Second Edition European Urology Today EUT Congress News 32nd Annual Congress of the European Association of Urology Sunday, 26 March 2017 London, 24-28 March 2017

Hurdles in managing renal cancer EAU strengthens ‘Sleepless Nights’ session offers insights on legal pitfalls ties across borders By Erika de Groot By Joel Vega dock’ as he presented his arguments for performing a renal tumour biopsy (RTB). Leigh, who specializes The EAU’s engagement with the European Union Insights into the legal pitfalls and challenges of in medical negligence, pressed Bex on his rationale (EU), the different EAU Offices’ new projects, and the offering balanced and optimal treatments to kidney for RTB, to which Bex conceded that there are no announcement of newly elected officers topped the cancer patients were explored and debated in reliable approaches for diagnosing an oncocytoma agenda yesterday at the annual General Assembly. Plenary Session 1, a newly introduced format where before surgery. a legal veteran subjected three urologists to intense EAU Members cross-examination regarding their surgical strategies. Leigh emphasized that despite the low statistics on As of March 2017, there are a total of 15,409 EAU risks and complications, patients view the matter in members, the majority of whom are active members In a well-attended and applauded session, expert an altogether different way. The loss of a kidney or (7,397), alongside 3,608 junior members, 2,441 active medical litigation lawyer Bertie Leigh (GB) put suffering the consequences of complications is international members, and 531 junior international Professors Alex Bex (NL), Karim Bensalah (FR) and traumatic for patients. members. Vsevolod Matveev (RU) under intense questioning to Prof. Karim Bensalah faces intense cross-examination by elicit insights into the crucial decisions they made for lawyer Bertie Leigh (seated) as Mr. Tim O’Brien moderates “Doctors should offer patients alternatives which are New appointments kidney cancer patients. realistic to them, all of the options available to them, New roles were and must relay the information in a form that announced during the ‘’Each of these cases, in different ways, raises doctors should be “recording their uncertainties in patients can understand,” added Leigh. “You must meeting. Prof. Jens questions about the conventional ways of treating the way in which they communicate with patients.” make records of the advice you give them. Doctors Sønksen (DK) was elected patients. As a lawyer I am particularly concerned are diligent in recording the results of their Chapple discusses as the new EAU Adjunct about consent counseling and how patients are Mr. Tim O’Brien, as moderator, presented three cases investigations, but when it comes to recording their EAU-EU engagement Secretary General – handled because these are very difficult positions for with the first case involving a small renal mass (less advice, they write nothing. If it’s not written down, it Clinical Practice with 92% urologists to take,” said Leigh, as he stressed that than 3cm) in an elderly patient. Bex was first ‘in the won’t stand up in court,” said Leigh. of the vote. He said: “My plans include strengthening urological practice in Europe through expansion of the clinical update meetings; continued work with dissemination and evolution of the EAU; the clinical guidelines and growth of our online profile; and Cutting-edge techniques at Live Surgery through the EAU Junior Ambassadors.” ESUT, ERUS, EULIS pull out all the stops in Live Surgery session Other appointments included Prof. Anders Bjartell (SE), a member of the Guidelines Office Board who took on the role of EAU Research Foundation By Joel Vega A five-member panel composed of Mr. Chris Anderson Chairman, succeeding Prof. Peter Mulders (NL). (GB), Dr. Alberto Breda (ES), Dr. Rafael Sanchez-Salas Assoc. Prof. Christian Gratzke (DE), Associate Editor of Maintaining the EAU’s tradition of presenting Live (FR), Prof. Peter Tenke (HU), and Dr. Patricia European Urology and member of the EAU Guidelines Surgery sessions, yesterday three section offices Zondervan (NL) gave additional commentary and panel on BPH/male LUTS, is the new Editor-in-Chief presented the newest techniques in robotic and asked the surgeons to explain the preparations and of European Urology Focus. Prof. Alberto Briganti (IT), minimally invasive surgeries used in aggressive steps they took for the crucial surgical maneuvers. member of the Scientific Congress Office and the EAU prostate, bladder and kidney diseases as well as Guidelines Office Board, is the Editor-in-Chief of the stone treatment. Professors Alexander Haese (DE), Jens-Uwe new publication European Urology Oncology. Stolzenburg (DE) and Peter Wiklund (SE) were the first The EAU Section of Uro-Technology (ESUT) collaborated three surgeries broadcasted from Guy’s Hospital with EU engagement with the EAU Robotic Urology Section (ERUS) and the Haese demonstrating his technique in robotic The EAU cited stronger links with Members of the EAU Section of Urolithiasis (EULIS) to organise a full-day Live Surgery audience use 3D glasses to follow the wide-screen neurosafe RP. European Parliament (MEPs) and other EU partners series of simultaneous surgeries and pre-recorded transmission from Guy’s Hospital via the advisory tasks it has fulfilled. EAU Secretary videos that showed advances in surgical techniques and Stolzenburg took the audience through the crucial General Prof. Chris Chapple (GB) said the EAU raises approaches including as, amongst many others, 3D-4K steps in performing a nerve-sparing approach that not only its own profile but also that of urology, as nerve-sparing radical prostatectomy (RP), bipolar techniques that are necessary,” said ESUT chair Prof. involved meticulous dissection. well as building relationships, by providing scientific bladder tumour resection with photodynamic diagnosis Evangelos Liatsikos. With the live broadcasts advice to MEPs and the European Commission (PDD), and robotic neobladder reconstruction. transmitted directly from Guy’s Hospital in London to Despite intermittent disruptions in satellite through initiatives such as the EAU white paper on the eURO Auditorium at the congress venue, the connections the panel provided insightful Prostate Cancer and the strategic relationships with “This complex programme aims to show the current audience were guided by actual commentary from the commentary and audience questions were also the EU Joint Action on Cancer Control (CANCON) and advances in imaging and the new instruments and participating surgeons. directed to the surgeons. MEPs Against Cancer (MAC).

EAU-RF thanks Mulders

By Loek Keizer at the session. Mulders pointed to NIMBUS as one of the studies that generated a huge international Saturday afternoon saw the EAU Research database, which will allow the foundation to present ® Foundation hold its Special Session, giving delegates data for many years to come. NGage : an update on currently-running research projects, Reach for the original. trials and registries. The session also featured a “A real achievement of the Foundation is the presentation by Dr. Alvaro Aytes (ES), the EAU-RF’s establishment of the career track fellowship for NGage newest career track fellow. Prof. Peter Mulders (NL) non-urological researchers. This helps us attract Nitinol Stone Extractor chaired the session, having been succeeded as such researchers to the EAU to work on urological chairman of the EAU-RF by Prof. Anders Bjartell (SE) projects.” at the General Assembly earlier that morning. “I’ve always said that the Research Foundation Looking back at his eight years as Chairman of the depends on its activities. I will continue to advise the EAU-RF, Mulders reflected on the uniqueness of the EAU-RF and should I initiate any new projects in the Foundation. “The EAU is the only professional future that could be facilitated by the EAU-RF, that association with its own clinical trial office. In that would of course be my first choice.” MEDICAL respect, we’ve had a lot of opportunities for conducting trials in prostate, bladder and kidney For further coverage of projects of the EAU-RF, See © COOK 01/2017 URO-D32084-EN-F cancer.” All ongoing EAU-RF projects were presented pages 20 and 29

Sunday, 26 March 2017 EUT Congress News 1 Today’s Industry A long history of British MRI: A game Sessions contributions to urology changer in PCa Industry sessions and Workshop, all starting at 17:45 hrs EAU History Office explores early developments screening?

Navigating the world of OAB: Lightening the load, staying on track By Loek Keizer A new study, coming from the Dutch part of the ASTELLAS - Room Copenhagen, North Hall European Randomised study for the Screening of (Level 1) Many of the biggest names in the history of British Prostate Cancer (ERSPC) has found that MRI-based Urology echoed through the ExCel London venue screening can reduce overdiagnosis by 50% and Checkpoint inhibitors: Summary of latest data in yesterday morning, as their contributions to the field reduce unnecessary biopsies by 70%, potentially GU cancers were presented and analysed from a historic changing the equation for prostate cancer (PCa) BRISTOL-MYERS SQUIBB - Room London, perspective. Sir Henry Thompson, Sir Peter Freyer screening. North Hall (Level 1) and Terrence Millin were extensively eulogized, as were more recently departed pioneers like John This work, the first to confirm that the use of MRI in A multidisciplinary forum: How can we improve Blandy and John Fitzpatrick. a population-based screening setting may be viable, management of hormone-sensitive prostate was presented at this congress. Dutch researchers cancer? Thanks to many contributions from historically- have compared the outcomes from the TRUS-biopsy FERRING PHARMACEUTICALS - Room Vienna, minded BAUS members, the History Office’s annual approach with an MRI-based screening approach in North Hall (Level 1) thematic session was expanded into a three-hour a group of heavily pre-screened men. They took “Special Session” on Saturday morning. In addition to 6-core TRUS-biopsy samples from 177 men, and Overcoming obstacles in medical management presenting some highlights from local (insofar as the 12-core TRUS-biopsy samples from 158 men: the 158 of BPH patients British Empire can be considered “local”) urology, the men who received a 12-core TRUS-biopsy had first GSK - Room Berlin, North Hall (Level 1) session also gave time to two contributors to this Prof. Paul Weindling presenting detailed new research on been given an MRI scan. If the MRI showed a year’s Congress Gift: Urology Under the Swastika. urologists and other medical professionals who were forced to suspicious area, then further MRI- targeted biopsy Multidisciplinary perspectives on managing flee to the UK when the Nazi party came to power in Europe. samples were taken. bladder cancer: Hope is on the horizon Truly international PEERVOICE - Room Stockholm, North Hall (Level 1) While intending to serve as an overview of British “This could change the balance of the equation” said urology, British history being what it is made the being born on the Indian subcontinent, serving lead author Dr. Arnout Alberts (Erasmus Medical Novelty in premature ejaculation morning session more international than one might within the Empire or, in the case of Thompson, Centre, Rotterdam). “It means that population-based RECORDATI SPA - Room Amsterdam, initially expect. The profiles of the 19th and early 20th treating 19th century global high society. prostate cancer screening with MRI instead of North Hall (Level 1) century urological surgeons created a veritable atlas TRUS-biopsy has a significantly better risk/benefit of the once global British Empire. Britain and European Refugees ratio and could offer real benefits to men at risk of New light on prostate cancer The second part of the session focused on the prostate cancer. Now we have shown that MRI STEBA BIOTECH - Room 7, Capital Suite (Level 3) Mr. Michael Dinneen (GB) presented a detailed publication Urology Under the Swastika, the end of a screening has potential, we need confirmatory biography of Sir Peter Freyer (1851-1921), beginning “seventeen-year process” for its editors Prof. Dirk studies in a true screening setting to allow us to get Revealing Moses: Revolutionary new Holmium with his childhood and education in Ireland shortly Schultheiss (DE) and Dr. Friedrich Moll (DE). a better handle on the statistics and costs.” technology Industry workshop by LUMENIS - Room 9, after the Great Famine. Freyer signed up for the Schultheiss gave an introduction to the topic, as well Capital Suite (level 3) Indian Medical Service (IMS), serving in India for as an overview of the book’s major findings. He The researchers found that the 6-core TRUS-biopsy, many years before joining the staff at St. Peter’s introduced one of its contributors, medical historian 12-core TRUS biopsy and MRI-targeted biopsy Hospital for the Stone in London in 1897. He pioneered Prof. Paul Weindling (GB), who proceeded to explain method all had a similar detection rate for more his eponymous technique for total enucleation of the the role Britain had in accepting medical dangerous (high-grade) cancers; however using the prostate, popularizing its implementation. professionals (including urologists) who escaped the MRI-targeted biopsy method the majority of men European Urology Today emergence of National Socialism on the continent. (70%) did not need a biopsy at all as the MRI scan As war broke out in Europe in 1914, Freyer rejoined had shown no suspicious areas. In addition to Editor-in-Chief the IMS, having remained fluent in Hindustani from Between 1930 and 1945, 6000 medical professionals potentially eliminating 70% of biopsies, the Prof. M. Wirth, Dresden (DE) his earlier stretch with the service. Freyer was (of which 4258 were physicians) entered the United MRI-targeted biopsy only approach meant that the knighted in 1917, and in 1920, he was elected the first Kingdom, the largest single group coming from number of men who were overdiagnosed with Section Editors president of the section of urology of the Royal Society Poland. Other sizeable groups were Germans, non-aggressive cancer was reduced by half. Prof. T. E. Bjerklund Johansen, Oslo (NO) of Medicine. This cemented his reputation as “the first Austrians (including Sigmund Freud and his family Mr. Ph. Cornford, Liverpool (GB) leader of British Urology”. and staff in 1938) and Czechoslovakians. Alberts said MRI screening for prostate cancer will Prof. O. Hakenberg, Rostock (DE) Prof. P. Meria, Paris (FR) be more expensive than the currently used approach, Dr. G. Ploussard, Paris (FR) Freyer passed away in 1921, and was buried in Clifden, Many entered Britain as a first step to emigrating to but introducing mammography screening a Prof. J. Rassweiler, Heilbronn (DE) Ireland. Mr. Dinneen showed a picture of Freyer’s the United States or beyond, but several generation ago was also expensive. “ We have to Prof. O. Reich, Munich (DE) gravestone, which is due to be restored in 2021 for the “concessionary schemes” were introduced to decide if it’s worthwhile. In this study we achieved a Dr. F. Sanguedolce, London (GB) centenary of his death. re-qualify physicians, nurses and dentists. These 70% reduction in biopsies and a 50% reduction in Dr. S. Sarikaya, Ankara (TR) immigrants were able to find employment after the overdiagnosis of insignificant prostate cancer: if Freyer’s was just one of the biographies presented at establishment of the National Health Service shortly larger studies can reproduce these results it will Founding Editor the session, which had serious international after the Second World War, as there was a demand mean a considerable saving further down the line,” Prof. F. Debruyne, Nijmegen (NL) connections with several of the profiled urologists for qualified specialists. explained Alberts. Editing and Coordination J. Vega Onsite Reporting and Editing E. de Groot L. Keizer Breakthroughs in andrology T. Parkhill J. Vega Plenary Session 2 explores ‘hot’ topics in andrology Communications and Promotion J. Bloemberg By Erika de Groot Mr. David John Ralph (GB) discussed that as priapism M. van Gurp duration increases, the success for conservative I. Moerkerken New insights into the gold standards, developments therapy decreases and surgical management P. Pigmans and controversies within andrology were deliberated increases. Early insertion of a penile prosthesis in today in the state-of-the-art lectures of the “Hot priapism maintains penile length, aids easy insertion, Advertising and treats the condition. Alternatively, late insertion of L. Schreuder topics in andrology” session chaired by Prof. Dr. Francesco Montorsi (IT) and Prof. Hein Van Poppel penile prosthesis result in penile shortening and Lay-Out/Printing (BE). difficult implantation. D. Blom G. Smit The Plenary Session commenced with the presentation Ralph mentioned the pre-requisites of penile implants EUT Editorial Office of Dr. Peter B. Østergren (DK) on testosterone therapy for patients with Peyronie’s disease such as refractory PO Box 30016 in men with prostate cancer (PCa). He stated that high erectile dysfunction, distal flaccidity, significant hinge 6803 AA Arnhem endogenous T levels are not associated with an effect, ossified/calcified plaque or, for example, those The Netherlands increased risk of PCa, and that testosterone who cannot have a grafting procedure due to vascular T +31 (0)26 389 0680 replacement therapy (TRT) is not associated with an disease F +31 (0)26 389 0674 increased risk of aggressive PCa but may increase the [email protected] risk of being diagnosed with low-risk PCa due to more Dr. Ulla N. Joensen (DK) stated that male reproductive vigorous monitoring. He added that TRT appears safe development depends on normal early feotal testicular Disclaimer in men curatively treated for low-risk PCa but there function. She said normal germ cell development in “Normal germ cell development in fetal life determines later No part of European Urology Today (EUT) may be are only few available studies with small sample sizes. feotal life determines later reproductive capacity, and reproductive capacity” reproduced without written permission from the Østergren emphasised that TRT is not recommended in that timing is everything with reference to the Communication Office of the European Association of Urology (EAU). The comments of the reviewers are their men with untreated PCa. masculinization programming window. Joensen said own and not necessarily endorsed by the EAU or the translation to clinical recommendations of the patients with irreversible non-obstructive azoospermia Editorial Board. The EAU does not accept liability for the consequences of inaccurate statements or data. Despite According to Dr. Yacov Reisman (NL), large multicentre, advancements in understanding how these processes (NOA). Compared to the conventional TESE, microTESE of utmost care the EAU and their Communication Office well-conducted trials are essential for establishing work are difficult because this is a system that cannot almost doubles the chance of successful SSR. Colophon cannot accept responsibility for errors or omissions. evidence to facilitate a standard algorithm to approach be interventionally studied. scrotal pain. He said that reversible causes should be Dr. Ferdinando Fusco (IT) discussed that male ruled out before any treatment, and testicles should be Men should not be considered infertile until they have contraception remains an important area of research, spared whenever possible. A multidisciplinary a microTESE and are found to be infertile according to and introduction of new forms of male contraception approach that includes psychological, sexual and Mr. Majid Shabbir (GB). MicroTESE should be the gold based on both hormonal and non-hormonal physical therapy modalities, should be considered. standard survival sperm retrieval (SSR) technique for paradigms are wanted and needed.

2 EUT Congress News Sunday, 26 March 2017 Imaging and prostate cancer Imaging technologies have still some way to go Congress news...... 1 By Tom Parkhill ESUI, Prof Georg Salomon (DE), who will take the still need to study the ability of images to rule out Congress highlights ...... 2/3 group forward to the winter meeting in Barcelona. significant diseases”. At the 2015 conference we asked, “Is the train of Update on hereditary prostate cancer. . . . 4 prostate imaging gathering speed?” Well now we Prof. Nicolas Mottet (FR), Chairman of the EAU Walz summed up the session: “We learned that we Robot-assisted RP: Managing inguinal can say it is not only gathering speed, it is roaring Prostate Cancer Guidelines Panel confirmed the probably get less benefit than we should for the money hernias...... 6 ahead”. evidence base. “Can we use an MRI to rule out biopsy, which we spend. The technology should only be used if the answer is probably ‘no’, certainly not yet”. He it changes how we treat the patient, not just because Is every man fertile?...... 7 With these words, Prof. Jochen Walz introduced the stated that imaging is only useful if it can change the we have the technology. Some would like to do MRI Photodynamic therapy for prostate cancer. . 8 session addressing the hottest topics in urological outcome, but noted that we don’t yet have clear data before any biopsy, as happens with mammography, imaging “How to get the most out of prostate cancer to justify routine MRI use; and it still needs to be used but the comparison isn’t completely valid. In France for Benign Prostatic Enlargement (BPE). . . . .9 imaging” organized by the EAU Section of Urological in conjunction with other diagnostic techniques – it example, a mammography costs around €80, and PS3: Debate on low-risk BCa ...... 10 Imaging (ESUI) in cooperation with the EAU Section of can add information, rather than replace other whereas an MRI costs €350. In addition, the Urological Research (ESUR) and the European Society techniques. infrastructure needed is still significantly different. Non-muscle invasive bladder of Nuclear Medicine (EANM). cancer (NMIBC)...... 11 Mottet noted that just about all the published reports Clinical Guidelines...... 12 But despite this progress, the session concluded with come from expert centres, with high levels of Do not miss this today: considerable caution about the distance yet to be expertise and strong teams, so it is not yet a routine Filling the GAP...... 13 travelled before imaging becomes routine. technique. Posters & Videos - The Prize Winners Biomarkers for immune checkpoint inhibitors...... 14 The meeting heard that the growth in the field has Prof. Alberto Briganti (IT) confirmed the cautious Special presentations on stage at the been impressive, with 1400 published papers in the approach “Imaging is here to stay, and we are e-Poster Area at 11.00 hrs. Ureterocutaneostomy...... 15 last year. Walz also introduced the new chair of the looking forward to the next developments, but we Congenital lifelong urology...... 16 Adreno-cortical carcinoma...... 18 EAU-RF PRECISION study recruits ahead of schedule ...... 20 Urothelial cancer ...... 21 BCG-unresponsive bladder cancer. . . . 22 Personalised approach to antagonising ERG in PCa...... 23 New Endoscopic Stone Treatment. . . . . 24 Male contraception: Where are we going?. . 25 Testosterone therapy in men with prostate cancer ...... 26 Patient selection for adjuvant treatment of high-risk NMIBC...... 29 Overcoming obstacles in patient communication...... 30 Current issues in urological nursing care. . 31 EAU Secretary General Prof. Chris Chapple (r) and Henriet Wieringa open the three-day Exhibition at London ExCel Day 2 Award Gallery

Best Paper on Fundamental Research: Best Paper on Clinical Research: First Prize Best Abstract (Oncology): First Prize Best Abstract (Non-Oncology): I. Ahmad (Glasgow, United Kingdom) J. Steinestel (Muenster, Germany) R. Seiler (Bern, Switzerland) H. Langenhuijsen (Nijmegen, The Netherlands)

Second Prize Best Abstract (Non-Oncology): Third Prize Best Abstract (Oncology): Best Scientific Paper Fundamental Research in European Best Scientific Paper Clinical Research in European Urology: M. Ilg (Chelmsford, United Kingdom) N. Fossati (Milan, Italy) Urology: A. Ross (Baltimore, United States of America) J. Weinreb (New Haven, United States of America) and Sponsored by ELSEVIER J. Barentsz (Nijmegen, The Netherlands) Sponsored by ELSEVIER

Best Scientific Paper in European Urology: Best Scientific Paper on Robotic Surgery in European Best Booth Award 2017: STEBA BIOTECH E. Baco (Oslo, Norway) Urology: K. Ghani (Ann Arbor, United States of America) Bertrand Gaillac MD, Prof. Chris Chapple, Dr. Stefan Spaniol, John Rewcastle PhD, Silvestre de Lima Neto, Prof. Avigdor Scherz Sponsored by ELSEVIER Sponsored by VATTIKUTI FOUNDATION

Sunday, 26 March 2017 EUT Congress News 3 Update on hereditary prostate cancer Family history- a major risk factor for prostate cancer development

Dr. Patrick C. Walsh DNA sequences of known chromosomal location that University are consistently co-inherited with the disease in Distinguished Service multiplex families. Within two years we’re pleased to Professor Emeritus identify the first prostate cancer susceptibility gene on The James Buchanan chromosome 1 (1q24-25) but disappointed when our Brady Urological findings could not be replicated by other investigators. Institute Soon, linkage was reported by others at numerous Baltimore, Maryland other loci but again few were consistently confirmed (USA) and none fulfilled the criteria for a high penetrance allele like BRCA1/2.

