. 18. Lamerle J, Voute PA, Tournade MF, et al. Preoperative versus postoperative radiotherapy, single versus multiple courses of Actinomycin D in the treatment of Wilms’ tumor. Preliminary results of a controlled clinical trail conducted by the International Society of Paediatric Oncology (SIOP). Cancer 1976; 38:647–​54. 19. Lemerle J, Voute PA, Tournade MF, et al. Effectiveness of preoperative chemotherapy in Wilms tumor: results of an International Society of Paediatric Oncology (SIOP) clinical trial. J Clin Oncol 1983; 1:604–​9. 20. Mitchell C, Pritchard-​Jones K, Shannon R, et al. Immediate nephrectomy versus preoperative chemotherapy in the management of non-​metastatic Wilms’ tumour: results of a randomised trail

21. 22.

23.

24. 25. 26.

27.

28. 29.

30. 31. 32.

33.

34. 35. 36. 37. 38.

39.

(UKW3) by the UK Children’s Cancer Study Group. Eur J Cancer 2006; 42:2554–​62. Pritchard-​Jones K, Moroz V, Vujanic G, et al. Treatment and outcomes of Wilms’ tumour patients: an analysis of all cases registered in the UKW3 trial. Ann Oncol 2012; 23:2457–​63. Green DM, Breslow NE, Beckwith JB, et al. Treatment with nephrectomy only for small, stage I/​favorable histology Wilms’ tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2001; 19:3719–​24. Vujanic GM, Kelsey A, Mitchell C, Shannon RS, Gornall P. The role of biopsy in the diagnosis of renal tumours of childhood: results of the UKCCSG Wilms tumour study 3. Med Pediatr Oncol 2003; 40:18–​20. D’Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms’ tumor: results of the second National Wilms’ Tumor Study. Cancer 1981; 47:2302–​11. D’Angio GJ, Breslow N, Beckwith B, et al. Treatment of Wilms’ tumor. Results of the third National Wilms’ Tumor Study. Cancer 1989; 64:349–​60. Green DM, Breslow N, Beckwith B, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1998; 16:3744–​51. Green DM, Breslow NE, Beckwith JB, et al. Comparison between single-​dose and divided-​dose administration of dactinomycin and doxorubicin for patients with Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1998; 16:23–​45. Ritchey M, Daley S, Shamberger RC, et al. Ureteral extension in Wilms’ tumor: a report from the National Wilms’ Tumor Study Group (NWTSG). J Pediatr Surg 2008; 43:1625–​9. Ritchey ML, Shamberger RC, Haase G, Horwitz J, Bergemann T, Breslow NE. Surgical complications after primary nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. J Am Coll Surg 2001; 192:63–​8. Cotton CA, Peterson S, Norkool PA, et al. Early and late mortality after diagnosis of Wilms tumor. J Clin Oncol 2009; 27:1304–​9. Green DM, Beckwith JB, Breslow NE, et al. Treatment of children with stages II to IV anaplastic Wilms’ Tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1994; 12:2126–​31. Ritchey ML, Green DM, Breslow NB, Moksness J, Norkool P. Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms’ tumor. A report from the National Wilms Tumor Study Group. Cancer 1995; 75:600–​4. Hamilton TE, Ritchey ML, Haase GM, et al. The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group. Ann Surg 2011; 253: 1004–​10. Lall A, Pritchard-​Jones K, Walker J, et al. Wilms’ tumor with intracaval thrombus in the UK Children’s Cancer Study Group UKW3 trial. J Pediatr Surg 2006; 41:382–​7. England RJ, Haider N, Vujanic GM, et al. Mesoblastic nephroma: a report of the United Kingdom Children’s Cancer and Leukaemia Group (CCLG). Pediatr Blood Cancer 2011; 56:744–​8. Leclair MD, El-​Ghoneimi A, Audrey G, Ravasse P, Moscovici J, Heloury Y. The outcomes of prenatally diagnosed renal tumors. J Urol 2005;173:186–​9. Rousseau-​Merck MF, Nogues C, Nezelof C, Martin-​Cudraz B, Paulin D. Infantile renal tumors associated with hypercalcemia. Arch Pathol Lab Med 1983; 107:311–​4. Howell CG, Othersen HB, Kiviat NE, Norkool P, Beckwith JB, D’Angio GJ. Therapy and outcome in 51 children with mesoblastic nephroma: a report of the National Wilms’ Tumor Study. J Pediatr Surg 1982; 17:826–​31. Breslow NE, Beckwith JB, Perlman EJ, Reeve AE. Age distributions, birth weights, nephrogenic rests, and heterogeneity in the pathogenesis of Wilms tumor. Pediatr Blood Cancer 2006; 47:260–​7.