Genome-wide association studies to search for The identification of germline mutations in hereditary complex disease cancers is of great importance. These mutations make Next, investigators became excited about the influence it possible to identify individuals who are at high risk of SNPs, and the possibility that a large number with for developing the disease (e.g. BRCA1/2 in breast each having a very small effect would be the answer. cancer) and to develop targeted therapeutic These studies led to the successful identification of over approaches directed at events that drive tumor 100 SNPs associated with prostate cancer risk. initiation and progression (e.g. renal cancers). Although the relative increase in risk for any single SNP is small, the risk increases as the number of inherited For this reason, for the last three decades this has been risk SNPs increases but these appear to explain only an area of intense investigation at the Brady Institute. about 25% of the risk associated with a positive family Today, based on twin studies, we know that prostate history and the clinical utility of these findings remains Figure 1: Schematic diagram in a case-control study of men with a history of hereditary prostate cancer and radical prostatectomy cancer is more heritable than other common cancers, uncertain. including ovarian, kidney, breast and colon cancer. Paradoxically, although the genetics of these less Where is the missing heritability – rare variants? the maternal or paternal lineage; 2) early onset from genetic testing utilizing a panel of DNA repair heritable malignancies is well established, there is still So where is the missing heritability? Going back to the prostate cancer (age ≤55 years); or 3) prostate cancer genes for the impact it can have on their individual much that is unknown about the genetic pathogenesis drawing board, but this time armed with high- with a family history of the BRCA1/2 mutation or other treatment options (the use of platinum and PARP of prostate cancer. For this reason, I selected this topic throughput next-generation sequencing (NGS), we cancers (e.g., breast, ovarian, pancreatic). inhibitors rather than taxanes), as well as information and thought I would tell the story of our search for the again searched for rare variants with the hope that to be shared with family members regarding risk of missing heritability of the disease. there may be multiple rare variants that contribute a Who should be referred to a genetic counselor for prostate cancer and other BRCA2 related cancers, e.g. large effect. genetic testing? First: men of Nordic descent are up five pancreas, breast, ovarian. Family history is a major risk factor to 10 times more likely to carry a high risk HOXB13 The story begins in 1987 when a 49-year-old man HOXB13 allele, and thus men in this group should be offered In closing, it is important to emphasize that this effort asked me if prostate cancer was hereditary. When I Our first use of NGS was in collaboration with screening for mutations in this gene. Men testing has been led by Dr. William Isaacs who has dedicated asked him why he wanted to know he responded that investigators at the University of Michigan who had positive should be counseled about earlier and more his skill, intellect, and energy for the last three decades his father, his father’s three brothers, and his reported linkage at 17q21. We identified one particular intensive disease screening. to uncover the genetic pathogenesis of prostate cancer. grandfather died from the disease. At that time, it was missense variant mutation in a homeobox gene called This talk and these discoveries are a tribute to his common knowledge that women with a mother or HOXB13, changing glycine to glutamine at codon 84 or Second, men with a family history of the BRCA1/2 brilliance and perseverance. sister who had breast cancer had a two-fold higher risk G84E. We were especially interested in this gene as it mutation. Also there is consideration to extend testing for developing it. So why didn’t I know the answer to was already known to be prostate-specific in its to men where the likelihood of a BRCA 1/2 mutation is Monday 27 March his question. Because the available literature on expression pattern, and in mice it plays a critical role in high: family history of a first-degree relative with 10.30-10.50: Plenary session 05, Update on prostate cancer was sparse. There was information the development and maintenance of normal prostate breast/ovarian/pancreatic cancer or personal history of hereditary prostate cancer from the Utah Mormon genealogical registry but it was function. This time confirmatory studies involving many breast cancer. Third: men with CPRC. They may benefit unclear if these findings could be applied to the thousands of men unequivocally established HOX B13 general population or whether they represented a rare as the first validated prostate cancer susceptibility founder mutation in an isolated population of men. To gene. Clinically, this mutation is particularly important determine if the same were true in another population to be aware of in men with Swedish or Finnish we undertook a case-control study of 742 consecutive ancestry. men who underwent a radical prostatectomy at Hopkins using their spouses or female companions as BRCA1/2, DNA Repair, and Mismatch repair mutations a control. Our findings, which confirmed a 2.2 fold Twenty years ago BRCA2 was implicated as an increased risk for men with one first-degree relative, important gene for prostate cancer by studies in were soon confirmed by four other studies that Icelandic families and more recently Eeles and her reported similar results. research group at the Royal Marsden provided additional evidence that defective BRCA2 genes are Familial aggregation is genetic associated with inherited risk of more aggressive NO W The next step was to determine whether this familial prostate cancer. However, it was only within the last THERE’S aggregation was caused by inherited genetic factors or couple of years that we learned of their impact on the from shared environment. Using the same population, development of castration-resistant prostate cancer we performed a segregation analysis that (CRPC). demonstrated the best model predicted autosomal dominant inheritance of a rare (0.3%) high penetrance A study by the Step up to Cancer research group, which risk allele in families with early age of diagnosis and carried out the first in-depth sequencing of men with multiple affected family members. This study CRPC, demonstrated that 6% of men with CRPC had demonstrated for the first time that prostate cancer is deleterious germline mutations of BRCA2. When inherited in Mendelian fashion and provided a coupled with other genes involved in DNA repair (like foundation for gene mapping studies of heritable ATM, and the mismatch repair genes in Lynch prostate cancer. Finally, based on the segregation syndrome, e.g. MSH2) the total number of CRPC OPDIVO delivers superior OS vs. everolimus analysis we developed a definition for hereditary patients with inherited mutations rose to over 12%. In prostate cancer (HPC): three or more first-degree a study at Hopkins, together with our colleagues at in adult patients with advanced RCC relatives (father, son, or brother); or three generations NorthSHore, we found that in men who died from (grandfather, father, son); or two first-degree relatives prostate cancer prior to age 65, 10 to 12% carried after prior therapy if both were less than 55 years old at the time of mutations in BRCA2/BRCA1 and ATM. diagnosis. OPDIVO as monotherapy is indicated for the treatment of Have we been looking in the wrong place? Two major genetic influences: Monogenetic and No one knows for sure, but based on the recent patients with advanced RCC after prior therapy in adults complex discovery that patients with lethal and aggressive It has been estimated that 5%-10% of prostate cancer prostate cancer who do not have a strong family may be considered hereditary. Armed with this history can carry DNA repair mutations in their o information we set out with the hope of finding these germline, maybe we have been looking at the wrong Visit BMS at Booth N K12 to learn more offending mutations, a journey that has taken over 20 patients. Our studies have always concentrated on men years and is not yet finished. I will pause for a minute with multiple affected family members who are alive. OS – overall survival; RCC – renal cell carcinoma to describe the two major categories of genetic Instead, if future studies concentrate on patients with Information about this product, including adverse reactions, precautions, contra-indications and method of use can be influences. Monogenic disease is caused by mutations lethal and advanced disease it is possible we will found at: https://www.medicines.org.uk/emc/medicine/30476. Prescribers are recommended to consult the summary that are rare but have high penetrance in causing the uncover many previously unknown important of product characteristics before prescribing. Legal classification: POM disease, like the breast cancer genes BRCA1/2. In pathways. Marketing Authorisation holder: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, contrast, complex disease is caused by common genetic Uxbridge UB8 1DH, United Kingdom. Tel: 0800-731-1736. variants (single nucleotide polymorphisms, SNPs) that Clinical implications Adverse events should be reported. Reporting forms and information can be found at have low penetrance, and for this reason it takes many Family history is a major risk factor for development of www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bristol-Myers Squibb of them to cause disease, like Type 2 diabetes mellitus. the disease. The history should include age at Medical Information on 0800 731 1736 or [email protected]. diagnosis of prostate cancer in both paternal and Linkage analysis to identify loci for rare high maternal lineages and a complete list of other cancers. 1506UK1602055-01 01/17 penetrance alleles Factors suggestive of a genetic contribution to prostate © 2017 Bristol-Myers Squibb Company Initially, we used linkage analysis to search for the rare cancer include the following: 1) multiple affected high penetrant genes. Linkage analysis is used to first-degree relatives with prostate cancer, including identify the chromosomal location of a gene by finding three successive generations with prostate cancer in

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UKMED01170028 - ARAMIS & ARASENS 2017 EAU - Print ADVERT 02_02_17 v06.indd 1 2/2/17 6:41 AM

UKMED01170028 - ARAMIS & ARASENS 2017 EAU - PRINT ADVERT (295mm x 420mm) Robot-assisted RP: Managing inguinal hernias Experienced and skillful robotic repair of inguinal hernias

Prof. A. Erdem Canda Before starting the rTAPP procedure, it is important to Mesh materials the completion of the RARP seems to be a safe and Yildirim Beyazit obtain a watertight urethro-vesical anastomosis that Before repairing the inguinal hernia defect with a easy procedure to perform by taking specific University is confirmed by distending the bladder mesh material, lateral and superior edges of the precautions and having the proper training and School of Medicine intraoperatively with sterile saline solution (Photo 2). peritoneum are freed creating a space to locate the knowledge to avoid a further operative procedure for Ankara Ataturk In addition, it is also important to have a good mesh. There are different mesh types available on the the patient. Training & Research hemostasis that could be tested by decreasing the market to use for hernia repair. In addition to the Hospital intra-abdominal pressure to 5 mmHg before starting polypropylene mesh materials, bio-absorbable coated References Department of the hernia repair. Likewise, a preoperative sterile permanent mesh materials are also available to cover 1. Nielsen ME, Walsh PC. Systematic detection and repair of Urology urine culture should also be confirmed. the defect. Mesh size could be adjusted according to subclinical inguinal hernias at radical retropubic Ankara (TR) the size of the defect. Before inserting the mesh prostatectomy. Urology 2005;66:1034-7. Our technique of rTAPP inguinal hernia repair was material through the assistant port into the 2. Stranne J, Johansson E, Nilsson A, Bill-Axelson A, reported and presented previously at the EAU ERUS abdominal cavity, the bedside surgeon and the nurse Carlsson S, Holmberg L, Johansson JE, Nyberg T, Ruutu Robotic-assisted radical prostatectomy (RARP) is 2016 Meeting (9). During the transperitoneal RARP always change gloves before handling and M, Wiklund NP, Steineck G. Inguinal hernia after radical increasingly being performed for the surgical procedure a large peritoneal incision is made on the manipulating the mesh material to decrease the risk prostatectomy for prostate cancer: results from a management of localized prostate cancer and, to lateral sides of both medial umbilical folds, below the of contamination. Thereafter, the mesh material is randomized setting and a nonrandomized setting. Eur some extent, some patients might have level of umbilicus opening the preperitoneal space. If introduced into the abdomen through the 11 mm sized Urol. 2010 Nov;58(5):719-26. preoperatively detectable or intraoperatively bilateral extended pelvic lymph node dissection is assistant port (Photo 3). 3. Sánchez-Ortiz RF, Andrade-Geigel C, López-Huertas H, identified inguinal hernias (IHs) (Photo 1). also performed then the lymphatic tissues around Cadillo-Chávez R, Soto-Avilés O. Preoperative external iliac arteries and veins up to the ureters are Rarely, omentum, bowel segments or even urinary International Prostate Symptom Score Predictive of It was reported that 33% of the patients had all cleared giving the console surgeon a good bladder could be found as herniated into the hernia Inguinal Hernia in Patients Undergoing Robotic incidental IHs during radical retropubic prostatectomy anatomical exposure of the important vascular sac and these structures should be carefully Prostatectomy. J Urol. 2016 Jun;195(6):1744-7. (RRP) (1). In a study carried out at Karolinska structures. It is important to include the peritoneal decompressed. Following the application of the mesh 4. Lee DK, Montgomery DP, Porter JR. Concurrent University Hospital, 1,411 consecutive patients who dissection lateral to the internal inguinal ring. It is material over the defect, laparoscopic applied tacks transperitoneal repair for incidentally detected inguinal underwent RRP or RALP were included (2). The also important to particularly pay attention to vascular (absorbable or non-absorbable) could be used to hernias during robotically assisted radical prostatectomy. cumulative risk of IH development at 48 months was and pain triangles during dissection. Vascular triangle secure the mesh over the hernia defect (Photo 4). Urology. 2013 Dec;82(6):1320-2. 12.2%and 5.8% for RRP and RARP groups, includes external iliac vein, external iliac artery, Alternatively, a suture material could be also used for 5. Kaler K, Vernez SL, Dolich M. Minimally Invasive Hernia respectively (p<0.05) suggesting that RARP leads to a femoral branch of genitofemoral nerve and femoral this purpose. Attention should be paid not to injure Repair in Robot-Assisted Radical Prostatectomy. J decreased risk of IH development (2). nerve, whereas pain triangle includes femoral branch spermatic cord, testicular artery, genitofemoral nerve, Endourol. 2016 Oct;30(10):1036-1040. of genitofemoral nerve, femoral nerve and lateral epigastric artery or external iliac vessels during mesh 6. Teber D, Erdogru T, Zukosky D, Frede T, Rassweiler J. It is important to make a proper physical examination cutaneous nerve of thigh. application and securing. Prosthetic mesh hernioplasty during laparoscopic radical preoperatively to identify asymptomatic and prostatectomy. Urology. 2005 Jun;65(6):1173-8. subclinical inguinal hernias before the RARP If a bio-absorbable 7. Finley DS, Rodriguez E Jr, Ahlering TE. Combined procedure. A preoperative abdominal computed coated permanent mesh inguinal hernia repair with prosthetic mesh during tomography or ultrasound might also be helpful in is used, peritoneum transperitoneal robot assisted laparoscopic radical identifying asymptomatic inguinal hernias before could be left open prostatectomy: a 4-year experience. J Urol. 2007 Oct;178(4 surgery. It might be difficult to diagnose inguinal otherwise it should be Pt 1):1296-300. hernias preoperatively particularly in obese patients. closed over the mesh by 8. Finley DS, Savatta D, Rodriguez E, Kopelan A, Ahlering It was suggested that men with preoperative lower using a running TE. Transperitoneal robotic-assisted laparoscopic radical urinary tract dysfunction have an increased risk of a absorbable suture (Photo prostatectomy and inguinal herniorrhaphy. J Robot Surg. hernia at RARP and should be counseled about the 5). An abdominal drain is 2008;1(4):269-72. potential need for concurrent hernia repair (3). introduced and is 9. Canda AE, Atmaca AF, Bedir F, Ozer M, Ardicoglu A. Therefore, due to the preoperative evaluation if the removed during the Concurrent robotic trans-abdominal pre-peritoneal (TAPP) inguinal hernia(s) is/are diagnosed before RARP the postoperative follow-up. inguinal herniorrhaphy during robotic-assisted radical patients could then also be preoperatively counseled On postoperative Day 7, prostatectomy. ERUS Video abstract. European Urology and informed about the possibility of repairing hernia urethral catheter is Supplements, Volume 15 Issue 7, September 2016. at the same session. removed following a confirmation of no Monday 27 March In published literature, many colleagues reported that leakage on cystography. 10.30-10.50: Thematic session 18, Masterclass inguinal hernias are a common intraoperative finding RARP Semi-Live; Management of inguinal during RARP, and concurrent hernia repair with the Robotic repair of the hernias during robot assisted radical use of a mesh material is a safe and effective inguinal hernias by using prostatectomy additional procedure with reasonable increased Photo 1: Appearance of an inguinal hernia during RARP mesh materials following operative time (4-8). If the inguinal hernia is not (Courtesy of Author’s Photo Archive). repaired at the same session following the completion of the RARP procedure, it might be more difficult to repair it via laparoscopic or robotic surgery in the following months after the RARP procedure since there might be severe intra-abdominal adhesions due to the RARP procedure. In addition, this would be a second surgical impact on the patient with additional anesthesia exposure.

A first-generation cephalosporin is administered for antibiotic prophylaxis. Following completion of the RARP procedure, a robotic trans-abdominal pre- peritoneal (rTAPP) inguinal herniorrhaphy is performed by using a mesh material.

For those who are not experienced in performing a robotic/laparoscopic inguinal hernia repair, it might be useful to participate in hands-on training courses in this field to acquire training and experience. In addition, it might be useful to have a general surgeon colleague to supervise the initial cases if needed. Photo 2: Appearance of a water-tight urethra-vesical anastomosis following the completion of Photo 4: Application of titanium tacks on the sides of the mesh material to secure it over the the RARP procedure (Author’s Photo Archive ). defect by laparoscopic applier (Author’s Photo Archive). Surgical anatomy It is important to understand and know the surgical anatomy to properly repair the inguinal hernias. Inguinal canal is lined by the aponeuroses of the abdominal oblique musculature that runs the deep (internal) inguinal ring to the superficial (external) inguinal ring. The deep inguinal ring is formed by an opening in the transversalis fascia. The superficial ring is formed by a gap in the external oblique aponeurosis.

Normally, inguinal canal includes spermatic cord (vas deferens, testicular artery, testicular veins, genital branch of the genitofemoral nerve) and ilioinguinal nerve. Hernias protruding through a weakness in the transversalis fascia lateral to the rectus abdominis, medial to the inferior epigastric vesseks and above the inguinal ligament is named as direct inguinal hernia. The hernia protruding through the deep inguinal ring, lateral to the inferior epigastric vessels and anteromedial to the spermatic cord is regarded Photo 3: Appearance of the introduced and located mesh material covering the inguinal hernia Photo 5: Peritoneum is closed over the mesh using a running absorbable suture and a drain is as indirect hernia. defect in the abdomen (Author’s Photo Archive). introduced (Author’s Photo Archive).

6 EUT Congress News Sunday, 26 March 2017 Is every man fertile? Pharmacological and surgical ways to fertility in young men

Mr. Majid Shabbir hormonal parameters. The management strategy Consultant Urologist depends on the level and nature of the obstruction, as Oncological microsurgical testicular sperm Specialist in summarized in the figure below. Effective reversal of extraction (Onco-microTESE) Andrology and obstruction allows restoration of normal fertility, with Genito-urethral the advantage of allowing natural conception for the Reconstruction, first and subsequent children. Analyses have shown Guy’s and St Thomas’ reconstructive techniques can achieve live birth rates Hospital comparable to IVF/ICSI, but with better cost- London (GB) effectiveness. By avoiding the need for IVF, correction of obstruction also has the advantage of avoiding the need to medically stimulate the female partner for egg retrieval, thereby avoiding some of the additional Fertility is an emotive topic. The strong desire to father potential complications and costs associated with a child and pass your family name and genes to the assisted conception techniques. next generation is considered important culturally, epidemiologically, socially, and psychologically. Reconstructive techniques may not be appropriate in Fertility is construed as a marker of masculinity in couples only looking to have one child or those with many cultures, and a source of shame to those who older female partners. Delays to return of sperm in the are unable to achieve it. ejaculate after successful dis-obstruction in some cases may mean that by the time the male partners fertility is Fertility issues have shaken the corridors of power, and optimized, their female partners fertility potential may even changed the cultural landscape at the highest have reduced to a point where the couples overall levels of society. With this year’s biggest urological fertility potential is worse. Management of the male event in Europe taking place in London, the occasion partner must therefore always be in the context of the gives cause to remember the history of English royal couple. A: Ex-vivo dissection of the removed testis. B: Tumour (right) is reflected to one side. C: Lower power assessment of seminiferous households long since passed and the trials of King tubules (left) away from tumour (right). D: Identification of individual dilated tubule (circled) from which sperm is successfully Henry VIII. extracted.

Henry VIII and his first wife, Catherine of Aragon, had problems with fertility. Their marriage bore six Testis cancer and oncofertility Genetics children, including three male heirs, but all were Approximately 40-50% of men with testis cancer have A number of genetic conditions are known to be either stillborn or died in the first two months, except impaired fertility at presentation, of which up to 10% associated with infertility. Screening of patients with their daughter Mary. Catherine’s inability to produce a are azoospermic (NOA). Currently patients with testis NOA allows detection of recognizable chromosomal male heir led Henry to annul this marriage in favour of cancer are recommended to consider fertility anomalies, which occur in <10% of cases. his wife’s lady-in-waiting, Anne Boleyn. This move led preservation prior to orchidectomy, although this is to a break with the Catholic Church and Rome, the not considered essential at this step. In most units, In the majority of NOA patients, no clear abnormality development of the Church of England and the semen cryopreservation is performed after surgery, can be found. It may be that while the larger structural dissolution of the Monasteries. but prior to subsequent chemotherapy, despite the chromosomes are normal, smaller genomic negative impact of surgery on overall fertility abnormalities may exist. One such example is the Fortunately, issues with fertility don’t shape history potential. presence of certain anomalies on the Y chromosome, and nations in the same way in the modern era! such as the AZFa or AZFb micro-deletions. These are However, the impact of such problems can significantly In our unit, we have taken a proactive approach to present in only a very small number of cases, but are affect relationships and lead to feelings of inadequacy fertility preservation, assessing all patients’ testicular known to be associated with no spermatogenesis, and and detachment in men unable to produce offspring. function and hormones prior to orchidectomy, with if detected no surgical sperm retrieval should be Medical and Surgical Options for Obstructive Azoospermia (OA) cryopreservation of semen at first presentation. This offered. Screening therefore allows selection of this Male factor infertility 1. Ejaculatory duct obstruction –surgical management with allows detection of those with unexpected NOA, in very small group with no fertility potential. Those with Male factors account for approximately 50% of issues Transurethral resection of the ejaculatory ducts (TURED) whom we offer an onco-microTESE (See above). This other abnormalities may have successful SSR, and can with a couple’s fertility. While there are a few rare 2. Retrograde ejaculation –pharmacotherapy aimed at bladder procedure allows the safe oncological removal of the be offered genetic counseling and pre-implantation genetic conditions where a man may have no fertility neck (Pseudoephedrine, Imipramine) or urine alkalinisation) testis via an inguinal approach, with subsequent genetic diagnosis. potential at all, in the main, environmental factors and 3. Vasal or Epididymal obstruction – microsurgical ex-vivo microTESE dissection of sperm from the health issues are the most common causes of male reconstruction by vasovasostomy or epididymovasostomy removed testis to allow maximal fertility preservation The detection of novel biomarkers in NOA is an area of factor infertility. As such, a man’s fertility potential is 4. Testicular obstruction – surgical sperm retrieval (TESA) from adjacent tissue that would have been resigned great interest. Genomic and proteomic analysis of often a barometer of his health, and infertility a to the ‘scrapheap’ of the pathology specimen. This infertile men will be one of the most important steps in symptom of underlying disease. approach has allowed successful fertility preservation the future to identify single nucleotide changes and Non-obstructive azoospermia in 60% of cases without having to involve the markers which may predict fertility potential with more Developments in reproductive techniques have Non-obstructive azoospermia accounts for contralateral testis. accuracy, and allow a clearer understanding of transformed the landscape of infertility management. approximately 60% of all azoospermia cases, and ‘idiopathic’ male factor infertility. The ideal would be The advent of intracytoplasmic sperm injection (ICSI) remains the most challenging scenario in male factor A proactive drive to improve fertility preservation in the identification of markers such as those used in just over two decades ago provided the greatest boost infertility. Apart from the few cases of cancer patients at first presentation may prevent cancer diagnosis and follow up, which may guide to severe male factor infertility management. By hypogonadotrophic hypogonadism, who respond subsequent disappointment once the irreversible infertility diagnosis and management with more allowing single sperm cells to be injected directly into extremely well to hormonal stimulation to recover their iatrogenic effect of treatment has been inflicted. accuracy. Ongoing investigations in this field may lead to viable oocytes, this technique opened up a world of fertility potential, this group of infertile men fare less the biggest changes and refinement in the management possibility to those previously considered infertile. well with medical and surgical intervention. Varicoceles of infertile men since ICSI, but given the vastness of the While this has been an undoubted success, it has lead Challenging and controversial areas of management This has been an area of controversy for many years, task, this remains some way off at present. to a shift away from understanding and correcting the are discussed below. based on the flawed analysis of Evers and Collins underlying cause of male factor infertility, to one that published in the Lancet in 20033. Subsequent review Final thoughts simply overcomes it with assisted reproductive Surgical sperm retrieval- MicroTESE of the original data a decade ago found that confining In those who cannot achieve fertility, alternatives such techniques. Surgical sperm retrieval (SSR) is the primary option in the analysis to only those with clinically significant as donor sperm and adoption remain alternative those with irreversible NOA. Of all the available SSR varicoceles and infertility resulted in a significant routes to fatherhood. UNICEF estimate approximately When considering the causes of male infertility, the techniques, microTESE has the greatest chance of improvement in pregnancy rates after correction of 13 million children are without parents worldwide, problem can be primarily divided into: success. Compared to conventional TESE, microTESE the varicocele4. Despite this, most reproductive while WHO estimated approximately 48 million couples almost doubles the chance of successful SSR (weighted medicine specialists still do not treat varicoceles were unable to have a child in 2010. In a utopian 1. Issues with spermatogenesis, or means 33% vs. 54% in meta-analysis1), allowing pro-actively. society, neither should exist. As such the question 2. Issues with sperm delivery. considerably more men the chance to progress to ICSI. should change from one asking ‘Is every man fertile’, MicroTESE is also successful in those men with There are a number of ways in which a varicocele to one, which asks ‘Is every man able to be a father?’ Detailed assessment of the patient including previous failed conventional TESE. may affect fertility, from the effects of the increased As I discovered when I became a father myself, there is examination of the testes and scrotal contents, temperature, to its effect on hormones, certainly much more to it than just passing on your assessment of hormone profile and semen analysis In our series, 65% of men deemed infertile by spermatogenesis, and DNA fragmentation. Meta- genetic code. allow the urologist to pinpoint where the underlying conventional TESE had sperm found on subsequent analyses have shown correction of varicoceles can issue may be. microTESE, including azoospermic men after previous lead to significant improvements in sperm counts and New techniques and developments in the management chemotherapy. Similar findings have been described in motility. Other studies have shown reduced DNA of male factor infertility continue to allow us to reduce The most challenging situation is azoospermia, where other series. This finding has lead to the conclusion fragmentation and spontaneous miscarriage rates the proportion of infertile men who are considered no sperm are seen in the ejaculate. Azoospermia that men should not be considered infertile until they after correction. Randomized control trials have also beyond assistance. Thankfully, the fate of nations no affects approximately 10-15% of infertile men. Even in have a microTESE and are found to be infertile. Using shown that treatment of clinically significant longer hangs in the balance! this extreme, infertility can be effectively managed and hormonal stimulation with HCG/HMG prior to redo varicocoles can improve the chance of spontaneous restored. While not every man with azoopsermia is surgery may further enhance these success rates, pregnancy with an odds ratio of 3.04, and NNT 5.27 in References fertile, more have fertility potential than one would although the best regime and combination of drugs men with oligozoopsermia5. 1. Deruyver Y et al Andrology 2014 2:20-24 expect and they may achieve fatherhood using a variety remains unclear at present and an area that requires 2. Okada H et al. 2002 J Urol 168, 1063–1067. of techniques. better coordinated multi-centre trials. In those with NOA and clinically significant 3. Evers J & Collins J. Lancet. 2003 May 31;361(9372):1849-52. varicoceles, treatment can lead to sperm recovery in 4. Ficarra V et al Eur Urol. 2006 49(2):258-63. Obstructive azoospermia When one considers the significantly lower the ejaculate in up to 32%6. Even in those who remain 5. Abdel-Meguid TA et al Eur Urol 2011 59(3):455-61 In approximately 40% of cases, azoospermia is due to complication rates of microTESE compared to azoospermic, subsequent SSR after varicocele repair 6. Abdel-Meguid TA J Urol. 2012 187(1):222-6 a structural, or ‘functional’, obstruction in the sperm conventional TESE, despite its more invasive nature2, significantly increased the chance of SSR by 2.67. 7. Esteves SC et al Asian J Androl. 2016 18(2):246-53 pathway. Problems may occur at any point from its it becomes clear that microTESE should be the gold inception in the seminiferous tubule to its delivery at standard SSR technique in NOA. Despite this, there are Despite its inclusion into EAU and AUA guidelines, a Saturday 25 March the external urethral meatus. In obstructive cases, the still more fertility centres worldwide undertaking a proactive approach to the management of clinically Plenary Session 2, Hot topics in andrology testicular structure and function is normal, with normal conventional rather than microsurgical SSR. significant varicoecles is still slow on the uptake.

Sunday, 26 March 2017 EUT Congress News 7 Photodynamic therapy for prostate cancer Treatment strategy in low-risk PCa may change with photodynamic therapy

Prof. Arnulf Stenzl cancer study is a vascular – acting photosensitizer Dept. of Urology consisting of water – soluble, Palladium – substituted Eberhard-Karls- bacteriochlorophyll derivative. If activated with University Tuebingen low-power monochromatic (laser) light at 753nm, a Tuebingen (DE) reactive oxygen species (ROS) is formed which then may lead to ROS-mediated necrosis.

Since Padeliporfin is a vascular-targeted photodynamic therapy it is restricted to well- vascularized tissues (such as parenchyma but not capsular or fascial structures). Furthermore, in a solid parenchymatous organ such as the prostate the sensitizer can only act The principles of photodynamics, i.e., light-induced where a monochromatic light source can reach it, activation of intracellular or extracellular which means the laser fibers have to be placed in or photosensitizers which can be used for diagnostic near lesions made visible by imaging. and/or therapeutic purposes in non-muscle invasive bladder cancer have been well-known to urologists. Vascular-targeted photodynamic therapy It has also been used for many years in the treatment Several weeks ago a prospective randomized study of neurosurgical tumors as well as upper respiratory including 413 patients from 47 institutions throughout tract, gynecologic and dermatologic lesions with Europe and a minimum follow-up of 24 months has variable success. been published, comparing vascular-targeted photodynamic therapy with active surveillance in Its use for prostate cancer is relatively new. There patients with low-risk prostate cancer. This is to date have been many in-vitro and in-vivo studies using the only prospective randomized study comparing any Padeliporfin as the sensitizer, activated by approved or experimental focal therapy with active anesthesia consisted of an intraprostatic placement of Nevertheless, the remarkable results of this study may intraprostatic laser light omitting fibers. The wave surveillance. optical fibres through a perineal raster followed by change the strategy in low-risk and maybe even low/ length and dosage in humans was set at 753nm with intravenous application of the photosensitizer intermediate-risk patients with prostate cancer. It may a fixed power setting of 150mW/cm leading to an “Nevertheless, the remarkable Padeliporfin. After 12 and 24 months the prostate was be a tool for a tissue-sparing form of treating prostate energy dose of 200J/cm. The time necessary to re-biopsied. Twenty-four months after the initial cancer which will benefit patients that may have an achieve this fixed dosage is 22min 15sec. results of this study may change the treatment a negative biopsy result was observed in “under-staged” disease, and the small number of strategy in low-risk and maybe even 49% of the vascular-targeted photodynamic therapy patients that may develop metastases despite an Many photosensitizers have been tested for group versus 14% in the active surveillance group, initially proven Gleason 3+3=6 score disease. And it photodynamic diagnosis and treatment. Some low/intermediate-risk patients with being highly statistically significant. might help men who are seeking non-surgical photosensitizers such as aminolaevulinic acid and its prostate cancer. It may be a tool for treatment despite different advice because they can´t derivatives use an enzyme defect in the hem synthesis Several facts have changed since this study was live with subjective uncertainty of living with a which only occurs in certain tumour cells. The a tissue-sparing form of treating initiated several years ago. The technique and quality malignant disease. subsequent accumulation of protoporphyrin IX can be prostate cancer which will benefit of a prostatic MRI have improved and a made visible with monochromatic light at a wave multiparametric MRI is in some centers nowadays used Recent developments in imaging including length of 428 nm. patients...” as a selection criterion for the initial biopsy as well as multiparametric MRI, PSMA-PET- MRI and navigation- a marker for active surveillance. Active surveillance is a assisted tools/MRT biopsy will further make focal In a more concentrated form or by using different The majority of those patients included in this study more widely accepted strategy for low-risk prostate therapy more accurate by improving prediction of sensitizers a singlet oxygen formation is provoked (86% and 87% in the vascular- targeted photodynamic cancer despite the fact that under-staging may occur prognosis, better targeting of relevant tumor lesions, leading to cell destruction and necrosis. The therapy and active surveillance group, respectively) and some patients with a long life expectancy cannot and aiming re-biopsies at the previous sites of biopsy photosensitizer Padeliporfin used in the prostate were stage T1c. The two-hour treatment under general accept the psychological burden. put in storage.

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8 EUT Congress News Sunday, 26 March 2017 Benign Prostatic Enlargement (BPE) Evaluation, drugs, surgery or new interventional treatment

Mark J Speakman The majority of our patients still present because of Taunton & Somerset bothersome LUTS although a significant and important NHS Foundation minority present because of either acute or chronic Trust retention. Most guidelines agree on the important Dept. of Urology issues for the clinical history, examination and Musgrove Park evaluation and it is good to see that more and more Hospital guidelines are correctly promoting the frequency Taunton (GB) volume chart or bladder diary as equal to, or even more important than a symptom score such as the IPSS.

Inflammation Several studies4,5 have demonstrated the activation of This article will highlight some points in a chronic inflammatory prostatic responses in the stimulating, dynamic and rapid fire session with 16 pathogenesis and progression of both benign and contributors to the programme. Plenary Session 4 malignant prostatic disease. Approximately half of will cover the understanding of LUTS/BPH, BPE and our patients with LUTS who come to surgery have BPO and its presentation, evaluation and treatment signs of chronic inflammation on histological with slightly more emphasis on the newer surgical analysis. It is possible therefore that new therapeutic options rather than the drug treatments. It will be molecules may in the near future be targeted to chaired by the EAU Secretary General Chris Chapple modify these inflammatory pathways which could and Piotr Radziszewski (PL). then delay or avoid symptom and disease progression. In a subset of the MTOPS study6 in 1. The session will start with a state-of-the-art patients who had a pre-study prostate biopsy, no presentation on the importance of recognizing the patients without histologic inflammation developed UroLift system delivery steps: (a) release safety lock, (b) deploy needle, (c) retract needle, delivering capsular tab and tensioning role of inflammation in LUTS/BPE pathogenesis by retention and more recently in an analysis of the monofilament, (d) attach urethral end piece and trim monofilament. Photo: Thomas McNicholas, et al, European Urology Archives one of the key investigators and authors in this REDUCE trial4 it was shown that the presence of field, Mauro Gacci (IT). chronic inflammation was associated with both the severity and the progression of LUTS/BPH. 2. This is followed by a high-level debate on the their own guidelines and larger organisations like the slowing. The principal surgical options have been value of urodynamics in LUTS/BPE evaluation and Urodynamics EAU provide their high-quality guidelines free for resection, enucleation and/or vaporization and treatment planning, chaired by Henry Woo (AU) Most of us would agree that formal urodynamics can members and non-members alike. In the early days these have led to generally acceptable long-term and debated by Matthias Oelke (DE) and Nikesh add useful information to the comprehensive workup these were often based on the ‘ex cathedra’ outcomes with reasonable safety. Most of these Thiruchelvam (GB), taking the pro and con of men with LUTS, particularly those being statements of senior urologists but they are now procedures are operator dependent and we tend to positions, respectively. This debate is likely to be considered for surgical intervention. It is however an predominantly based on evidence-based medicine believe that success depends upon the degree of ‘won’ by the better proponent of their case invasive test that some patients find unpleasant. and therefore of a much higher quality, although relief of obstruction of the bladder outlet. although it is hoped that the results of the Those surgeons who do routine urodynamics tend to there are methodological issues that vary between ongoing UPSTREAM study will answer this advocate that surgery should only be performed in them and thereby affect the quality. In addition, the Whilst some of these procedures have required uncertainty in the relatively near future. those men with proven bladder outlet obstruction. uptake and utilisation of these guidelines by their hospitalization the latest developments are focused Advocates for restricted use stress the lack of members is less than it should be; a good example on trying to achieve an outpatient / daycase or 3. Next there will be patient cases in three different evidence of better outcomes after urodynamics and would be the underutilisation of frequency volume office-based procedure without the need for general clinical scenarios presented by Andrea Tubaro (IT) of course the associated costs. Do the benefits charts (bladder diaries) even though they are anesthesia. There has also been greater awareness and we hope to identify how to select appropriate therefore outweigh the disadvantages? The recommended in all good guidelines. amongst patients of some of the sexual and surgical interventions and agree when it is not UPSTREAM7 trial has addressed this very question in ejaculatory dysfunctions from some of the more appropriate to offer surgical intervention a systematic and randomised way and it is hoped Emerging technologies traditional approaches. This has led to even more (Discussants Alexandre De La Taille [FR] and Mark that Marcus Drake (GB) and co-workers will provide Surgical interventions for LUTS/BPO have evolved minimally invasive therapies such as intra-prostatic Speakman, [UK]) us with a definitive answer in 2018. considerably over the last 10 to 15 years and the injections (still undergoing clinical trials) and pace of development is showing no signs of innovations such as the Neotract Urolift™ device that 4. Most of us now fully accept the importance of When to operate? have been introduced after a well-structured high-quality Guidelines in the evaluation and This is not an easy decision and certainly not as easy investigational clinical trials process (unlike some of management of our patients and particularly their as many of us thought it was when we were junior Table 1: Treatment Options for LUTS/BPO the innovations in the past). value to our juniors in training. Dr Stavros Gravas registrars. Surgery can often be highly beneficial but if (GR) will present the essentials of what matters in patients get results below those they had expected, or • Conservative measures There have also been a variety of ablation these documents and educate us on the strengths if they get complications they can subsequently be • Medical Treatments; techniques ranging from the use of high frequency and perhaps some of the weaknesses of their very difficult patients to manage. If at all possible 0 single or combinations ultrasound to water vapor (Rezum and Procept different forms. therefore, patients should always be encouraged to • Surgery aquablation). Within the realm of interventional have a trial of medical or conservative therapies 0 Conventional; radiology there has also been increasing success 5. Over the last few years there has been a plethora before proceeding to surgery. The only strict exception - TURP(mon & bipolar), TUIP, TUVP, Open with prostate artery embolization. It is unlikely that of new technologies in the surgical management would be high pressure chronic retention. 0 Minimally invasive surgery robotic assisted simple prostatectomy will be of LUTS/BPO and the next section chaired by - laser techniques cost-effective. A comprehensive list of treatments is Christian Gratzke (DE) describes the latest In reality patients need to ‘earn’ their operation and - prostate injection treatments8 provided in Table 1. developments in surgical progress using three be demanding surgery before plans are made. They - stents fundamentally different modalities; Electricity need to be made fully aware of all the possible - prostatic urethral lift (Urolift® System)9 Editorial Note: Due to space constraints the reference (presented by Thomas Herrmann, DE), Light alternative therapies and the potential for - prostate artery embolization10 list has been omitted. Interested readers can email at (Cesare Marco Scoffone, IT) and Water (Neil complications and symptom failure for each of them. - transurethral RF water vapor [email protected] for a complete listing. Barber, GB). This should be a highly illuminating It can be better to do what we may believe is the thermaltherapy (Rezum® System)11 programme. second-best solution if that is the well informed - robot-guided water ablation Sunday 26 March choice of the patient. Understanding and managing (PROCEPT Aquablation™)12 8.45-9.15: Plenary Session 4 : Benign Prostatic 6. Many of us have patients who are still bothered patients’ expectations is now an important and time - Histotripsy Enlargement (BPE): Evaluation, drugs, surgery or with symptoms even after what appears to be consuming part of our role. - Robotic assisted simple prostatectomy new interventional treatment good case selection, a seemingly complete work-up and apparently successful surgery. We are now much more knowledgeable on which Therefore a state of the art presentation by Karel patients require mono-therapy with drugs and which Everaert (BE) follows which will update us on the require combination therapies, and Claus Roehrborn latest thinking and provide important tips about and others have highlighted the importance of how to avoid or deal with these problems if they identifying which of our patients are at a greater risk occur. of LUTS progression and those more likely to develop complications of their disease. The reasonable 7. The session finishes with the ‘blockbuster’ question is, are we as thoughtful about which surgical UROLOGY presentation from Claus Roehrborn (US), the modality to offer our patients as we are with the ‘Emperor’ of LUTS/BPE who will give us his drugs? Should this be based on prostate size or on the CLEARLY valuable personal explanation of, to borrow from type of LUTS that they suffer? Do storage and voiding DEFINED Donald Rumsfeld, …the known and unknown symptoms behave differently after surgery? Is there a (by many of us) unknowns of the diagnostic and value in offering more minimally invasive therapies to therapeutic pathways. our younger patients wishing to avoid ejaculatory problems? Whilst accepting that there is a greater Terminology probability that they will require further surgery in Since the seminal BMJ paper1 by Paul Abrams over 20 the future or should we promote a more definitive years ago we have gradually moved away from procedure as first choice? Clearly patient choice and ‘prostatism’ and hopefully everywhere, except the the limitations of the local health care organisation Cheers! USA, also stopped using the term ‘BPH’ as a clinical will strongly influence these decisions. Have an after-work beer with us at our booth B43 syndrome, as BPH is first and foremost a pathological and discover our clearly defined urology solutions. definition. We now recognise that using LUTS is the Guidelines correct terminology as it is neither gender nor Clinical Practice guidelines addressing the First come, first served. Every evening as of 17.00! organ- specific. The UK NICE guideline2 and that of management of men with LUTS/BPH began appearing 3 the EAU and many others have correctly moved to in the urological journals in the early 1990s and the Hitachi Medical Systems Europe Holding AG this terminology to define the storage, voiding and number and quality of these have increased year on www.hitachi-medical-systems.eu post-micturition symptoms. year. Most national urological associations publish

Sunday, 26 March 2017 EUT Congress News 9 PS3: Debate on low-risk BCa

Dirk Schultheiss Mr. Hugh Mostafid with low-risk NMIBC compared with a standard Friedrich Moll Consultant Urologist five-year surveillance schedule. The results of this and Senior Lecturer model showed that a reduced surveillance protocol ee Royal Surrey County was associated in a reduction of nearly 50% or 4000 Hospital pounds per patient in costs with only a negligible dont oet The University of reduction in clinical effectiveness. Surrey to i Guildford (GB) Based on this, NICE recommended that in the UK patients with low risk/grade NMIBC with no recurrence UROLOGY o one at 12 months should be discharged back to primary care and importantly their primary care physician under the it should not perform regular investigations such are The current EAU guidelines on non-muscle invasive urine cytology to monitor for recurrence. However SWASTIKA bladder cancer (NMIBC) recommend cystoscopic patients were to report any visible haematuria follow-up for five years in patients with low- grade immediately. The guidelines were published in NMIBC but this is only a Grade C recommendation as February 2015 and in the two years since, the majority there is little high quality evidence in this area. of urology departments in the UK have adopted this strategy. Although as yet no scientific literature has Indeed the EAU guidelines themselves state that been published on outcomes following this change, ‘tumour recurrence in the low-risk group is nearly the British Association of Urological Surgeons (BAUS) always low stage and LG/G1. Small, Ta LG/G1 papillary have been monitoring the situation closely and as yet recurrence does not present an immediate danger to no concerns have been raised by UK urologists. the patient and early detection is not essential for successful therapy’ (LE:2b). Many departments report a significant easing of their cystoscopic workload following the change which has The UK National Institute for Health and Care enabled them to focus on faster cystoscopic oo nde te ti Excellence (NICE) develops practice guidelines for the investigation of new haematuria referrals. Interestingly, National Health Service (NHS) in England and the NICE there is anecdotal evidence that new low-risk NMIBC Edited by Dirk Schultheiss and Friedrich Moll Bladder Cancer Guidelines were developed by a panel patients are happy to be discharged at one year, of 15 experts and published in 2015. One of the most whereas patients with established LR NMIBC who are notable recommendations was that patients with low between years one to five seem more reluctant to be The rise of national socialism and fascism and the grade NMIBC could be discharged at one year as long discharged, which suggests that what the patients are subsequent occupation of the continent during the Second as they had been free of recurrence at both their three told at the outset about their disease follow-up has a and 12 month cystoscopies. strong influence in how acceptable reduced World War dramatically infl uenced and destroyed the careers surveillance is for patients. of urologists and the development of the young specialty It is known that the outcome of cystoscopy at three months is a strong predictor for future recurrence and Reference of urology. This new publication by the EAU History Offi ce patients who are free at three months form a 1. A surveillance schedule for G1Ta bladder cancer allowing documents the fates of urologists in this period and explores particularly low-risk group of patients with a efficient use of check cystoscopy and safe discharge at 5 recurrence rate between years one to five of only 12% years based on a 25-year prospective database. the effects of the war on our fi eld. none of which developed progression (Mariappan and Mariappan P, Smith G. J Urol. 2005 Apr;173(4):1108-11. Smith 2005). Given the lack of high quality evidence and costs and workload implications of cystoscopic Sunday 26 March surveillance in this group the NICE guidelines group 09.00-09.15: Plenary Session 3, Redefining and developed a model to assess the clinical and economic optimising contemporary bladder cancer care, Debate impact of a reduced one-year follow-up in patients

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204_17_ENDOCAM_Logic_4K_270_194_en_EAU17_day2.indd 1 15.02.2017 14:44:59 10 EUT Congress News Sunday, 26 March 2017 Non-muscle invasive bladder cancer (NMIBC) Where should we focus future efforts?