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40. Rohrschneider WK, Weirich A, Rieden K, Darge K, Troger J, Graf NUS. US, CT and MR imaging characteristics of nephroblastomatosis. Pediatr Radiol 1998; 28:435–​43. 41. Seibel NL, Li S, Breslow NE, et al. Effect of duration of treatment on treatment outcome for patients with clear-​cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2004; 22:468–​73. 42. Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–​2005. Cancer 2009; 115:4218–​26. 43. Mazzoleni S, Bisogno G, Garaventa A, et al. Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer 2005; 104:183–​90. 44. Punyko JA, Mertens AC, Baker KS, Ness KS, Robison LL, Gurney JG. Long-​term survival probabilities for childhood rhabdomyosarcoma. A population-​based evaluation. Cancer 2005; 103:1475–​83. 45. Perez EA, Kassira N, Cheung MC, Koniaris LG, Neville HL, Sola JE. Rhabdomyosarcoma in children: a SEER population based study. J Surg Res 2011; 170:e243–​51: 46. Turc-​Carel C, Lizard-​Nacol S, Justrabo E, Favrot M, Philip T, Tabone E. Consistent chromosomal translocation in alveolar rhabdomyosarcoma. Cancer Genet Cytogenet 1986; 19:361–​2. 47. Oberlin O, Rey A, Lyden E, et al. Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 2008; 26:2384–​9. 48. De Corti F, Dall’Igna P, Bisogno G, et al. Sentinel node biopsy in pediatric soft tissue sarcomas of extremities. Pediatr Blood Cancer 2009; 52:51–​4. 49. Punyko JA, Mertens AC, Gurney JG, et al. Long-​term medical effects of childhood and adolescent rhabdomyosarcoma: a report from the childhood cancer survivor study. Pediatr Blood Cancer 2005; 44:643–​53. 50. Raney B, Anderson J, Jenney M, et al. Late effects in 164 patients with rhabdomyosarcoma of the bladder/​prostate region: a report from the international workshop. J Urol 2006; 176:2194–​5. 51. Rodary C, Gehan EA, Flamant F, et al. Prognostic factors in 951 non-​metastatic rhabdomyosarcoma in children: a report of the Intergroup Rhabdomyosarcoma Workshop. Med Pediatr Oncol 1991; 19:89–​95.

urological malignancies in children

52. Martelli H, Haie-​Meder C, Branchereau S, et al. Conservative surgery plus brachytherapy treatment for boys with prostate and/​or bladder neck rhabdomyosarcoma: a single team experience. J Pediatr Surg 2009; 44:190–​6. 53. Alanec S, Shukla AR. Bladder malignancies in children aged 500 umol/​l) was between 202 and 746 per million population per year. AKI is common in hospitalized patients. A large American study demonstrated an overall incidence of AKI of 5% in a hospitalized population, using a definition of AKI as an increase in serum creatinine of >44 µmol/​L (0.5 mg/​dl) above the measured baseline value. AKI was associated with decreased renal perfusion (42%) or major surgery (18%) in the majority of cases. The major predictors of poor prognosis included a reduced urine output (76 mg/​dl). The BEST kidney study compared outcomes for patients with AKI in intensive care units with early or late initiation of dialysis. Patients were eligible for the trial if they presented with AKI defined as a BUN >84 mg/​dl or a urine output