Prof. Marko Babjuk tract. For this reason their contribution in daily beneficial effect of HAL FC on recurrence rate in for patients with BCG failures and, even more Department of practice is limited. patients with TURB was confirmed by a multicentre, importantly, more effective treatment which could Urology prospective, randomised trial and by a raw-data- replace BCG as a primary treatment option after Hospital Motol and Typical observation has very low reproducibility of based meta-analysis of controlled trials. A meta- TURB. 2nd Faculty of achieved results. The reason is not only extremely analysis reported in the HAL arms showed an increase Medicine high variability of bladder cancer antigen in detection of tumour lesions across all-risk groups What is new in adjuvant treatment? Promising data Charles University characteristics, but also difficulties with and an absolute reduction of 9% in recurrence rates have been presented on enhancing the efficacy of Prague (CZ) standardization of samples collection as our group within 12 months5. MMC using microwave-induced hyperthermia in demonstrated in presented studies3. Apparently, patients with high-risk tumours. In one RCT non-invasive bladder cancer detection remains a “Our research must be focused comparing one year of BCG with one-year MMC and significant challenge for future research activities. microwave-induced hyperthermia in patients with also on improvement of patients´ intermediate and high-risk bladder cancer, a reduced Bladder cancer is the 11th most common diagnosed Improve results of transurethral resection (TURB) selection for a second TURB. RFS at 24 months in the MMC group was cancer and significant cause of tumour-related deaths The treatment strategy of NMIBC is based on complete demonstrated. worldwide. Although we observe global reduction of TURB, individually followed by intravesical We should concentrate on bladder cancer mortality in recent years, its more chemotherapy or immunotherapy instillations. TURB characteristics achieved by initial There are available several technologies which positive trend is not possible without new represents the critical step in the management of increase the temperature of instilled MMC. They are achievements and comprehensive research activities. NMIBC. The aim of the procedure is to establish the resection...” based on different principles than microwave-induced There are several areas, which seems to be critical to histological diagnosis, determine the tumor stage and hyperthermia and must be evaluated separately. The achieve better clinical results. grade and achieve complete removal of papillary In NBI, the contrast between normal urothelium and data about their efficacy in prevention of recurrences non-muscle-invasive tumors. Unfortunately although hyper-vascular cancer tissue is enhanced by selection are however still lacking. Improve efficacy of primary prevention TURB is a frequently performed procedure which of specific wavelength of light. Initial studies have Several etiological factors in bladder cancer were should be familiar to all urologists, its results are far demonstrated improved cancer detection by identified and confirmed many decades ago, which from optimum and both the diagnostic and NBI-guided biopsies and resection and also the brought unique opportunities for primary prevention therapeutic purposes are not always completed. reduction of recurrence rate for low-risk tumours if and reduction of disease incidence and mortality. Indeed, tumors are frequently overlooked and left NBI is used during TURB6. Unfortunately, not all expectations and promises were behind during initial resection or, more importantly accomplished. and dangerously, their depth of invasion can be SPIES is based on a new software platform, which underestimated. uses the different light wavelengths to produce There is no doubt that the most important risk factor images with different contrast specifications. Its for bladder cancer development on a population basis To overcome these limitations, the second resection clinical benefit however needs to be confirmed. is, at present, tobacco smoking. Recently published (second TURB) performed after two to six weeks was meta-analysis of cohort and case-control studies incorporated in our treatment algorithms. The current More attention is also paid to the technique of estimated pooled relative risk of bladder cancer version of European Association of Urology (EAU) resection. It was demonstrated that the method of between current and former smokers of 3.47 and Guidelines recommends considering a second TURB if “en-bloc” resection performed with monopolar or 2.04, respectively. Moreover, both current smokers there is a suspicion that the initial resection was bipolar current, Thulium-YAG or Holmium-YAG laser Figure 2-B: Narrow Band Imaging (RR 1,53) and former smokers (RR 1,44) have a higher incomplete and when the pathologist reported no provides high quality of achieved specimen even in risk of bladder cancer mortality compared to muscle tissue in the specimen, with exception of TaG1/ tumours over 1 cm7. Its definitive role in daily practice non-smokers1. LG tumours and primary CIS. Furthermore, it should should be specified in the future. References be performed when a T1 tumour was detected at the 1. Cumberbatch MG, Rota M, Catto JWF, La Vecchia C. The initial TURB. Our research must be focused also on improvement Role of Tobacco Smoke in Bladder and Kidney of patients´ selection for a second TURB. We should Carcinogenesis: A Comparison of Exposures and The second TURB can detect residual tumour in 33 to concentrate on characteristics achieved by initial Meta-analysis of Incidence and Mortality Risks. Eur Urol 55% of cases staged as T1 by initial resection. More resection, like T1 sub-staging or lymphovascular in press. importantly, the likelihood that muscle-invasive invasion, which could specify the risk of tumour 2. Marie Ng, PhD1; Michael K. Freeman, MPH1; Thomas D. disease is detected by second resection of initially T1 persistence or under-staging. Interestingly, in a Fleming et al. Smoking Prevalence and Cigarette tumour ranges from 1.3-25%, and it increases to 45% retrospective evaluation of a large multi- Consumption in 187 Countries, 1980-2012 JAMA if there was no muscle in the initial resection. It has institutional cohort of 2,451 patients with BCG- 2014;311:183-192. been demonstrated that a second TURB can increase treated T1G3/HG tumours, the second resection 3. Brisuda A, Pazourkova, E. Soukup V, Horinek A, Hrbácek recurrence-free survival and improve outcomes after improved recurrence-free survival (RFS), J, Capoun O, Svobodova I, Pospisilova S, Korabecna M, BCG treatment. progression-free survival (PFS) and overall survival Mares J, Hanuš T, Babjuk M. Urinary Cell-Free DNA (OS) only in patients without muscle in the Quantification as Non-Invasive Biomarker in Patients We should not forget, however, that a second TURB is specimen from initial resection8. with Bladder Cancer. Urol Int 2016, 96(1):25-31. Figure 1-A: White Light just the “rescue” procedure. The recommendation to 4. Babjuk M, Soukup V, Petrik R et al.: 5-aminolaevulinic repeat surgery in a significant number of patients acid induced fluorescence cystoscopy during with NMIBC must be critically discussed and our effort transurethral resection reduces the risk of recurrence in How effective are we in smoking prevention? should be concentrated on improvement of the quality stage Ta /T1 bladder cancer. BJUI, 2005, 96, 798-802. According to recent data, global modeled age- of the first TURB. How to perform the optimal initial 5. Burger M, Grossman HB, Droller M, et al. Photodynamic standardized prevalence of daily tobacco smoking in TURB? The essential requirement is modern diagnosis of non-muscle-invasive bladder cancer with the population older than 15 years decreased from equipment and surgery performed by well trained hexaminolevulinate cystoscopy: a meta-analysis of 41.2% in 1980 to 31.1% in 2012 for men and from surgeon. detection and recurrence based on raw data. Eur Urol 10.6% to 6.2% for women. Because of population 2013;64:846-54. growths however the number of daily smokers There were several modalities presented which could 6. Naito S, Algaba F, Babjuk M, et al. The Clinical increased from 721 million in 1980 to 967 million in improve visualization of the tumour lesion and can be Research Office of the Endourological Society (CROES) 2012 worldwide. Moreover, the decrease of the categorized as PDD (flouorescence cystoscopy), NBI Multicentre Randomised Trial of Narrow Band prevalence was less pronounced in last two years of (narrow band imaging) and SPIES. The principle of Imaging-Assisted Transurethral Resection of Bladder the analysis compared to previous period2. PDD is based on selective accumulation of Tumour (TURBT) Versus Conventional White Light protoporphyrin IX in tumor tissue after intravesical Figure 2-A: White Light Imaging-Assisted TURBT in Primary Non-Muscle- Although the first warning report on the health instillation of 5-aminolevulinic acid (5-ALA) or, invasive Bladder Cancer Patients: Trial Protocol and effects of smoking was released more than 50 years preferably, hexaminolevulinate (HAL). Protoporfyrin IX 1-year Results. Eur Urol 2016;70:506-15. ago, we are apparently not very successful in emits intensive red fluorescence after illumination Improve efficacy of adjuvant treatment after TURB 7. Kramer MW, Rassweiler JJ, Klein J, et al. En bloc reducing smoking prevalence. More intensified with blue light. The principles of the adjuvant treatment are resection of urothelium carcinoma of the bladder efforts will be needed, to my opinion, and not only individually tailored intravesical chemotherapy or (EBRUC): a European multicenter study to compare in less developed countries. Moreover, to implement immunotherapy instillations. The indication is based safety, efficacy, and outcome of laser and electrical en more effective preventive measures we need to on patients´ stratification into three risk groups, bloc transurethral resection of bladder tumor. WJU understand in more details molecular principles of which is specified in EAU guidelines (EAU guidelines 2015;33:1937-43. cancerogenesis. on NMIBC). 8. Gontero P, Sylvester R, Pisano F, et al. The impact of re-transurethral resection on clinical outcomes in a large Improve non-invasive bladder cancer detection Major problems represent patients with high-risk multicentre cohort of patients with T1 high-grade/Grade The detection of both primary and recurrent bladder tumours, which progress in a significant number of 3 bladder cancer treated with bacille Calmette-Guerin. cancer is based on endoscopic examination, which is cases. The only treatment modality which can reduce BJUI 2016;118:44-52. time-consuming, expensive and, particularly, the risk of tumour progression is BCG intravesical 9. Sylvester RJ, van der MA, Lamm DL. Intravesical bacillus bothersome for patients. Desirably, at least some immunotherapy9. We understand today that to Calmette-Guerin reduces the risk of progression in cystoscopies could be replaced with less invasive achieve optimal efficacy, BCG must be used including patients with superficial bladder cancer: a meta-analysis methods. the maintenance schedule. of the published results of randomized clinical trials. J Urol 2002;168:1964-70. During recent decades, several tests which detect Figure 1-B: Photodynamic Diagnosis In spite of that, we are aware of several limitations. 10. Arends TJ, Nativ O, Maffezzini M, et al. Results of a either soluble or cellular -based markers of urothelial BCG fails in a not negligible subgroup of patients - Randomised Controlled Trial Comparing Intravesical carcinoma in urine have been introduced. The most it was demonstrated that in T1G3 tumours the Chemohyperthermia with Mitomycin C Versus Bacillus promising of them are prepared for routine It was confirmed that with this method we can detect five-year disease-related death rate reaches 11.3% Calmette-Guerin for Adjuvant Treatment of Patients application and some of them (UroVysion (FISH), significantly more tumor lesions comparing to despite BCG therapy. BCG has several side-effects with Intermediate- and High-risk Non-Muscle-invasive Immunocyt/uCyt +, Nuclear matrix Protein 22, BTA stat standard white light investigation and reduce the and is not tolerated by all recipients; moreover, we Bladder Cancer. European urology 2016;69:1046-52. and BTA TRAK) received FDA approval. These methods number of residual tumours. Moreover, our group are facing today the enormous market shortage of have, according to various authors, greater sensitivity presented several years ago that 5-ALA induced the drug, worldwide. Moreover, after failure of BCG Sunday 26 March in bladder cancer detection than cytology. However, fluorescence cystoscopy used during TURB can reduce treatment there is no reliable bladder-sparing 8.00-8.15: Plenary Session 3, Redefining and their disadvantage is the high rate of false positive the recurrence rate in Ta T1 bladder UC4. Until now, option which could prevent patients from radical optimising contemporary bladder cancer care results in patients with other diseases of the urinary this observation was confirmed by further trials. The cystectomy. Apparently, we need effective treatment

Sunday, 26 March 2017 EUT Congress News 11 Clinical Guidelines Aren’t we all stakeholders? European Association Prof. Dr. James organisations/stakeholder groups, medical In addition, the GO recently carried out a N’Dow professionals and their associations (also from prioritisation exercise to identify and of Urology Chairman, EAU bordering specialties), healthcare funders, industry, rank clinical topics that should be Guidelines Office politicians and charity organisations. addressed in the 2018 EAU Guidelines. Dept. of Urology, This was done through a process of University of Whilst there is agreement regarding the importance structured consultation of a large Pocket Guidelines Aberdeen, Aberdeen of stakeholder involvement in the guidelines stakeholder base. While it is still early (UK) development process, effectively incorporating all key days, this may become a standard stakeholders in this process is a considerable element of EAU guidelines 2017 edition challenge. ‘Consideration must be given on how to methodology. manage and optimise involvement of all these groups in a formalised guidelines development Over the past two years, the EAU GO The EAU Guidelines Office (GO) has been expanding process which includes: has heavily invested in the their activities over the past years, supported by a development of systematic reviews number of designated Committees including: the GO • Guidelines topic selection; as a means to ensure that guidelines Methodology Committee, chaired by Prof. Dr. Richard • Panel development; recommendations are based on the Sylvester and the GO Guidelines Associates • Decision on the remit (the scope of a guideline best available scientific evidence. Committee, chaired by Prof. Dr. Thomas Knoll. – what needs addressing?); Whilst this has been highly The GO, together with both committees, have made • Development of recommendations; and successful, and will continue into great strides in improving the methodological quality • Review of results. the future, a number of important of the EAU Guidelines. clinical questions elude this process The UK National Institute of Clinical Excellence (NICE) since either no high level evidence However, one area that will require particular have a very robust methodology in place for has been published, or the attention in future update cycles is stakeholder stakeholder involvement, which serves as a model for available publications do not engagement in the EAU guidelines development many other guidelines developers. However, allow for a clear conclusion process. Stakeholder participation is an established translating such models to an international setting is because they present feature of high-quality clinical guidelines challenging. contradictory findings. Having a development. The GO’s anticipation is that inclusion transparent process in place, which can of all key stakeholders in the development process In particular, meaningful engagement of patients in address such questions in a structured fashion, will will result in better guidelines, better adherence by clinical guidelines development has posed a be hugely beneficial. In this situation formalised conflicts of interest (COI). To address the issue, Prof. patients and clinicians and improved care whilst challenge to the EAU GO. Some EAU Guidelines consensus finding will allow all stakeholders to reach Dr. Anders Bjartell and a team of EAU GO Panel Chairs potentially increasing cost-effectiveness. Panels include a patient advocate, but a sustainable agreement on such controversial subjects. For this have developed a policy document addressing the method on how to progress this further across all of reason an EAU consensus group, chaired by Prof. Dr. handing of potential conflicts. What are ‘stakeholders’, a definition may be:‘any our Panels, has been lacking. However, with the Axel Bex, has been set up to develop a protocol to group or individual who can affect or is affected by assistance of Prof. Dr. Rachel Giles (Patient Advocate guide this process. The GO firmly believes that in The GO sincerely hope that when we reach out to you the achievement of the organisation’s objectives’. in the EAU Renal Cell Cancer Guidelines Panel on order to maximise outcomes for this consensus to learn your views, you will enthusiastically engage behalf of the International Kidney Cancer Coalition) process, stakeholder engagement is key. Another with us since all EAU members are key stakeholders This involves all individuals and groups that ‘use’ a potential model has been developed. Recently, a future project for the GO is public review of all in all of the activities of the organisation. clinical guidelines, are subjected to them, or are scientific paper mapping out the various aspects of pre-publication guidelines documents. Other contributors to their content. Obviously, all of you, this process was accepted for publication1. The organisations are already following such an approach Reference at EAU17 are our stakeholders, without exception. authors consider that transparency, accountability with highly positive result. 1. MacLennan SJ, et al. Eur Urol prior to print. Changing Other stakeholders in clinical guidelines and harmonisation of patient care based on the best current practice in urology: improving guideline development include, but are not limited to: available scientific evidence are core elements of Ultimately, all these processes rely on transparency as development and implementation through stakeholder patients, their carers and families, patient this process. well as the management of all stakeholders’ potential engagement. TP 59 1.0 02/2017/A-E

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12 EUT Congress News Sunday, 26 March 2017 Filling the GAP How to include MRI for active surveillance of low-risk prostate cancer

Prof. Chris Bangma still improving, the new kid on the block is genetic Chairman, profiling. All of the technologies mentioned have their Department of individual diagnostic and prognostic value, and their Urology relative importance varies over time. Here we focus on Erasmus University MRI as part of a multiparametric risk evaluation in men Rotterdam (NL) with newly diagnosed and low risk cancers.

Wishful thinking In a perfect world, there would be no overdiagnosis, and AS as a treatment option would not exist. However, as long as it is difficult to accurately predict the life expectancy of a man of 50 years, electing to undergo Ivo Schoots screening because he has a first-degree relative (a Associate professor, father or brother) or a female relative with breast Radiology cancer, we need to live with the uncertainty that over Erasmus University time a symptomatic prostate cancer can surface. And Figure 2: The care path for active surveillance (A.R.Alberts, Erasmus MC). The top line depicts current Active Surveillance Medical Centre the longer the period for our predictions is, the larger PRIAS-MRI study protocol. Confirmatory MRI with targeted biopsies within 12 months of diagnosis may add to the earlier Rotterdam (NL) the uncertainty will be. This means that we better diagnosis of low-risk tumours (or to upgrading), but at the cost of missing some upgraded tumours compared to systematic refrain from looking ahead more than 10 to 15 years confirmatory TRUS biopsies. Offering systematic biopsies in case of negative MRI to men with increased risk by PSA-density or (with the likely exception from having a very low serum genomic profiling may optimize the care path (blue path). PSA below the age of 50). So men will screen (and remain to be screened by physicians), and cancers will be diagnosed based on the histologic evaluation of targeted biopsies and additional upgrading of low-volume studies so far. Still, the number of men biopsies. low-risk tumours towards intermediate or even being followed for at least five years needs to grow, Sophie Bruinsma high-risk tumours in ca. 10% of cases, not detected since at the moment sufficient imaging data is available Postdoctoral Now we hope of course, that histologic biopsies will by systematic TRUS guided biopsies. This is on top in less than 5% of the 14,000 participants. To assess the researcher, become unnecessary to diagnose prostate cancer, and if of the value of repeated systemic TRUS directed value of MRI for the future management of AS, from Department of by non-invasive testing with imaging, urine and blood biopsies itself, which already corrects grading in ca. 2017 to 2019, the database will be retrospectively Urology tests we can claim that a person will not be affected by 20% at confirmatory biopsies. However, would the complemented and prospectively extended with data of Erasmus University symptomatic prostate cancer, that would be ideal. That, diagnosis be dependent on targeted biopsies only, more modern patients diagnosed by MRI. Medical Centre however, is unlikely to happen during our careers. then 10 % of relevant tumours would be missed Rotterdam (NL) What might happen is that an individual can be upfront due to the lack of systematic biopsies. Where there is no MRI provided with a likelihood of not having a relevant Active surveillance has turned out so far as a safe cancer for the next 10 years, based on urine and blood This means that MRI can reduce the upfront treatment option for men with low-risk cancers, as less tests, enriched with information obtained by imaging misclassification by correction of targeted biopsies in than 3% of men develop metastases due to missing when needed. And this in combination with an men that were selected with low-risk tumours tumour progression during the follow-up of 15 years The public awareness on prostate cancer has individualised advice for re-screening in case there is a (according to standard criteria) but did not have an MRI [Klotz, JCO 2015]. These results have been obtained introduced individual screening on a large scale in low-risk. Also it is reasonable that in case of an before diagnostic biopsy. This is important as the main predominantly on protocols without the use of MRI. many societies around the world. As a result, prostate increased risk on prostate cancer an adjusted scheme reason for reclassification within one year in AS This means that the use of MRI aims at improving the cancer incidence has changed profoundly. for diagnostic biopsies will be provided, sometimes protocols currently is an upgrading by confirmatory outcome of follow-up, reduce the initial with systematic biopsies, sometimes with targeted biopsies (due to missing the index lesion) or misclassification as soon as possible, and reduce the While the highest rates are still found in western biopsies only, to minimize the number of unnecessary underestimating the size of the lesion. Correction of this number of unnecessary biopsies needed for the societies (Torre 2012), statistics show the steepest diagnostic biopsies. misclassification might correct for 20% of men being management of men on AS. Maybe MRI can even help incline in prostate cancer diagnoses in Asian countries treated incorrectly by active surveillance according to to extend the number of men included for AS, for (Figure 1). The widespread use of screening of healthy In fact it looks like the figure below, in which a regular current risk categories. example by selecting men with visible small-volume men has resulted in decreases in cancer-related care path for active surveillance is depicted, together tumours and Gleason 3+4=7 without aggressive mortality. However, any screening procedure carries a with the option of additional MRI for targeted biopsies Unfortunately, current data shows that MRI also misses histologic or genetic components. It also means that the risk of over-diagnosis, i.e. the diagnosis of a clinically of visual PIRAD 3-5 lesions. relevant tumours by around 10 %. These tumours are traditional protocols that are in use around the world insignificant cancer that would not have been not visible on MRI, so would be missed in any strategy remain very valuable and safe to follow. A message discovered in the absence of screening, and that would No gold standard that makes use of targeted biopsies only. We do not well conveyed when discussing the frontiers of new not harm the patient. In turn, overdiagnosis has led to Because of the slow growth and metastatic potential, know how to correct for this false negative result of MRI developments. overtreatment, with the potential for unnecessary side the follow-up of low risk tumours takes many years. apart from performing systematic biopsies. However, effects. The amount of unavoidable over-diagnosed Therefore, at least for the next decade or so, we need to we may suspect these hidden non-visible tumours if we The evaluation of the dataset created by the cancers is rising, as it is proportional to the intensity of accept the surrogate endpoint of 1) predefined risk consider other risk factors, like an increased PSA- Movember Foundation in The Global Action Plan screening. As in addition the population of many groups for treatment decisions (based on tumour stage, density. Offering systemic biopsies only to those at Prostate Cancer Active Surveillance (GAP3) Initiative countries continue to age, not only the number of serum PSA levels, biopsy Gleason score and other risk higher risk, whether due to increased PSA-density or will provide a start to their second phase action diagnosed cancers grows, but also the prevalence of parameters) at the time of diagnosis, at the time of based on genomic profiling, may save a large number constructing a data set of actual MRIs during the men with cancers that need to be observed lifelong. reclassification and at conversion towards invasive of unnecessary systematic biopsies (Figure 2). follow-up of cancers worldwide. From this, treatment, and 2) the histologic outcome of radical collaborating urologists and radiologists will work Active Surveillance (AS) of low risk prostate cancer prostatectomy. These risk classes may alter in due time MRI for Follow up during the next two years on the validation of therefore remains an important asset in the care of when genetic information will be added to the Gleason Men on AS have been followed with MRI (Felker 2016, radiologic parameters in relation to the clinical data. prostate cancer patients, until a reliable marker is score and tumour volume as predominant parameters Frye 2016), but the amount of consistent data appears found that will indicate the future development of of prognosis. Validation of the use of MRI remains to be sparse. We have no clue at this moment how Key points: symptomatic metastatic cancer in every man diagnosed. related to these surrogate endpoints. lesions change over time, and if so, which changes are 1) Active surveillance for low-risk prostate cancer is The key to making sure that AS is the appropriate relevant. We do not even have a reporting system that an unavoidable treatment option to reduce or delay treatment approach for the patient is determining as Confirmatory MRI: Within one year after diagnosis has been applied systematically in a standardized overtreatment; certainly as possible that the tumor is currently not The fundamental question regarding MRI is whether fashion. There is still a lot of work to do, and it can only 2) Multiparametric magnetic resonance imaging is life-threatening or is at a low-risk of spreading or we are able to see and distinguish the relevant and the be done if the radiologic community will standardize being increasingly mobilized to support patient getting worse, thereby delaying or avoiding irrelevant tumours by MRI, and whether we need reporting and production of MRI. Or when new selection for AS as well as for monitoring those unnecessary treatment. To do so, we rely on risk histologic proof by biopsy. What do we know? So far, technology replaces the variability introduced by already on AS; assessments methods for individual patients on AS. we have been exploring several things: readers of MRI. Furthermore, they have spent a lot of 3) Confirmatory biopsies as a combination of Traditionally, these include serial measurement of effort in the automatic reading of parameters related to systematic and MRI-targeted biopsies substantially serum PSA levels, digital rectal examination and 1) We have evaluated MRI by relating it to radical the density and contrast intensity of identified lesions. improve misclassification of men previously surveillance biopsy sampling. prostatectomy specimens. It shows that MRI The international multidisciplinary PRECISE group of selected for AS compared to systematic biopsy visualises relevant tumours, but not all, and that ESO is working on the development of preliminary findings only; But meanwhile, multiparametric magnetic resonance the PIRADS or Likert system does not completely recommendations for reporting of individual MRI 4) The role of MRI for follow-up is still unclear due to imaging is being increasingly mobilized to support parallel the Gleason grading [Homburg 2013, studies in men on AS and for researchers reporting the lack of standardized evaluation of MRI, and lack of patient selection for AS as well as for monitoring those Schoots 2015]. We need histology to confirm the outcomes of cohorts of men having MRI on active knowledge in the interpretation of results; already on AS. As this technology and outcome data are nature of the MRI lesions observed. surveillance. 5) The Movember Foundations’ Global Action Plan 2) We have re-evaluated Prostate Cancer Active Surveillance (GAP3) project men, selected for AS by Filling the gap: GAP3 (Bruinsma, 2015) represents a unique and extensive resource to traditional criteria, with The reports of individual series on the value of MRI in assess the value of MRI for the future management confirmatory MRI (after the diagnostic process have been supportive for the use of AS; and three, but within 12 in active surveillance, but the proof of the pudding is in 6) AS in the absence of MRI (involving traditional months from time of the eating. In the worldwide consortium initiated by the protocols) in underprivileged areas remains a safe diagnosis) to see if all Movember Foundation, a global charity with a vision to treatment option. diagnosed cancers were change the face of men’s health, a database has been visible. It is clear that not constructed over the last two years which comprises Editorial Note: Due to space constraints the reference all men on AS have visible data on more than 14.000 men with prostate cancer list has been omitted. Interested readers can email at lesions (Marliere 2014, Da treated by AS in 25 centers from the USA, Canada, [email protected] for a complete listing. Rosa 2015, Kamrava 2015, Australasia, the UK and Europe. The Global Action Plan Walton Diaz 2015, Recabal Prostate Cancer Active Surveillance (GAP3) Initiative Saturday 25 March 2016, Ma 2016). MRI may provides the means to analyse these data, including Meeting of the EAU Section of Urological Imaging give additional those men that underwent an MRI at some point (ESUI) in cooperation with the EAU Section of information that improves during AS. These real- time clinical experiences, and Urological Research (ESUR) and the European the diagnosis by systemic also the further analysis of their MRI images, will Society of Nuclear Medicine (EANM) 2000 4a4 Figure 1: Increase of incidence of prostate cancer (per 100.000) in the world (Torre 2012) biopsies, and results in provide answers that cannot be obtained from the

Sunday, 26 March 2017 EUT Congress News 13 Biomarkers for immune checkpoint inhibitors A key concern: Identify patients who may benefit from new strategies

Prof. Shahrokh F. dampening effect on immune feedback, permitting deficient tumors –determined by microsatellite prognostic value of tumor-infiltrating immune cells has Shariat tumor cells to escape immune surveillance. instability analysis – had an improved objective consistently been shown in various tumor types, its Department of response rate (62 vs 0%) and disease control rate (92 predictive role is still under investigation. Urology PD-L1 protein expression vs 16%)2. This is interesting for us urologists since Comprehensive Early studies have shown promising results when upper tract urothelial carcinoma carries a significant Today, the era of truly personalized immunotherapy is Cancer Center testing pretreatment tumor biopsy specimens for cell alteration rate in mismatch repair genes. While further well within reach – heralding further acceleration and Medical University of surface PD-L1 protein expression using studies are needed, these data suggest that targeted innovations in patient care. Two future areas that Vienna immunohistochemistry. The preferred expression cutoff next-generation sequencing panels or microsatellite sound promising are molecular imaging with Vienna (AT) for PD-L1 positivity was set at 5%. Meanwhile this instability analyses may potentially be a more time and radionuclides tagged to antibodies like anti-cytotoxic candidate predictive biomarker has been tested in cost–effective surrogate of the mutational load of T-lymphocyte antigen-4 or anti-PD-L1 and immune various anti-PD-1 and anti-PD-L1 therapeutic studies tumors. surveillance with monitoring of the T-cell receptor with varying degrees of success. In general, while repertoire in both tumor tissue and peripheral blood The field of immuno-oncology has witnessed increased PD-L1 expression correlates with improved The link between mutational load and response to samples. Building on the significant benefits that have unprecedented success in recent years, with several response to PD-1/PD-L1 inhibitor treatment, it has also immune checkpoint inhibitors is likely to be due to the already been demonstrated in multiple tumor types, programmed cell death 1 (PD-1) and PD-L1 inhibitors become clear that there is a proportion of patients production of neo-antigens by tumor cells compared the incorporation of state-of-the-art high-throughput obtaining US FDA and EMA registration and withPD-L1-negative tumors who still respond to with somatic cells. Single nucleotide mutations may predictive or response biomarkers will improve our breakthrough drug therapy designation in multiple therapy. Currently, the only companion diagnostic for lead to changes in peptide sequences producing T-cell ability to select patients for stratified immunotherapy, tumor types such as bladder and kidney cancers. PD-L1 expression approved by the FDA is the pharmDx neo-antigenic peptides that are prone to immune identifying those who are most likely to respond to test of PD-L1 IHC 22C3 to assess PD-L1 expression prior attack. A greater mutational load may thus translate to treatment while minimizing the risks of immune- Immune checkpoint blockade activates cellular- to pembrolizumab use, which has been FDA- approved a higher number of neo-antigens, which may related toxicities. mediated immune response against tumor cells. for bladder cancer. Nivolumab has been FDA-approved potentially lead to greater T-cell dependent cytokine Preclinical studies have shown that blockade of either with a complementary but not mandatory PD-L1 IHC production and tumor cell kill when immune References PD-1 or its ligands improve T-cell effector function, 28–8 PharmDx diagnostic. checkpoint blockade is lifted. 1. Rosenberg JE, Hoffman-Censits J, Powles T et al. and blockade of PD-L1 increased infiltration of Atezolizumab in patients with locally advanced and tumor-reactive CD8+ T cells in mouse models. Besides It is important to realize that while PD-L1 positivity may In advanced melanoma treated with ipilimumab, a metastatic urothelial carcinoma who have progressed the PD-1/PD-L1 pathway, another immunomodulatory potentially correlate with improved response rate and neo-epitope signature was correlated with survival3. following treatment with platinum-based chemotherapy: mechanism that has been exploited in the clinical survival, multiple studies have repeatedly shown that In urologic cancers, there are no such studies yet. a single-arm, multicentre, Phase II trial. Lancet 387(10031), setting is cytotoxic T-lymphocyte antigen-4 (CTLA-4), there is a small but definite proportion of patients with The inherent challenges in the study of neo-antigens 1909–1920 (2016). a surface receptor on effector T cells that interacts with PD-L1-negative tumors who continue to benefit from are that not all may elicit a T-cell response. While there 2. Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors antigen-presenting cells, leading to T-cell arrest. Other treatment. Excluding such patients from potentially may be shared antigens present in the majority of with mismatch-repair deficiency. N. Engl. J. Med. 372(26), new targets of immunomodulation that are under life-prolonging treatments on the basis of tumors, it may be the unique antigens present within 2509–2520 (2015). active investigation include TIM3, an immune immunohistochemical expression thus remains a each patient that are necessary to elicit 3. Snyder A, Makarov V, Merghoub T et al. Genetic basis for checkpoint molecule frequently co-expressed with clinical and ethical dilemma. This, together with the immunogenicity. While the correlation of mutational clinical response to CTLA-4 blockade in melanoma. PD-1, and LAG3, a co-stimulatory receptor that biological and technical complexities of PD-L1 load and neo-antigens may be scientifically promising N. Engl. J. Med. 371(23), 2189–2199 (2014). decreases cytotoxic T-cell function. expression using immunohistochemistry, limits PD-L1’s as a tool for the prediction of response to immune 4. Sharma P, Shen Y, Wen S et al. CD8 tumor-infiltrating utility as a predictive biomarker. checkpoint inhibitors, further investigation is still lymphocytes are predictive of survival in muscle-invasive These breakthroughs are reaching us in an age where required to confirm their clinical utility. urothelial carcinoma. Proc. Natl Acad. Sci. USA 104(10), cancer treatment strategies are evolving from an Multiple tumor factors contribute to the challenge of 3967–3972 (2007). all-comer approach with cytotoxic chemotherapies to assessing PD-L1 expression of an isolated tumor Finally, there is a complex host of factors in the tumor biomarker-driven strategies with molecular targeted specimen at a single time point as a critical indicator in microenvironment, which collectively influence Sunday 26 March agents where patients with potentially actionable determining if a patient may benefit from anti-PD-1 or immunomodulatory effects to either promote or 11.10-11.25: Thematic Session 6, Immuno- mutations/molecular alterations are matched with anti-PD-L1 therapy. Due to the adaptive nature of PD-L1 combat tumor growth. Strong lymphocytic infiltration oncology: Changing treatment paradigms in renal rational antitumor therapies. Despite showing and its upregulation by pro-inflammatory conditions, has been shown to be associated with improved and urothelial cancer promising efficacy, immune checkpoint inhibitors fail PD-L1 expression levels tend to be dynamic rather than patient outcomes in bladder cancers4. While the in a substantial percentage of patients in addition to stagnant, raising questions as to whether a single causing toxicities and substantial financial burden. It tumor sample that may have been taken at the time of is, therefore, critical to identify patients likely to a patient’s original diagnosis is truly reflective of the benefit from such therapies and develop strategies to current state of disease, especially after multiple lines differentiate responders from non-responders early of antitumor therapy. during treatment. PD-L1 expression also tends to be focal, mainly Unfortunately, to date, the search for robust bordering areas of tumor cells and lymphocytes, analytically and clinically validated biomarkers that leading to concerns of sampling error by missing the can accurately and reliably predict response to tumor-immune interface and thereby rendering false immune checkpoint inhibitors has been without negative results. Indeed, in a study that assessed success. A specific problem for immune checkpoint matched patient samples from primary and secondary inhibitors is that conventional treatment response sites of disease from patients with RCC, there was criteria to immunotherapies using standard imaging discordant tumor cell PD-L1 staining in 20.8% of techniques are not optimal assessment strategies. patients, raising concerns that inter-tumor ChM in Urology They may sometimes be misleading due to the tumor immunologic heterogeneity may confound the accuracy flare phenomenon which represent a pseudo- of overall tumor PD-L1 expression status. Additionally, progression of tumor due to inflammatory cell PD-L1 is expressed not only on tumor cells but other PART-TIME ONLINE MASTER OF SURGERY DEGREE PROGRAMME infiltration or necrosis of tumor due to treatment components in the tumor microenvironment, such as response. This is further compounded by the poor macrophages and lymphocytes. Determining if positive correlation between response rates and overall PD-L1 expression is actually meaningful on such cells is survival as evidenced by the subgroup of patients who currently an area of active research. This two year part-time Masters programme in Urology, taught achieve durable long-term responses despite not entirely online, is offered by the Royal College of Surgeons of developing an objective radiological response. As Candidate predictive biomarkers such, in addition to predictive biomarkers, there is a Emerging alternative candidate predictive biomarkers Edinburgh and the University of Edinburgh, and leads to the need to seek biomarkers that can reflect treatment include the tumor’s mutational load, neo-antigens, degree of Master of Surgery (ChM). response more accurately and to serve as surrogate tumor infiltrating immune cells and the tumor intermediate end-point markers. microenvironment. While correlation of response to immune checkpoint inhibitors with driver mutations PD-1 and PD-L1 have been assessed as predictive has been largely unsuccessful, there is mounting Based on the UK Intercollegiate Surgical Curriculum, the markers of response to PD-1/PD-L1 inhibitors. While evidence that mutational load may correlate with PD-1 expression may be the most intuitive choice as response to immune checkpoint inhibitors. Melanoma, programme provides the opportunity for advanced trainees in a predictive biomarker of response to PD-1 lung and bladder cancers – malignancies in which PD-1 Urology to study modules relevant to their declared specialty inhibitors, early studies indicated that PD-L1 and PD-L1 inhibitors are now approved – ranked as the expression showed better correlation with antitumor tumors with the highest median mutational load. and supports learning for professional urology examinations response. Nonetheless, correlation with clinical FRCS(Urol) and FEBU. outcomes has not been consistent. PD-L1 can be Most recently, a Phase II study of atezolizumab in expressed both constitutively due to oncogene patients with advanced bladder cancer evaluated the activation and the dysregulation of signaling mutational load of enrolled patients, and showed that pathways, or induced in an adaptive fashion by the median mutational load was significantly higher in “I found the experience of this degree pro-inflammatory factors such as IFN-γ. responders compared with non-responders (12.4 vs 6.4 per megabase; p < 0.0001), independent of The Cancer rewarding and informative, with the Tumors with constitutive PD-L1 expression have also Genome Atlas subtype or immune cell subgroup1. benefit of seeing the quality of my been linked to specific oncogenes, such as While costs of genomic sequencing has been steadily phosphate and tensin homolog loss, EGFR activation decreasing over the past decade, whole exome and practice improve. “ and the janus kinase/signal transducers and whole genome sequencing and their respective data activators of transcription pathway in T-cell analyses remain challenging in terms of the associated lymphoma. However, the majority of other tumors, relative financial costs and time implications as well as which express PD-L1 appear to have dynamic levels bio-informatic challenges, limiting their large-scale For futher information please email:[email protected] of PD-L1 expression, which are influenced by the application in the routine clinical setting. tumor microenvironment and a host of inflammatory factors. The upregulation of PD-L1 leads to increased \While PD-1 inhibitor trials in colorectal cancer have www.urochm.rcsed.ac.uk binding to T cells through PD-1, creating an overall been disappointing, patients with mismatch-repair

14 EUT Congress News Sunday, 26 March 2017 Ureterocutaneostomy UUCS is a good option for frail and elderly patients

Prof. Armin Pycha • Pull through both ureters at least 1.5 cm above patients a ureterocutaneostomy is a good option and Sigmund Freud skin level will experience a renaissance, as age alone can not University • Observe arterial capillary bleeding from both be an exclusion criteria for cure or palliation. Medical School ureter stumps and spontaneous urine ejaculation However, only simple and reproducible approaches Vienna (AT) • The greater omentum is brought through the gap, will stand the test of time. Department of completely wrapping both ureters Figures 8: Pull-through maneuver completed Urology • The omentum is fixed with single stitches Vicryl Editorial Note: Due to space constraints the reference General Hospital of 3/0 to the rectus fascia at the outer and the inner list has been omitted. Interested readers can email at Bolzano side [email protected] for a complete listing. Bolzano (IT) • Both ureters are spatulated on a length of at least 1.5cm Sunday 26 March • A single stitch Monocryl 6/0 unites both ureters in 11.30-11.45: Thematic Session 8, Challenges in There are two epidemiological phenomena, which the middle on the deepest point (knot to the urinary tract reconstruction are overlapping and gaining more and more outside) to create a “fish mouth” stoma importance. First, the population of western • Check again if both ureters are showing capillary countries is ageing by an estimated threefold increase bleeding and if spontaneous urine ejaculation is in the number of octogenerians within the next 30 present years. Second, the peak incidence of bladder cancer • Fixation of the ureter-ends in Butterfly-technique Figures 9: Pull-through maneuver completed is at 85 years (1-4). to the skin-edges by single stitches of Monocryl 5/0 Consequently, the incidence of invasive bladder cancer • Stenting of the ureter with Mono-J 7 or 8 Charr. (BC) will increase, due to a stage shifting with age • Fixation of the ureteric stents with two single towards muscle invasiveness at first presentation (5) stitches 2/0 and simultaneously the registered comorbidity in • Placement of a urine bag newly diagnosed and aged BC patients will increase as well (6). In the future, we will be confronted more Postoperative care Figure 1: The stoma position often with the need of radical cystectomy (RC) in aged Fluid balance, blood count and creatinine control and frail patients. every day. Antibiotic treatment is continued until 10th postoperative day followed by a long term prophylaxis Radical cystectomy is a major procedure and until the stents are removed. This happened normally Figure 10: Both ureters fixed and wrapped by the greater associated with a significant rate of postoperative after 90 days and was followed by an endovenous omentum complications in up to 60% (7-9) and 90-day pyelogram. We start on Day 1 with the mobilisation of mortality rates of approximately 10-37% (9). Most of the patient and with the oral nutrition. the complications develop in the early postoperative period and are derivation-related (7,9). Therefore, it is Results essential to tailor the right diversion correctly to the Early postoperative complications following radical individual patient, minimising the risk and pelvic surgery are closely related to the type of urinary Figure 2: The cross-over maneuver completed maximising the patient‘s benefits. We present a diversion. Intestinal complications after an end-to- modified technique of the ureterocutaneostomy end anastomosis often start a chain reaction with a (UUCS) which is an often used but rarely reported fatal outcome. Due to a bowel rest and overextension derivation, especially in so called “high-risk patients” of the intestine the patient develops an intestinal (frail) or in interventions with palliative character (7). compartment syndrome with secondary pulmonary We present a technique which does not require and renal insufficiency (9). intubation of the ureters and does not have a higher risk of stoma stenosis (11). It was first reported by In our published series of 130 high risk patient, we Roth in 1967 (12) and later on evaluated and published compared ileal conduit vs. colon conduit vs. by August (13) and Winter (14). ureterocutaneostomy (UUCS) (15). The highest intestinal complication rate showed the ileal conduit Figure 3: Circular excision of the skin in former marked stoma Indications, limits, risks and contraindications group with 34.5% the colon conduit group had 5.8% region To date we used this incontinent urinary diversion whereas the UUCS group had none of them. The UUCS only in high-risk patients, in palliative RC, in severe group showed 4.8% of stoma complications requiring concomitant intestinal disease and in severe surgical re-intervention and 19.5% of asymptomatic obliterative arteriopathy. It is of limited use in obese dilatation grade II following Emmett (15). The use of patients and /or patients irradiated by external beam omentum significantly reduced the risk of stoma radiation and contraindicated in patients with short stenosis. In the last years we prolonged the stent Figures 11 and 12: Stoma construction ureteric stumps or poorly vascularized ureters. placement until Day 90 after surgery which decreased further stoma complications. In cases of stoma Preoperative management obstruction, mono-J catheters can be reinserted and Consultation of the patient by an enterostomal changed every three to six months. Stoma correction therapist. The stoma has to be placed in the upper left can be performed later using a buccal mucosa graft. Figure 4: Incision of the fascia in a cross-like fashion (or right) abdominal quadrant (about the half way between umbilicus and xyphoid in a pararectal Final remarks position). Subcutaneous prophylaxis for deep vein Quality of life (QoL) is an important outcome in all thrombosis is started the evening before surgery. forms of cancer treatment and takes into account the Nowadays we do not use intestinal preparation. physical, mental and social well-being of the patient. Antibiotics: Cephalosporines of third generation in The goal of QoL can be achieved trough a curative combination with 1.5g of Metronidazole at beginning approach, by palliation or in extreme cases through of surgery and after 6 hours. abstention of any therapy. One of the main problems of QoL is the subjective experience and the difficulty of Figure 13: Stoma completed Operative technique step by step: reproducibility. • Landmarks are: xyphoid, 12th rib, umbilicus, Figure 5: The length of both ureters after the cross-over superior anterior iliac spine and symphysis However, patients with primary muscle invasive maneuver is checked • Normally during cystectomy, the distal part of the bladder cancer, who also suffer from high competing ureters is just divided and intubated by a ureteric co-morbidity, rarely benefit from a conservative catheter strategy (16). The high disease specific mortality and • The left ureter is mobilized sparing the testicular the high disease-related complication rate hardly artery and respecting the mesoureter until the compromise the remaining life span. Therefore, the ureteropelvic junction standard policy in muscle invasive TCC is still RC with • Mobilisation of the right ureter until 3 cm under lymphadenectomy, which provides the best long-term the ureteropelvic junction results (17,18). • Cross over to the left site of the right ureter between the Treitz-Ligament and the inferior Nevertheless, we know that higher age and serious mesenteric artery. Do it as high as you can. comorbidity were independent indications for • Passing the mesocolon the ureter is brought to abstaining from cystectomy (6). A way to minimize Figure 6: The greater omentum is divided and an omentum flap the retroperitoneum (cave: the mesoslit has to be complications in RC is to avoid intestinal surgery. The is created Figure 15: Stoma examples large enough to avoid kinking) modified UUCS is an alternative to the standard ileal conduit in high-risk patients as well as in elderly frail Placement of the stoma: patients with bladder cancer. The epidemiologic trend • Removing of a suitable circular skin-flap (never will lead to an increased demand of RC in risky and smaller than 1.5 cm in diameter) frail patients. Creativity and innovations are required • Removing of a circular button of subcutaneous fat to face the upcoming challenges. until the anterior rectus sheath. It will later be substituted with greater omentum. Ageing population • Cross incision of the anterior sheath The western population is ageing and the mean age • Blunt creation of a gap in the rectus muscle of cystectomised patient is increasing. Well- • Cross incision of the posterior rectus sheath and established continent diversions are mandatory in the peritoneum on the tip of the underlying finger younger and healthier patients. For the old and oldest Figure 7: he size and the length of the omentum flap is checked Figure 14: Stoma 36 months after construction

Sunday, 26 March 2017 EUT Congress News 15 Congenital lifelong urology Multidisciplinary team: Best suited for patients needing care for congenital anomalies

Mr. Dan Wood treatment. Anecdotally, it is common for them to independence, the healthcare relationship shifts Some of the work will involve controversial decisions Institute of Urology at report negative experiences if they are seen in a away from their parents or carers, taking and thus needs to be dealt with as part of University College setting that appears not to cater for their needs. In responsibility to the patient themselves. This can be multidisciplinary teams. In some groups the timing London Hospitals some, this is because their expectations may be difficult for a variety of reasons relating patient, and nature of surgery or the increasing development London (GB) unreasonably high – naturally this needs to be parents, politics and finance. of patient understanding and their own questions managed so that all parties are realistic but that around existing standards of care provide clinical, patients have excellent care maintained. In short – it Above all, the service needs energy and expertise surgical, moral, ethical and intellectual challenges will depend on the staff involved and the from a multidisciplinary team who have dedicated that clinicians must confront11. environment but if these patients are seen in a busy time for these patients. This allows investment and general clinic it may be much more difficult to tackle development of the service in the first instance and By definition, paediatric urologists are passionate some of their needs. The importance of this is that specialist clinics and surgery in the long-term. about these patients and have a strong desire to see teenagers can be very difficult to engage with - this that they have good ongoing care. This needs to be Children born with congenital anomalies of the is most obvious in young men3. Published data We know that some conditions are vulnerable to late comparable to their previous care. Whilst there are genitourinary tract receive the highest level of care in suggests that some specialties are running transition renal failure – these include posterior urethral valves pockets of interest - the aim of the working group is their paediatric life. This has led to a dramatic well4 and that as a result, health outcomes may be – whilst important, early changes can be subtle and to educate and encourage adult urologists to develop improvement in outcomes. Survival is now regarded improved5. awareness is important to allow detection and an interest in these patients and provide specialist as normal – even in the face of major anomalies. understanding risk factors becomes important6. care as part of their practice. We hope that this With support from both the European Society of stimulus will enliven interest in the adult urological This is as a result of surgical innovation and Paediatric Urology and the European Association of Whilst many have worked hard to produce community. excellence in specialist centres combined with Urology, we have formed a working group. The aim information on outcomes some conditions appear to proactive care (such as intermittent self catherisation) of this group is to promote the care of these patients have complication rates potentially worse than In the long-term the working group hopes to see the early in life. Surgical developments, alongside other by contributing to both annual meetings. The originally published. It is important to emphasise development of wider academic work, the ability for specialties, such as intensive care have led to a potential for further innovation such as joint that this is not because of bad surgery – many interested clinicians to communicate and network realistic rise in expectations. meetings with specialist groups such as ESGURS, factors appear to play a part – not least the with similarly interested colleagues. This can only ESAU and ESFFU exists and the work of Prof. Piet underlying disease and puberty. However, to take help with providing clinical support for those working Parents and, latterly, patients now anticipate Hoebeke and his team in organizing the first joint hypospadias as an example we have no clear in this field and, as a result, improve care for all reasonable urinary function and as a profession we meeting between ESGURS and the ESPU in 2015 understanding about the denominator, patients across the board. aim to offer this. These are combined with demonstrated the potential to be found in such standardization of the condition and the surgery. expectations relating to sexual and reproductive projects. This means that in the current environment it is a Ultimately, with the engagement of a wider group of function all contributing to an expectation for a huge challenge to produce data that gives the real clinicians all will benefit. In the long-term the quality of life comparable to their peers1,2. We have welcomed support from the ESPU, EAU, SIU outcomes for complications such as stricture, development of educational programs, fellowships and BAUS in supporting educational sessions within fistulae and re-operation rates7,8. and guidelines may ensue. We would welcome The paediatric urological community has cared for a their meetings. We have collaborated with colleagues, interest from any clinicians and would be delighted to group of patients who have and are continuing to as part of the AUA, and contributed to sessions in the Other patients need monitoring following complex support those who have interest and aptitude for the reach adolescence and adulthood. Despite excellent American meetings too. reconstruction – looking for factors such as metabolic care of these patients. care many of these patients continue to need change, stones and infection. Others will need long-term surveillance and revision surgery. Many The value of this is to establish a means by which reconstruction in adolescence and adulthood whilst Editorial Note: Due to space constraints the reference will have concerns about normality, function, these teenagers and young adults can receive around 60% of those who have had bowel list has been omitted. Interested readers can email at cosmesis and significant fears relating to anaesthesia, lifelong care, when it is needed. There is no one incorporated into their urinary tract in childhood will [email protected] for a complete listing. needles and further surgery. model that works in all settings. The principles are need further surgery in adulthood. There is a huge based on preparation and transition where the child range of potential interest. This is a field that is early Sunday 26 March These teenagers are knowledgeable (and some develops their own understanding of their diagnosis, in its development and the population of patients 11.30-11.45: Thematic Session 7, Paediatric expert), they quickly recognize healthcare staff who treatment and takes responsibility for their needing care will inevitably grow – creating a wide urology are not familiar with their condition or prior healthcare needs. As they develop this range of clinical and academic opportunities9,10.

da Vinci® LIVE Surgery

Please join our live surgeries on Sunday, 26th March • 14:00 - 17:00 Room Copenhagen (Boulevard, Level 1)

LIVE da Vinci Si® Partial Nephrectomy Surgery Operating Surgeon Ben Challacombe • Guy’s Hospital, London

LIVE da Vinci Xi® Nephroureterectomy with Integrated Table Motion Operating Surgeon Christophe Vaessen • la Pitié -Salpêtrière Hospital, Paris

Moderators Peter Wiklund - Karolinska lnstitutet, Stockholm Prokar Dasgupta - Guy’s Hospital, London Jens-Uwe Stolzenburg - University of Leipzig, Leipzig

The da Vinci® Xi® Surgical System is a CE Marked medical device of class 2b (CE 0543) under the European Medical Devices Directive (93/42/EEC) manufactured by Intuitive Surgical, Inc. To obtain complete information, including the intended purpose of the device as well as cautions and warnings, please refer to the user manuals of the da Vinci Xi Surgical System, Table Motion user manual, instruments and accessories user manual and other product information. ©2017 Intuitive Surgical, Inc. All rights reserved. PN 1033104-EU Rev A 2/17

16 EUT Congress News Sunday, 26 March 2017 ADVERTORIAL

This article is written and funded by Meta-analysis1 re-reviews the current body of evidence New insights and recommendations on decreasing the risk of progression in bladder cancer

Blue-light cystoscopy (BLC) has shown promise in muscle-invasive bladder cancer.5 The largest and most improving detection of bladder tumours and is recent publication included in the review re-analysed increasingly becoming a standard in clinical practice.1 the dataset of a phase III randomised trial on HAL- vs. Just recently, the first meta-analysis showing the WL-TURB with regard to progression using the new impact of hexaminolevulinate-guided bladder cancer IBCG definition.5 Transurethral Resection of the Bladder (TURB) on reducing progression rates was published.1 At the “This is the first meta-analysis which shows a same time, the new 2016 French National Guidelines2 significant beneficial impact of NMIBC detection and (AFU) for the management of bladder cancer (BC) resection with HAL-guided TURB on progression. have been presented, in which blue-light cystoscopy Patients should therefore receive hexaminolevulinate- is recommended for the first TURB in the majority of rather than white-light-guided TURB [alone] at their the BC patients. first resection as this might allow more patients at risk of progression to be treated timely and adequately.” Clinical trials have shown that hexaminolevulinate Professor Gakis from the Department of Urology, (HAL) fluorescence cystoscopy improves the detection University Hospital Tuebingen, Germany, summarised of bladder tumours compared with standard the result of the review1. white-light cystoscopy (WLC), resulting in more efficacious treatment.3 A meta-analysis of raw data Diagnoses with BLC was also associated with had previously revealed an increase in the detection decreased risk of recurrence of non-muscle-invasive rate of carcinoma in situ (CIS) by 40%, and there were bladder cancer versus WLC in another recently almost 25% patients with at least one additional Ta/T1 published meta-analysis.6 This publication included References DOI:10.1016/j.eururo.2013.03.059 tumour seen with BL only (p < 0.001).4 Despite stratified analyses by use of 5-ALA and HAL. Findings 1. Gakis G, Fahmy O Systematic review and meta-analysis 5. Kamat A et al. The impact of blue light cystoscopy with improved detectability of bladder cancer with BLC, were similar when looking at short-term, on the impact of hexaminolevulinate- versus white-light hexaminolevulinate (HAL) on progression of bladder literature has not reported a beneficial impact on intermediate-term and long-term recurrence risk. guided transurethral bladder tumour resection on cancer – a new analysis. Bladder Cancer 2016;2(2):2733– progression in non-muscle-invasive bladder cancer Effects on short-term and long-term recurrence were progression in non-muscle invasive bladder cancer. 278. DOI: 10.3233/BLC-160048 (NMIBC). However, progression is one of the most statistically significant in trials that used HAL, and were Bladder Cancer 2016;2:293–300. DOI: 10.3233/BLC-160060 6. Chou R et al., Comparative effectiveness of fluorescent important clinical outcomes in non-muscle-invasive not statistically significant in trials that used 5-ALA.6 2. Rouprêt M et al. CCAFU French National Guidelines versus white light cystoscopy for initial diagnosis or bladder cancer as it indicates a worsening of disease.5 2016-2018 on bladder cancer. Prog Urol 2016;27 (Suppl surveillance of bladder cancer on clinical outcomes: Diagnostic with Blue-light cystoscopy for the first 1):S673–S91. DOI: 10.1016/S11663–7087(16)307043–7. systematic review and meta-analysis. J Urol. Article in A working group compared the results of HAL- vs. resection 3. Di Stasi SM et al. Hexaminolevulinate hydrochloride in press. DOI: http://dx.doi.org/10.1016/j.juro.2016.10.061 white-light guided TURB and found out that rate of Today, BLC is mentioned and recommended in the the detection of non muscle invasive cancer of the 7. Rouprêt et al. CCAFU French National Guidelines progression was significantly lower in patients in majority of Guidelines (Figure 2), including the recently bladder. Ther Adv Urol 2015;7(6):3393–50. DOI: 10.1177/ 2016-2018 on bladder cancer. Prog Urol 2016;27 (Suppl whom a TURB was performed with BLC versus WLC updated American Urological Association (AUA), 1756287215603274 1):S673–S91. DOI: 10.1016/S11663–7087(16)307043–7 alone.1 This recently published meta-analysis by Gakis Association Française d’Urologie (AFU) and Deutsche 4. Burger M et al. Photodynamic diagnosis of non-muscle- 8. Rouprêt et al. Cost effectiveness of TURBT of the bladder et al. included NMIBC studies published between Gesellschaft für Urologie (DGU) Guidelines from 2016. invasive bladder cancer with hexaminolevulinate with blue light in patients with non-muscle invasive 2000 and 2016 reporting on progression after HAL- cystoscopy: A meta-analysis of detection and recurrence bladder cancer in France. Progres en urologie (2015) 25, and WL-based TURB. Eligible studies were identified On November 17th, 2016, during the national meeting based on raw data. European Urology 2013;64(5):846–54. 2563–264. via PubMed search and a manual search of of the Association of French Urologists (AFU) in Paris, publications in journals not listed in PubMed. The France, the new 2016 French National Guidelines for ® selection excluded non-English articles, non-original the management of Bladder Cancer were presented.7 Prescribing Information Hexvix (hexaminolevulinate) Presentation: Hexvix 85mg, powder and solvent for solution for intravesical use. Pack of one 10mL glass vial containing 85mg of hexaminolevulinate as 100mg hexaminolevulinate articles (i.e. review articles with or without systematic The purpose of the Comité de Cancérologie de l’AFU hydrochloride as a powder and one 50mL polypropylene or glass vial containing solvent. After reconstitution in review or meta-analysis), editorials or case reports, (CCAFU) was to propose updated French Guidelines 50mL of solvent, 1mL of the solution contains 1.7mg hexaminolevulinate which corresponds to an 8mmol/L solution studies on 5-aminolevulinic acid (ALA)-based TURB, for non-muscle-invasive and muscle-invasive (MIBC) of hexaminolevulinate. Indications: This medicinal product is for diagnostic use only. Hexvix blue light fluorescence and repeated publications on the same cohort to bladder cancers. In order to evaluate references and cystoscopy is indicated as an adjunct to standard white light cystoscopy to contribute to the diagnosis and avoid publication bias. their levels of evidence, a Medline search had been management of bladder cancer, in patients with known or high suspicion of bladder cancer. Dosage and Method conducted covering diagnosis, treatment and of Administration: Hexvix cystoscopy should only be performed by healthcare professionals trained specifically in Overall more than 1,300 patients studied follow-up of bladder cancer between 2013 and 2016. Hexvix cystoscopy. The bladder should be drained before the instillation. Adults (including the elderly): 50mL of The review covered a total of 294 studies, of which 8mmol/L reconstituted solution is instilled into the bladder through a catheter. The patient should retain the fluid for approximately 60 minutes. Following evacuation of the bladder, the cystoscopic examination in blue light five were considered for final analysis (Figure 1). Of The new French Guidelines recommend blue-light should start within approximately 60 minutes. The cystoscopic examination should not be performed more than 3 the 1,301 patients in these five studies, 49.5% (n=644) cystoscopy for the first bladder cancer resection in the hours after Hexvix is instilled in the bladder. Also if the retention time in the bladder is considerably shorter than underwent BL TURB and 50.5% (n=657) had a WL majority of patients and for consecutive TURBs in one hour, the examination should start no earlier than after 60 minutes. No minimum retention time has been TURB. Progression was found in 6.8% of BL patients, many patients. This facilitates the most correct staging identified making examination non-informative. For optimal visualisation it is recommended to examine and map (44/644) and 10.7% of WL patients (70/657), which and grading, which is crucial for the optimal the entire bladder under both white and blue light before any surgical measures are initiated. Biopsies of all was statistically significant (median odds ratio: follow-up and management of the patient. In contrast mapped lesions should normally be taken under white light and complete resection should be verified by switching 1.64, 1.10–2.45 for HAL vs. WL; p = 0.01). Progression- to the former version of the Guideline the update to blue light. Only CE marked cystoscopic equipment should be used, equipped with necessary filters to allow both standard white light cystoscopy and blue light (wavelength 380-450nm fluorescence cystoscopy).Children and free survival was reported in a single study and was includes the situations in which diagnosis with BLC adolescents: There is no experience of treating patients below the age of 18 years. Contraindications: Hypersensitivity longer after BL TURB and showed a trend towards can reduce the risk of recurrence. A cost-effectiveness to the active substance or to any of the excipients. Porphyria. Warnings and Precautions: The possibility of improved survival (p = 0.05). study applied to the French system revealed a QALY hypersensitivity including serious anaphylactic/anaphylactoid reactions should always be considered. Advanced gain (an economic indicator aiming to estimate the life support facilities should be readily available. Post-marketing experience with repeated use of Hexvix does not The primary objective of the analysis was the rate of value of life) for the use of fluorescence guided TURB indicate that it represents a risk when used in follow-up in patients with bladder cancer however no specific progression due to the fact that a beneficial impact of with HAL starting with the first TURB of any NMIBC7,8. studies have been conducted. Hexaminolevulinate should not be used in patients at high- risk of bladder HAL-guided TURB on progression of NMIBC has not According to Morgan Rouprêt, Professor of Urology at inflammation, e.g. after BCG therapy, or in moderate to severe leukocyturia. Widespread inflammation of the bladder should be excluded by cystoscopy before the product is administered. Inflammation may lead to increased been confirmed in meta-analyses until now1. One the Pitié-Salpétrière Hospital, University Paris, and porphyrin build up and increased risk of local toxicity upon illumination, and false fluorescence. If a widespread reason may be that so far, clinical trials have used one of the authors of the Guidelines, “the strong level inflammation in the bladder becomes evident during white light inspection, the blue light inspection should be varying definitions or have failed to define disease of evidence associated with the newest data incorporated avoided. There is an increased risk of false fluorescence in the resection area in patients who recently have progression altogether.5 Therefore, the International into the European Guidelines for the use of blue light undergone surgical procedures of the bladder. Interactions: No specific interaction studies have been performed Bladder Cancer Group (IBCG) suggests a new cystoscopy should result in an increased level of with hexaminolevulinate. Pregnancy and Lactation: There are no or limited data on the use of hexaminolevulinate definition that goes beyond the commonly used urological care for the management of patients with in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to the reproductive increase in stage from non-muscle-invasive to bladder cancer in France.” toxicity. As a precautionary measure, it is preferable to avoid the use of Hexvix during pregnancy. It is unknown whether hexaminolevulinate/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast- feeding should be discontinued during the treatment with Hexvix. Animal studies do not indicate effects on female fertility. Male fertility has not been investigated in animals. Undesirable effects: Most of the reported adverse reactions were transient and mild or moderate in intensity. The most frequently reported adverse reactions from clinical studies were bladder spasm (2.4%), dysuria (1.8%), bladder pain (1.7%) and haematuria (1.7%). Other commonly (>1/100 to <1/10) reported adverse reactions are: headache, nausea, vomiting, constipation, diarrhoea, urinary retention, pyrexia and post-procedural pain. Prescribers should consult the SPC in relation to other side effects. The adverse reactions that were observed were expected, based on previous experience with standard cystoscopy and transurethral resection of the bladder (TURB) procedures. Overdosage: No case of overdose has been reported. No adverse events have been reported with prolonged instillation times exceeding 180 minutes (three times the recommended instillation time), in one case 343 minutes. No adverse events have been reported in the dose-finding studies using twice the recommended concentration of hexaminolevulinate. There is no experience of higher light intensity than recommended or prolonged light exposure. Pharmaceutical Precautions: This medicinal product must not be mixed with other medicinal products. For single use only. Hexaminolevulinate may cause sensitisation by skin contact. The product should be reconstituted under aseptic conditions using sterile equipment. Any unused product should be discarded. Legal Category: POM. Basic NHS cost: Hexvix 85mg £375 per vial. UK Marketing Authorisation Number: Hexvix 85mg: PL34926/0017. UK Marketing Authorisation Holder: Ipsen Ltd., 190 Bath Road, Slough, Berkshire, SL1 3XE, UK. Tel: 01753 627777. Date of preparation of PI: October 2015. Ref: UK/HEX00036(1) Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to the Ipsen Medical Information Department on 01753 627777 or medical. [email protected] UKHEX00164 February 2017 Hexvix® is the property of Photocure.

Sunday, 26 March 2017 EUT Congress News 17 Adreno-cortical carcinoma Surgery and medical treatments to improve oncological outcomes

Prof. Francesco Proliferation index as Ki-67 immuno-marker mitotic Need of adjacent organ resection Porpiglia count (Ki-67 index) may help the clinicians to When ACC is diagnosed in advanced stage, surgery is San Luigi Hospital - differentiate low-grade (Ki-67 <10%) and high grade extensive, implying additional procedures beyond Division of Urology ACC (>10%) and to guide clinical decision. Indeed, adrenalectomy, such as nephrectomy, resection of Orbassano (Turin) Ki-67 is a powerful prognostic marker in both pancreas tail and/or partial hepatectomy in order to Dept. of Oncology - localized and metastatic disease. get a R0 resection. University of Turin Turin (IT) Sequencing methods and genome-wide genomic Controversies exist on the need of nephrectomy even Figure 1: CT scan showing a large left ACC. studies, particularly with high-throughput sequencing when not macroscopically involved. Many years ago, (next generation sequencing - NGS) will probably play some authors advocated that nephrectomy would a role in the future in the field of ACC. help to decrease the high recurrence rate of ACC, because it would allow wide operative margins and Adreno-Cortical carcinoma (ACC) is a rare malignancy Staging avoid violating the tumor anatomic space, but this with an incidence of 0.7–2.0 cases/million/year. It has Two classification systems have been proposed for opinion has not yet been further validated. In a recent two peaks of incidence: the first one in the first ACC: the ENS@T staging system and the Union paper, our group demonstrated that adjunctive decade and the second one between 40 and 50 years. Internationale Contre le Cancer (UICC). The former nephrectomy does not modify the oncologic results of (Table 1) proved its superiority over the latter, both in adrenalectomy in the treatment of stage II ACC in Women are the most frequently affected (55–60%). European and in North-American studies; therefore, terms of recurrence-free and overall survival. Thus, ACC is associated with poor prognosis, with a 5-year its use is recommended. when there are no signs of ACC local invasion, survival rate of approximately 65%, 24% and 0 % for surgeons should make every effort to preserve the patients in stages I-II, III and IV, respectively. Surgery kidney. In the previously cited consensus on surgical Surgical resection plays a key role in the management treatment of ACC, renal-sparing resection of the upper Diagnosis of the disease, especially in its early stages, when pole fatty tissue is suggested when feasible. Figure 2: CT scan showing a small, left adrenal incidentalomas Most patients (40–60%) present steroid hormone there might still be a window for cure. Indeed, a with inhomogeneous central appearence. Patient underwent excess (glucocorticoids, mineralocorticoids, complete resection of the ACC (R0 resection) Recurrent or metastatic cancer laparoscopic adrenalectomy. Final pathology revealed a small androgens) or modifications of abdominal mass correlates with a better prognosis and represents the A few studies investigated the role on survival of the ACC, Weiss score 4, Ki-67 index <10%. (30%). Hormone hyper-secretion may lead to only chance of cure. On the contrary, an incomplete exeresis of metastasis in patients with recurrences. Cushing syndrome, virilization (in female patients, microscopic resection (R1), or an incomplete The German Group studied 100 patients who up to 10%) or, rarely, to feminization (in male macroscopic resection (R2) are associated with the underwent surgery for recurrence. Multivariate patients) or Conn syndrome (1-2% of ACCs). On the worst over-all survival. analysis showed that time to first recurrence > 12 contrary, in up to 20% of cases the diagnosis is months and resection of all the clinically apparent incidental. With the aim of providing standards for the disease had impact on progression-free survival and perioperative surgical care for patients with ACC, a overall survival. Similar results came from the Mayo The European Network for the Study of Adrenal collaborative working group from ENS@T and ESES Clinic Group. Moreover, repeated resection can be Tumors (ENS@T) suggests a pre-operative hormonal (European Society of Endocrine Surgeons) recently offered to patients with local recurrence after initial workup based (at least) on the assessment of basal proposed the “recommendations on the surgical resection of local recurrence if R0 resection is possible cortisol, ACTH, dehydroepiandrostenedione sulfate, management of ACC” that will soon be available. [Figure 3]. 17-hydroxyprogesterone, testosterone, androstenedione, estradiol, dexamethasone Open versus minimally invasive surgery Obviously, this kind of surgery is not for all patients: suppression test and urinary free cortisol. Contrast- Traditionally, open surgery has been considered the the time-to-first recurrence appears to be basic in enhanced thoraco-abdominal computed tomography gold standard surgical approach to ACC. Over the last predicting the course of the disease, and the risk of Figure 3: CT scan showing a local recurrence in a patient who is a minimum requirement in the study of ACC. decade some authors challenged the role of open morbidity and mortality associated with re- previously underwent adrenalectomy and nephrectomy for a adrenalectomy (OA) suggesting that laparoscopic intervention should be carefully considered. large pT3 left ACC, Weiss score 8, Ki-67 index >10%. Usually ACCs are large at presentation, being more adrenalectomy (LA) may be a viable option for stages than 6 cm in diameter in more than 90% of the cases I-II [Figure 2]. The current knowledge are mainly Finally, some authors suggested a role of the heated [Figure1]. Haemorrhage and necrosis are often based on retrospective studies and most of intra-operative peritoneal extracorporeal recommended if the lesion is amenable to a R0 reported; vascular invasion with a tumor thrombus laparoscopic series published by European and chemotherapy (HIPEC) in the treatment of peritoneal resection. extending within the left renal vein and/or the inferior American centres report small data series and lack of spread of ACC. To date, one clinical trial investigating vena cava (IVC) is not uncommon; metastases are long-term oncologic follow-up. In a recent meta- progression-free survival after the use of HIPEC with Medical therapies for advanced ACC frequently found at the baseline staging, most analysis 240 LA and 557 OA for ACC were compared; cisplatin is ongoing. The initial experience appears to Patients with locally advanced disease (stage III) or commonly at regional or paraortic/paracaval lymph no differences were found in time-to-recurrence, as be promising, although selection criteria will need to metastatic disease (stage IV) represent up to 45% of nodes, lung, liver and bone. well as for cancer specific survival, even if tumors that be developed and risk/benefit ratio should be cases at diagnosis. When feasible, surgery should be underwent laparoscopic treatment were smaller, with carefully considered. considered in addition to mitotane as systemic Gadolinium-enhanced Magnetic Resonance Imaging a higher proportion of them being localized (I–II treatment. (MRI) and chemical shift MRI may give the same stage) if compared to those who underwent open Other than surgery information as the CT scan but may better define an surgery (80.8 vs 67.7 %, respectively). Interestingly, Besides surgery, over the last years a significant effort In patients who failed mitotane as adjuvant therapy or eventual IVC invasion. Concerning the functional the development of peritoneal carcinomatosis at the has been made to improve the outcome of ACC disease, patients with large tumor burden and rapidly imaging, ACC showed a high 18F-fluorodeoxyglucose time of recurrence was higher for LA versus OA (RR: mainly with the use of protocols of chemotherapy. progressive disease, treatment with systemic (FDG) uptake but the routine use of FDG-PET still 2.39). The authors concluded that OA should be still chemotherapy should be considered. Based on the needs validation. Recently, the metomidate ([11C]MTO) considered the standard surgical management of ACC Adjuvant therapy for local disease results of the FIRM-ACT trial, which compared cisplatin, proved to be useful in identifying the adrenocortical even if laparoscopy may play a role in this setting, but As recurrence rate is high in patients undergoing etoposide plus mitotane (EDP-M) versus streptozotocin origin of the tumours because it specifically binds to in carefully selected cases. Tumor size is a major issue radical resection (up to 50%, in R0 patients) and even plus mitotane (Sz +M), the former became the first-line adrenocortical CYP11B enzymes, which has a key role as the risk of spillage or capsule rupture is more likely higher in patients with incomplete resection (up to regimen for patients with progressive metastatic in the synthesis of steroids. This new tracer seems to if the tumor diameter is over 8-10 cm; moreover, 80%), adjuvant treatment is of crucial importance. disease. In case of progression with EDP-M, be promising but is still under evaluation. imaging should exclude local invasion when an LA is Mitotane remains the mainstay in this setting (mainly gemcitabine may be used even the evidence is very low. planned. Anyway, when an LA is performed, the on the basis of the results of German and Italian Pathology principles of oncologic surgery have to be respected groups), being recommended for patients with Targeted therapies Macroscopy revealed a usually large, heterogeneous and the threshold for conversion to an open surgery potential residual disease (R1 or RX resection) and in The lack of an effective medical therapy for the lesion with a colour surface that ranges from brown should be low. patients with R0 resection with a high-risk disease. treatment of recurrent, advanced or metastatic ACC to yellow depending on the lipid content of the cells; compelled the researchers to identify new potential gross necrosis is virtually always present. LND In the setting of the adjuvant treatment, radiotherapy drugs. Several studies were performed to investigate Microscopically, invasion of tumor capsule, Lymph node dissection (LND) as a routine step of the should be at least mentioned. Despite the good the role of molecular target therapies in this setting, extra-adrenal tissue, lymphatic or blood vessels are surgery for ACC has not been extensively studied. Up results of this approach in the local control of the with poor results. Actually, inhibition of epidermal the typical features of ACC. The Weiss score is to this day it has not been proven to definitively affect disease, unfortunately none of the authors could growth factor receptor (EGFR), mammalian target of commonly used: it is composed of nine items (three the outcome. In general, retrospective data suggest demonstrate improvement of recurrence-free and rapamycin (mTOR), insulin-like growth factor 1 concerning the architecture, three the nucleus and that regional lymph-node involvement in ACC has a over-all survival in patients who underwent receptor (IGF-1R) and vascular endothelial growth three the presence of any type of invasion). The sum negative impact on over-all survival and is often the radiotherapy. factor (VEGF) had no impact on clinical outcomes of of the positive items (each one scores 1 if positive) cause of local recurrences. In terms of oncological the disease. On the contrary, the combination of defines the final score and a Weiss score > 3 defines outcome, the most important data comes from the Neoadjuvant therapy for borderline resectable ACC cixutumumab and temsirolimus that was investigated an ACC. German ACC registry and suggest a reduced risk of (BRACC) in a phase I study, seems to be promising even if local recurrence and disease-related mortality, when In a single retrospective study, some authors further studies are required. more than five lymph-nodes are removed. In a recent suggested the role of neoadjuvant chemotherapy Table 1: ENS@T stage classification. paper, location of lymph-node involvement during (mitotane alone or mitotane + etoposide/cisplatin or In an ongoing phase I study, the researchers are surveillance was reported: on the the left side, the etoposide/cisplatin alone) in patients with BRACC, investigating the role of ATR-101, a selective inhibitor ENS@T stage involvement was perirenal-cranial (48.3 %), defined as imaging suggesting a need for multi- of esterification of intracellular free cholesterol. This I T1, N0, M0 para-aortic (44.9 %), inter-aortocaval (24.1 %), and organ/vascular resection; imaging suggesting inhibition may activate the apoptotic pathway and II T2, N0, M0 perirenal ventro-caudal (13.8 %) whilst on the right potentially resectable oligometastases; and patients promote ACC cell death. side, lymph-node involvement was detected in the having marginal performance status/co-morbidities III T3-4, N1 perirenal-cranial (55 %), paracaval (10 %), inter- precluding immediate surgery. These authors Editorial Note: Due to space constraints the reference IV T1-4, N0-1, M1 aortocaval (30 %), and para-aortic (10 %) nodes. concluded that the favorable outcome of these list has been omitted. Interested readers can email at T1,tumor _ 5 cm; T2,tumor > 5 cm; T3, histologically proven patients, despite more advanced stage of disease [email protected] for a complete listing. tumor invasion of surrounding tissue; T4, tumor invasion of Based on this information, a routine loco-regional compared to those treated with surgery as first step, adjacent organs or venous tumor thrombus in vena cava or lymph-nodes dissection should be done at the time of suggests a benefit of neoadjuvant treatment (followed Sunday 26 March renal vein. Venous tumor thrombus is only a criterion in the adrenalectomy for highly suspicious or proven ACC. It by surgery) in patients with BRACC. 10.30.10.50: Thematic Session 5, Adrenal ENSAT classification. N0,negative lymph nodes; N1, positive should include (as a minimum) the peri-adrenal and Disorders, State-of-the-art Lecture, Adrenal lymph nodes. M0, absence of distant metastases; M1, presence renal hilum nodes. Enlarged lymph-nodes on Nevertheless, in view of the overall low response rate cortical carcinoma of distant metastases preoperative imaging should be removed. of available chemotherapy, upfront surgery remains

18 EUT Congress News Sunday, 26 March 2017 Science at your fingertips

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Sunday, 26 March 2017 EUT Congress News 19 EAU-RF PRECISION study recruits ahead of schedule Comparing MRI-targeted biopsy to standard trans-rectal biopsy in PCa patients

[HEAD, BOLD] EAU-RF PRECISIONDr Veeru study: Recruits Backgroundahead of schedule Primary Outcome: Research Fellowship (DRF-2014-07-146) and UK sites [SUBHEAD, ITALS] ComparingKasivisvanathan MRI-targeted biopsyThe to standardclassical pathway trans- rectalfor the biopsydiagnosis in ofPCa prostate patients Proportion of men with clinically significant are funded by the NIHR Clinical Research Network. PRECISION Study cancer is TRUS biopsy of the prostate following a cancer detected raised PSA. TRUS guidance is performed primarily for Participating centres Dr Veeru Kasivisvanathan Coordinator anatomic guidance and the ultrasound discriminates Secondary Outcomes include: Argentina PRECISION Study CoordinatorNIHR Doctoral Fellow in Urology poorly between cancerous and non-cancerous tissue. 1. Proportion of men with clinically insignificant • Centro de Urologia NIHR Doctoral Fellow in Urology University College Biopsies are concentrated in areas of the peripheral cancer detected Belgium University College LondonLondon Hospitals Hospitals zone, which harbors the majority of cancer. 2. Proportion of men with negative MPMRI who • Ghent University Hospital London (GB) London (GB) avoid biopsy Canada An alternative pathway for the diagnosis of prostate 3. Maximum cancer core length of most involved • Jewish General Hospital cancer in men with raised PSA is to perform a biopsy core Finland multi-parametric magnetic resonance imaging • Helsinki University Central Hospital The EAU Research Foundation (EAU-RF) PRECISION (MPMRI) to localize cancer and to use this information • Oulu University Hospital Trial (NCT02380027) began recruiting in February to influence conduct of a subsequent biopsy, known Key patient inclusion criteria France 2016. This is an international multi-centre randomised as an MPMRI-targeted biopsy. This pathway may offer 1. Men at least 18 years of age referred with clinical • Bordeaux University Hospital controlled study that compares magnetic resonance advantages over the classical pathway. suspicion of prostate cancer who have been • CHU Lille, University Lille Nord de France [BOLD]imaging-targeted The EAU biopsyResearch to standard Foundation trans-rectal (EAU -RF) PRECISION Trial (NCT02380027) began recruiting advised to have a prostate biopsy • Lyon HEH and Lyon Sud inultrasound February guided 2016. biopsy This isfor an the international diagnosis of prostate multi- centreStudy randomiseddesign controlled study that 2. Serum PSA ≤ 20ng/ml • Paris Pitie comparescancer in men magnetic without resonanceprior biopsy. imaging -targeted biopsyThe study to is standard an international trans -multi-centrerectal ultrasound randomised 3. Suspected stage ≤ T2 on rectal examination Italy guided biopsy for the diagnosis of prostate cancercontrolled in men withtrial, outwith prior470 men biopsy. randomised 1:1 ratio to (organ-confined prostate cancer) • Sapienza University of Rome, Italy Study status one of two arms. Men will either undergo TRUS • San Raffaele Hospital, Milan [SUBHEAD,The study is recruitingBOLD] Study ahead status of schedule with 267 biopsy, or will undergo a MPMRI and targeted biopsy Key patient exclusion criteria Germany Themen study recruited is recruiting in 11 months ahead at 18 sitesof schedule (Data correct with as 267 of men suspicious recruited areas. in 11 months at 18 sites (Data 1. Prior prostate biopsy • University Hospital Heidelberg correctof 12 January as of 2017).12 Jan Anticipateduary 201 7recruitment). Anticipated end date recruitment end date is October 2017. 2. Prior treatment for prostate cancer Netherlands is October 2017. 3. Contraindication to MRI or prostate biopsy • Erasmus University Medical Centre

• Radboud University, Nijmegen Medical Centre PRECISION recruitment The potential implications of this trial: Sweden Recruited to 12th Jan 2017: 267 patients • Introduction of an alternative prostate cancer • University of Gothenburg diagnostic pathway United Kingdom • A reduction in the number of patients undergoing • Basingstoke and North Hampshire Hospital prostate biopsy • Northwick Park Hospital 450 • A reduction in the number of biopsy cores taken • Princess Alexandra Hospital 400 per patient • Royal Free Hospital NHS Foundation Trust 350 Olivier Rouviere, Alain Ruffion, Michiel Sedelaar, Paras Singh, Panu Tonttila, Markku Vaarala, Geert• A reduction in biopsy-related sepsis, pain and • University College London Hospitals 300 Villeirs, Arnauld Villers, Jaspal Virdi. other side effects • Whittington Health Trust

250 • A reduction in the over-diagnosis of clinically USA Trial Management Group 200 UCL Clinical Trials Group: Chris Brew-Graves, Norman Williams, SamimPredicted recruitment Patel, Fatima Jichi, Susan insignificant prostate cancer • Chicago University Hospital Number of Patients 150 Tebbs • Mayo Clinic Rochester Actual recruitment 100 Funding • Weil Cornell Medical Centre 50 EAU Research Foundation The EAU Research Foundation provides their • USC Institute of Urology Wim Witjes, Christien Caris, Joke Van Egmond web-based database management system for 0 0 1 3 Background4 7 Month 9 12 15 18 21 24 26 collection of patient data and provides all sites per Note: For details on the project, visit https://uroweb. The classical pathway for the diagnosis of prostate cancer is TRUS biopsy of the prostate following patient recruited funding. The study coordinator, Veeru org/research/projects/ or contact the author at a raised PSA. TRUS guidance is performed primarily for anatomic guidance and the ultrasound Kasivisvanathan, is funded by a UK NIHR Doctoral [email protected] [BOLD]Chief Investigators Chief Investigatodiscriminatesrs poorly between cancerousHypothesis and non-cancerous tissue. Biopsies are concentrated in areas of the peripheral zone, which harbors the majority of cancer. CarolineCaroline Moore,Moore, Mark Mark Emberton Emberton The proportion of men with clinically significant cancer detected by MPMRI-targeted biopsy will be no less An alternative pathway for the diagnosis of prostate cancer in men with raised PSA is to perform a Investigators multi-parametric magnetic resonancethan thatimaging detected (MPMRI) by tostandard localize 12-corecancer and TRUS to use biopsy. this [BOLD]Manit Arya, Investigators Chris Bangma, Franck Bladou, Alberto information to influence conduct of a subsequent biopsy, known as an MPMRI-targeted biopsy. LLITE Manit Arya, Chris Bangma, Franck Bladou, Alberto Briganti, Marcelo Borghi, Silvan Boxler, Marc TE Briganti, Marcelo Borghi, SilvanThis pathwayBoxler, Marc may offer advantagesMethods over the classical pathway. A SIUM S PO Colombel, Sebastien Crouzet , Pieter De Visschere, Scott Eggener, Nicola Fossati, Jurgen Futterer, M Colombel, Sebastien Crouzet, Pieter De Visschere, Scott Men referred with clinical suspicion of prostate cancer Y ManeeshEggener, Nicola Ghei ,Fossati, Inderbir Jurgen Gill,[BOLD] Futterer, Boris Study Hadaschik, Maneeshdesign Gileswho Hellawell, have had Richard no prior Hindley, biopsy are Jim randomised Hu, Jonas to S The study is an international multi-centre randomised controlled trial, with 470 men randomised HugossonGhei, Inderbir, Veeru Gill, BorisKasivisvanathan, Hadaschik,1:1 ratio toGiles one Laurence Hellawell, of two arms. Klotz, Men eitherDrew will either standard Moghanaki, undergo 12-core TRUS Caroline TRUS biopsy biopsy, orMoore, will orundergo to Lance a MPMRI a MPMRI and Mynderse,Richard Hindley, Pierre Jim Mozer, Hu, Jonas targetedValeria Hugosson, biopsy Panebianco, Veeru of suspicious Antti areas.arm. Ranniko, In the MPMRIGregoire arm, Robert, areas of Monique the prostate Roobol, are Kasivisvanathan, Laurence Klotz, Drew Moghanaki, scored on a five-point scale of suspicion for clinically Caroline Moore, Lance Mynderse,[BOLD] Pierre Hypothesis Mozer, Valeria significant cancer: Chaired by Panebianco, Antti Ranniko, GregoireThe proportion Robert, of menMonique with clinically significant cancer detected by MPMRI-targeted biopsy will be Treating Urological Cancers no less than that detected by standard 12-core TRUS biopsy Professor Nicholas D. James Roobol, Olivier Rouviere, Alain Ruffion, Michiel 1 = Highly unlikely to be clinically significant cancer on Saturday 25th March Sedelaar, Paras Singh, Panu [BOLD]Tonttila, Methods Markku Vaarala, 2 = Unlikely to be clinically significant cancer New Twists and Turns In The Road Geert Villeirs, Arnauld Villers,Men Jaspal referred Virdi. with clinical suspicion3 =of prostateThe presence cancer ofwho clinically have had significant no prior biopsy cancer are is randomised to either standard 12 -core TRUSequivocal biopsy or to a MPMRI arm. In the MPMRI arm, areas Trial Management Group of the prostate are scored on a five4 -=point Likely scale to of be suspicion clinically for significantclinically significant cancer cancer: Professor Thomas H. Lynch (Ireland) UCL Clinical Trials Group: Chris Brew-Graves, Norman 5 = Highly likely to be clinically significant cancer 1 = Highly unlikely to be clinically significant cancer How far have we improved on prostate cancer management? Williams, Samim Patel, Fatima2 Jichi,= SusanUnlikely Tebbs to be clinically significant cancer Professor Lynch provided an overview of the advances in the diagnosis and 3 = The presence of clinicallyAreas scoring significant 3, 4cancer or 5 willis equivocal undergo targeted biopsy treatment of prostate cancer over the past century, with a focus on the evolving EAU Research Foundation 4 = Likely to be clinicallyonly. significant Up to three cancer MRI-suspicious areas will be role of hormone manipulation in therapeutic strategies for this disease. Wim Witjes, Christien Caris, 5Joke Van= EgmondHighly likely to be targetedclinically significantwith a maximum cancer of 4 cores per target With cancer care moving further towards individualized medicine, recent leading to a maximum of up to 12 cores per patient. developments and remaining challenges in the fields of robotic surgery Areas scoring 3, 4 or 5 will undergo targeted biopsy only. Up to three MRI-suspicious areas will be Visual registration or software-assisted registration targeted with a maximum of 4 cores per target leading to a maximum of up to 12 cores per and genetic profiling were also critically examined by Professor Lynch. patient. Visual registration or softwaremay be-assisted used. registrationPathologic mayfindings be used. from Pathologic all biopsies findings from all biopsies will be recorded and willcompared be recorded between and arms compared. between arms. Professor Susanne Osanto (The Netherlands) [BOLD] Study scheme Systemic therapy in RCC – current landscape and future directions Man with no prior biopsy referred with clinical suspicion of prostate cancer Study scheme Professor Osanto reviewed the latest advances in the second-line renal cell

carcinoma (RCC) setting, focusing on new agents that have recently reported significant survival benefit following first-line therapies. The impact of the Registration (n=470) expanding second-line options on clinical practice guidelines was also discussed.

1:1 Randomisation Professor Shahrokh F. Shariat (Austria)

Arm 1 (n=235) Arm 2 (n=235) The future of non-muscle-invasive bladder cancer management Professor Shariat presented the latest developments aimed at improving the management of non muscle-invasive bladder cancer (NMIBC) for patients. Multi-parametric MRI 10-12 core trans-rectal biopsy of Key topics in this field, covered by Professor Shariat, included preventive the prostate strategies, earlier and improved detection and resection of NMIBC, more accurate risk stratification, and less invasive risk-stratified follow-up.

MpMRI MpMRI

score 1,2 score 3,4,5

MRI-targeted biopsy * The Innovators in Bladder Cancer No biopsy TOPIC of the prostate OF THE “Bladder Cancer Topic of the Year” was voted on YEAR and the winner announced during the symposium.

2017 If you would like further details on the selected Please visit Topic of the Year, please visit the Ipsen booth. the Ipsen booth E16 Results given Results given Results given This meeting was initiated and funded by Ipsen Exib. Halls S7-S10 and included reference to Ipsen medicines relevant to the agenda topics. Treatment Decision Treatment Decision Treatment Decision 2017 UK/DEC09547c February Level 1 Questionnaire Questionnaire Questionnaire

20 EUT Congress NewsPrimary Outcome: Sunday, 26 March 2017 Proportion of men with clinically significant cancer detected

Secondary Outcomes include: 1. Proportion of men with clinically insignificant cancer detected 2. Proportion of men with negative MPMRI who avoid biopsy

3. Maximum cancer core length of most involved biopsy core

[BOLD] Key patient inclusion criteria 1. Men at least 18 years of age referred with clinical suspicion of prostate cancer who have been advised to have a prostate biopsy 2. Serum PSA ≤ 20ng/ml 3. Suspected stage ≤ T2 on rectal examination (organ-confined prostate cancer)

[BOLD] Key patient exclusion criteria 1. Prior prostate biopsy 2. Prior treatment for prostate cancer 3. Contraindication to MRI or prostate biopsy

[BOLD] The potential implications of this trial: • Introduction of an alternative prostate cancer diagnostic pathway Urothelial cancer How will immunotherapy change the treatment paradigm?

Prof. Robert J. Jones Combination therapy and patient stratification experience major immune- related toxicities which University of Glasgow Current data regarding the efficacy of mono-agent require a degree of clinical acumen and a high level Beatson West of anti-PD-1/ PDL-1 therapy strongly suggest that there of awareness if they are to be identified at a point Scotland Cancer are substantial benefits which are, nonetheless, where effective intervention can be made. When Centre afforded to only a minority of patients. This is managed in the context of broader oncology services, Glasgow (GB) evidenced by the prolonged duration of response seen the advent of immunotherapy in urothelial cancer will in only around 20 –25% of patients regardless of line present no additional challenge (as the issues are no of therapy (Balar et al. 2016(a); Balar et al. 2016(b); different than for other cancers). Bellmunt et al. 2016; Galsky et al. 2016; Rosenberg et al. 2016). This contrasts with first-line response rates However, where these patients are to be managed in to chemotherapy of 46 – 49% in first-line (von der isolation from other diseases, then the clinical Maase et al. 2005). challenges associated with diagnosis and Urothelial cancer, though common, is a very diverse management of immune toxicity may be considerable. disease. Advanced urothelial cancer spent many Efforts, so far, to define predictive markers which It is likely that some centres will opt to develop For many patients, there is still a high unmet need for better years as a poor relation amongst drug developers might allow the selection of patients for primary specific ‘immuno-oncology’ services (encompassing systemic therapies and the pharmaceutical industry with only minimal immunotherapy, or, moreover, those for whom the necessary skills and specialisms to deal with the progress being made in improving outcomes for chemotherapy may be a preferable alternative, have toxicities of these drugs, for example gastro- patients in the last two decades. failed to deliver a marker which could be used in the enterology, respiratory medicine, endocrinology and Beyond advanced disease clinic. Therefore, current knowledge would suggest critical care) to support the expected tidal wave of use The focus of this discussion has been on the immediate But this is changing. Checkpoint inhibitors have that there are risks in the wholescale replacement of of these drugs across multiple tumour types. applications of immune checkpoint inhibitors in shown clear evidence of activity in this disease and primary chemotherapy with mono-agent advanced urothelial cancer. However, trials are already are already impacting on outcomes for some patients. immunotherapy. Indeed, even in the second-line Place alongside stratified medicine underway to explore their role in settings other than The advent of these new technologies brings the setting, where, in unselected populations, As we get swept up by this important new class of advanced disease. These include trials in the post- opportunity to drive even better outcomes, but also immunotherapy clearly performs better on average drugs in urothelial cancer, it is important to consider cystectomy adjuvant setting, the neo-adjuvant setting, brings the threat of new toxicities and the risk that than chemotherapy (Bellmunt et al. 2016), it is that, for many, there is still high unmet need for and in combination with radical radiotherapy in muscle other active treatments become inappropriately possible that some patients would in fact derive more better systemic therapies, and we must not allow invasive bladder cancer and also in high risk non- sidelined. benefit from chemotherapy. momentum to be lost in the search for new targets muscle invasive bladder cancer (NMIBC). and new drugs in urothelial cancer. Current paradigm Thus, the inability to stratify patients who should Whilst it is premature to speculate how these trials Advanced urothelial cancer is generally regarded receive immunotherapy and those who should receive The current focus of drug discovery and drug will change treatment in the future, it is likely that as an inevitably fatal condition where the aim of chemotherapy is a pressing concern. One solution to development is to combine targeted therapy with immunotherapy will, in the future, be seen as an treatment is palliation and disease control with this concern could be offer patients combined therapy predictive biomarkers to deliver precision medicine. additional modality of care (rather than simply as a little or no chance of cure. This is despite the with both chemotherapy and immunotherapy Whilst it is possible that some patients needs will be substitute for chemotherapy) in the multi-modality observation that, even before the advent of delivered either in combination or in a sequential completely met by immunotherapy, it is certain that treatment of urothelial cancer. immunotherapy, there was a small percentage of regimen. In urothelial cancer, there are now ongoing for many they will not. patients who were long-term survivors following phase III trials of anti-PD-1 and platinum-based Editorial Note: Due to space constraints the reference chemotherapy (von der Maase et al. 2005; combination chemotherapy which may drive a change Trials are continuing to develop precision medicines list has been omitted. Interested readers can email at Bellmunt et al. 2012). in practice whereby the initial treatment of advanced in urothelial cancers (for example the ongoing [email protected] for a complete listing. urothelial cancer remains much as at present but with development of the fibroblast growth factor receptor It is widely acknowledged that a significant the addition of mono-agent checkpoint inhibitor for inhibitors, or the UK ‘ATLANTIS’ trial (www. Sunday 26 March proportion of patients will never be suitable for all patients where it is safe to do so (in combination clinicaltrials.gov)) but also to explore the role of 11.38-11.53: Thematic Session 6, Changing palliative chemotherapy due to comorbidities and with cisplatin or non-cisplatin based regimens and, targeted therapies in combination with treatment landscape of renal and urothelial performance status and that many of those who do conceivably, alone for those unsuitable for immunotherapy (for example in the ‘BISCAY’ trial cancer: The impact of immunotherapy receive chemotherapy suffer significant toxicity with chemotherapy). (www.clinicaltrials.gov)). little benefit. Despite relatively high response rates to first-line chemotherapy, the duration of benefit, for The Immuno-oncology (IO) tail and urothelial cancer most, is distressingly short, and prognosis after The checkpoint inhibitors have, to date, had more failure of chemotherapy is exceedingly poor. Whilst impact in advanced melanoma than in any other the broad concept of sequential ‘lines’ of palliative disease. The excitement here is largely generated by a chemotherapy is applied as much to urothelial cancer substantial minority of recipients who appear to as other more common solid tumours, in reality, very experience long-term, durable disease control. With few patients receive more than one line, and the mono-agent anti-CTLA4 therapy, it appears that around Call for Abstracts evidence to support the use of second-line 20% of patients assume a risk of all-cause death which chemotherapy is relatively weak. is little different from that of the age-matched, cancer-free population (Hodi et al. 2010). Submit your abstract by 28 April 2017 Patient stratification with regards to palliative chemotherapy is relatively simple with three groups When treated with combination anti-CTLA4 and at www.WCE2017.com defined: those who are suitable for cisplatin anti-PD-1, the proportion of long-term beneficiaries chemotherapy, those who are suitable for is even greater (Larkin et al. 2015). Whether this chemotherapy but not cisplatin, and those who are effect holds true in patients with urothelial cancer unsuitable for any type of chemotherapy. By and remains to be seen in long-term follow-up of large, there is no significant group of patients who recent and ongoing trials, but there is already a would be considered for ‘deferred’ chemotherapy as suggestion that this might also be the case in renal there is, for example, in advanced renal or prostate cancer patients treated with anti-PD-1, an effect cancer. The chemotherapy drugs that are used are which was previously well-described in patients all broad-spectrum cytotoxics and all, with the treated with high dose Interleukin-2 (McDermott et exception of vinflunine, have broad application al. 2015). The long duration of responses seen in across a range of different solid tumours. As a some patients with urothelial cancer may be an result, most clinics with capabilities to use early sign. chemotherapy will be capable of administering chemotherapy to patients with advanced urothelial This so-called ‘IO tail’ will impact on the way in which cancer and many patients are treated in centres with we regard systemic treatment for urothelial cancer: low volumes of patients with advanced urothelial for some patients, at least, the primary objective of cancer. treatment will no longer be symptom control, but long-term disease control with the expectation that What can we learn from other diseases? (melanoma these patients may die of unrelated causes. The fact and lung) that this benefit is only afforded to a minority further Immunotherapy, in particular the checkpoint reinforces the need for predictive markers, if only to inhibitors, is changing the way patients with a variety establish the treatment objective for the individual of advanced solid tumours are managed. They have patient. made their biggest impacts in melanoma skin cancer, where combination anti-PD-1 and anti-CTLA4 therapy Long-term treatment has become the mainstay of treatment for those fit One significant unknown is whether those that respond enough to receive it (Larkin et al. 2015) and, to checkpoint inhibitors need to continue treatment increasingly, non-small cell lung cancer where indefinitely. What is clear is that many patients will be anti-PD-1 therapy is now used as a salvage treatment spending longer on treatment than has been the case after failure of first-line chemotherapy (Borghaei et al. in the ‘cytotoxic era’. This has significant implications Register Now! www.WCE2017.com 2015) and in front-line treatment of selected patients for patients – for some of whom the morbidity (Reck et al. 2016). associated with long-term treatment will become more significant than that associated with the disease – but In renal cancer, anti-PD-1 therapy is widely used to also for clinical services which will need to increase treat patients who have failed at least one prior capacity to provide treatment. tyrosine kinase inhibitor (Motzer et al. 2015). Whilst the treatment paradigms in these diseases are also Toxicity management and service organisation still evolving, it is likely that the uro-oncology Immuno-therapy toxicity is dominated by auto- community will learn and adapt from experiences in immune events, many of which are tolerable and these other disease areas. manageable. However, a small percentage of patients

Sunday, 26 March 2017 EUT Congress News 21 BCG-unresponsive bladder cancer Recommendations from the International Bladder Cancer Group (IBCG)

Dr. Ashish M. Kamat induction course of BCG, a second induction course regulatory approval but especially with regards to 16 MD Anderson Cancer may be associated with a 50% response rate . benefit for our patients. Center However, for patients with persistent disease after Dept. of Urology two or more than two BCG courses – or with References MD Anderson Cancer progression of disease – there is minimal response 1. Mmeje CO, Guo CC, Shah JB, et al. Papillary Recurrence Center expected and the risk of invasive and even metastatic of Bladder Cancer at First Evaluation after Induction Houston (US) disease outweighs the minimal potential benefit. Bacillus Calmette-Guerin Therapy: Implication for Clinical Thus, if a patient is truly BCG-unresponsive and their Trial Design. Eur Urol. 2016;In press. high-grade bladder cancer persists after one or two 2. Lamm DL, Blumenstein BA, Crissman JD, et al. courses of BCG, additional BCG is not recommended. Maintenance Bacillus Calmette-Guerin Immunotherapy for Recurrent Ta, T1, and Carcinoma in situ Transitional Current Options Cell Carcinoma of the Bladder: a Randomized Southwest On behalf of the IBCG (Andreas Boehle, Maurizio Of course, patients are always seeking alternatives to Oncology Group Study. J Urol. 2000;163(April):1124-1129. Brausi, Roger Buckley, Marc Colombel, Ashish M. radical cystectomy, so it behoves us to objectively 3. Oddens J, Brausi M, Sylvester R, et al. Final Results of an Kamat, Donald Lamm, Raj Persad, Joan Palou, Mark consider and offer them such options. Prior to EORTC-GU Cancers Group Randomized Study of Soloway and J. Alfred Witjes) offering bladder-sparing therapies, thorough Maintenance Bacillus Calmette-Guerin rin in evaluation of sanctuary sites is paramount, including Intermediate- and High- risk Ta , T1 Papillary Carcinoma It is an inescapable fact that some patients treated with evaluation of the prostatic urethra and upper urinary of the Urinary Bladder: One-third Dose Versus Full Dose Prior to offering bladder-sparing therapies, thorough intravesical immunotherapy using Bacillus Calmette- tract. Enhanced optical imaging of the urothelium and 1 Year Versus 3 Years of Mainte. Eur Urol. evaluation of the prostatic urethra and upper urinary tract is of Guerin (BCG) will have recurrence of their disease. with blue light and/or narrow band imaging (NBI) 2013;63(3):462-472. doi:10.1016/j.eururo.2012.10.039. utmost importance However, not all such recurrences are cause for should ideally be used to provide for a more complete 4. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-Term concern and the definition of what truly defines failure tumor resection. Efficacy Results of EORTC Genito-Urinary Group of BCG therapy is critical when evaluating patients. Randomized Phase 3 Study 30911 Comparing Intravesical doi:10.3233/BLC-160048. Intravesical chemotherapy after BCG failure has been Instillations of Epirubicin, Bacillus Calmette-Guerin, and 9. Kamat AM, Sylvester RJ, Andreas B, et al. Definitions, End For example, the prognosis of patients with a attempted with several agents. Valrubicin remains Bacillus Calmette-Guerin plus Isoniazid in Patients with Points, and Clinical Trial Designs for Non–Muscle- low-grade recurrence is markedly better than those the only FDA-approved, intravesical agent for use in Intermediate- and High-Risk . Eur Urol. 2010;57(5):766- Invasive Bladder Cancer: Recommendations From the who develop a high—grade tumor1, to the extent that BCG-refractory CIS when cystectomy is not an option, 773. doi:10.1016/j.eururo.2009.12.024. International Bladder Cancer Group. J Clin Oncol. this is considered a ‘non-event’ by regulatory bodies. but has dismal response rates17. Other intravesical 5. Palou J, Laguna P, Millan-Rodriguez F, Hall R, Salvador- 2016;34(16):1935-1944. doi:10.1200/JCO.2015.64.4070. chemotherapies such as gemcitabine, mitomycin, Bayarri J, Vicente-Rodriguez J. Control group and 10. Lerner S, Dinney C, Kamat A, et al. Clarification of What are the factors that we must remember when taxanes have each demonstrated a hint of efficacy maintenance treatment with Bacillus Calmette-Guerin for Bladder Cancer Disease States Following Treatment of considering patient management? First, it is essential after BCG; however overall response rates are not carcinoma in siute and/or high grrade bladder tumors. J Patients with Intravesical BCG. Bl Cancer. 2015;1:29-30. to verify that the patient has indeed received optimal durable and so less than optimal. Based on Urol. 2001;165(May):1488-1491. doi:10.3233/BLC-159002. BCG therapy – i.e. BCG induction with a six-week mechanisms of action, chemotherapeutics have been 6. Kamat AM, Porten S. Myths and Mysteries Surrounding 11. Shah JB, Kamat AM. Strategies for Optimizing Bacillus induction course followed by three-weekly combined; of these combinations the most studied is Bacillus Calmette-Gue Therapy for Bladder Cancer. Eur Calmette-Guerin. Urol Clin North Am. 2013;40:211-218. maintenance given at 3, 6, 12, 18, 24, 30, and 36 sequential intravesical gemcitabine with either Urol. 2014;65(2):267-269. doi:10.1016/j.eururo.2013.10.016. months (SWOG maintenance)2,3,4.1 While other intravesical docetaxel or MMC. Reports from 7. Kamat AM, Flaig TW, Grossman HB, et al. Consensus Editorial Note: Due to space constraints the maintenance regimens (monthly or quarterly single-centre studies have demonstrated activity; statement on best practice management regarding the reference list has been shortened. Interested instillation) have been studied; these have been longer follow-up will be crucial to determine the role use of intravesical immunotherapy with BCG for bladder readers can email at [email protected] shown to be no better than induction alone and in our armamentarium. cancer. Nat Publ Gr. 2015;In press:1-11. doi:10.1038/ to request for the full list. hence do not constitute optimal therapy5,6,7. nrurol.2015.58. Electromotive drug administration (EMDA) enables 8. Kamat AM, Cookson M, Witjes JA, Stenzl A, Grossman Sunday 26 March Next it should be determined as to which category of optimization and deep penetration of HB. The Impact of Blue Light Cystoscopy with 8.30-8.45: Plenary Session 3, Redefining and BCG failure applies to the particular patient. “BCG chemotherapeutics. EMDA with mitomycin has been Hexaminolevulinate (HAL) on Progression of Bladder optimising contemporary bladder cancer care refractory” indicates persistent high-grade cancer six extensively studied including in the pre-TURBT Cancer – A New Analysis. Bl Cancer. 2016;2:273-278. months after the start of induction therapy, or a tumor setting, where it was shown to significantly increase that has progressed in either grade or stage8, disease specific survival18. Other studies have 3 months after the start of induction therapy. “BCG evaluated19 sequential BCG + EMDA MMC in relapse” indicates high-grade tumor recurrence after treatment-naive T1 NMIBC but data regarding efficacy achieving a disease-free state at six months. The term in this paradigm in BCG-unresponsive patients is “BCG unresponsive” has been adopted by regulatory lacking20. Chemohyperthermia (CHT) is another bodies (eg the FDA) to denote the highest risk patients strategy that has been used with MMC or epirubicin21. – this group includes patients who are BCG-refractory In one retrospective report of 111 BCG-unresponsive plus those who have BCG-relapse within six months patients with a median follow-up duration ranging of their last BCG exposure (eg after maintenance from two to 72 months, CHT was associated with therapy) provided they have received at least an one-year and two-year RFS of 85% and 56%, induction course and one maintenance course of respectively22. Other studies have similarly BCG9,10. The term “BCG intolerant” indicates a scenario demonstrated activity for CHT in CIS patients23 as well when a patient cannot tolerate an induction course as high-grade T1 tumours, with similar efficacy owing to treatment-related adverse effects, an among patients classified as BCG-failures and EAU atient normation uncommon situation today11. non-failures24. Thus, results are encouraging.

When we consider this subgroup of patients - the BCG A large multicentre phase II trial initially suggested unresponsive category - radical cystectomy is the only that BCG plus IFNα might be effective in patients with ew Topics Aailable standard salvage therapy that is currently available. prior BCG exposure. Long term follow-up and detailed While there have been numerous clinical trials in the analysis eventually demonstrated that among truly BCG failure setting (summarized in our review12, in BCG-unresponsive patients, the response rate to BCG • ryptorchidism press) it has been difficult to interpret these studies + IFNα at 24 months is around 20%25, similar to many • ypogonadism isit us at due to non-uniform definitions and end-points used. other agents. Along the IFN paradigm, gene therapy the EAU ooth Since placebo comparators are considered unethical with an adenovirus that expresses an IFNα transgene • eurourological disorders and reported single-arm trials have had widely has demonstrated a 35% 12 month response rate at 12 varying results, experts have proposed threshold months in the BCG unresponsive setting26 and is • Penile curature response rates to differentiate positive from negative currently being evaluated in a single-arm phase III trials. We have previously published our consensus trial (NCT02773849). • Penis cancer that disease-free response rates of 30% and 25% at • Phimosis 12 months and 18 months, respectively, for papillary Other strategies tumours (or complete response rates for carcinoma in Fortunately for our patients, there are several ongoing • Priapism situ (CIS)), can be considered as clinically clinical trials, and more in development, to address meaningful9. the problem of BCG unresponsive disease. These are • Primary urethral cancer summarized in our recent review12 and include studies Current recommendations with immune checkpoint blockade (anti-PD1 agents), • Testicular cancer So what are the current recommendations for patients growth factor receptor agonists, photodynamic • Urachal cancer with BCG unresponsive disease? The European therapy, viral gene therapy, viral oncolytic therapy, as Association of Urology (EAU) guidelines state that for well as novel chemotherapeutics and chemotherapy- patients who have failed BCG, radical cystectomy is delivery technology. In addition, there are strategies the preferred option and other treatment strategies being developed to enhance the efficacy of BCG itself are considered inferior13. However, it does allow for – for example, BCG intradermal priming to augment consideration of a repeat BCG induction course or response via antigen specific memory T cell response ew aigation Tool in intravesical chemotherapy for intermediate-risk will be the subject of the randomized PRIME trial (low-grade) tumours14. Similarly, the American (NCT02326168). idney Stones Urological Association (AUA) guidelines state that and A Treatment BCG-unresponsive patients should be offered radical While we remain optimistic and supportive of such cystectomy but if patients have not received adequate efforts, a word of caution is due. These clinical trials BCG treatment, they can be offered either a second must adhere to strict principles outlined earlier, and induction course or maintenance BCG15. adherence to well-defined disease states, plus well- defined and clinically meaningful endpoints. patientsuroweborg This recommendations stems from the observation Otherwise, the results of these trials will result in data that if a patient has persistent disease after a single that is uninterpretable in the context of not only

22 EUT Congress News Sunday, 26 March 2017 Personalised approach to antagonising ERG in PCa New findings define a therapeutically actionable pathway

4-9 Dr. Giuseppina progression . Prostate cancer can be considered a a therapeutically actionable pathway, modulation of Carbone model of a disease driven by transcriptional and which could have a broad impact on the treatment of IOR Institute of epigenetic events whereby changes in transcription ERG-positive prostate cancer. Oncology Research and epigenetic regulators play a critical role occurring Tumor Biology and at early stages and further throughout disease References Experimental progression10,11. We and others have shown the 1. Seth, A. & Watson, D.K. ETS transcription factors and Therapeutic presence of cross-talks between ETS factors and their emerging roles in human cancer. Eur J Cancer 41, Bellinzona (CH) epigenetic effectors12,13. Over-expression of ERG leads 2462-2478 (2005). to the induction of Enhancer of Zest Homolog 2 2. Hollenhorst, P.C., McIntosh, L.P. & Graves, B.J. Genomic (EZH2), which in turn mediates silencing of several and biochemical insights into the specificity of ETS genes12,13. EZH2 is the catalytic subunit of the transcription factors. Annu Rev Biochem 80, 437-471 Polycomb repressive complex 2 (PRC2) that catalyzes (2011). Cancer of the prostate is a leading cause of cancer histone H3 lysine 27 tri-methylation (H3K27me3)14. 3. Chen, Y., et al. ETS factors reprogram the androgen death in men worldwide. While localized prostate Interestingly, EZH2 has been recently shown also to receptor cistrome and prime prostate tumorigenesis in cancer is highly curable, nearly all patients with exert PRC2-independent functions, including response to PTEN loss. Nat Med 19, 1023-1029 (2013). metastatic disease progress to castration-resistant interaction with and methylation of various 4. Robinson, D., et al. Integrative clinical genomics of prostate cancers for which there are presently limited transcriptional regulators15-17. advanced prostate cancer. Cell 161, 1215-1228 (2015). treatment options. 5. Beltran, H. & Rubin, M.A. New strategies in prostate New data cancer: translating genomics into the clinic. Clin Cancer There is a high need to develop selective, context- New data from our group provide further evidence of Res 19, 517-523 (2013). dependent therapeutic strategies to manage the cross-talk between ERG and EZH2 and support a 6. Taylor, B.S., et al. Integrative genomic profiling of human metastatic prostate cancer. The identification of the novel mechanism leading to aberrant ERG activation prostate cancer. Cancer Cell 18, 11-22 (2010). pathways that, in a specific tumor context, lead to and prostate cancer progression. We have recently 7. Cancer Genome Atlas Research Network. Electronic disease progression and metastasis is an important examined more in depth the relationship between Figure 1: ERG and EZH2 cooperate and activate a pro- address, s.c.m.o. & Cancer Genome Atlas Research, N. step in developing more effective treatments based on ERG and EZH2 and have found that EZH2 fulfils a very tumorigenic and pro-metastatic program in ERG fusion positive The Molecular Taxonomy of Primary Prostate Cancer. Cell the tumor molecular and biological characteristics. important role in mediating ERG oncogenic activity. prostate cancers. This pathway is enhanced by PTEN loss. 163, 1011-1025 (2015). Protein lysine methyltransferases, such as EZH2, 8. Beltran, H., et al. Molecular characterization of E26 transformation-specific (ETS) transcription factors regulate the methylation of histone and non-histone neuroendocrine prostate cancer and identification of constitute a family of signal-dependent transcription proteins. Lysine methylation has recently emerged as and differentiation program13,22. More recent work new drug targets. Cancer Discov 1, 487-495 (2011). regulators with important roles in cell differentiation an important post-translation modification that can highlighted the important role of ERG ability to 9. Beltran, H., et al. Divergent clonal evolution of castration- and carcinogenesis1,2. The ETS gene family includes 28 profoundly affect the function of diverse non-histone interact with other epigenetic and transcriptional resistant neuroendocrine prostate cancer. Nat Med 22, members in the human genome. ETS factors share proteins18,19. Indeed, there are few examples of regulatory proteins, such as the epigenetic effector 298-305 (2016). the highly conserved DNA binding domain and transcription factors and epigenetic regulators BRD4 and the RNA binding protein EWS23,24. Notably, 10. Jeronimo, C., et al. Epigenetics in prostate cancer: biologic recognize similar ETS binding motifs in the promoter methylated by histone-modifying enzymes18,19. the discovery of this complex ERG interactome, along and clinical relevance. Eur Urol 60, 753-766 (2011). of target genes1,2. Nevertheless, individual ETS factors with our novel finding of the ERG/EZH2 crosstalk, activate or repress transcription of largely distinct We found that EZH2 induces lysine methylation of ERG opens new opportunities for understating the Editorial Note: Due to space constraints the subsets of genes. in cells and human tumors and that the physical molecular mechanisms of ERG induced oncogenesis reference list has been shortened. Interested interaction between the two proteins is instrumental and for development of targeted therapeutic readers can email at [email protected] Furthermore, ETS factors interact with distinct protein in this process20. EZH2, by interacting with ERG, strategies to reverse prostate cancer progression. to request for the full list. partners inducing different transcriptional and significantly enhances its activity and contributes to biological responses. These differences among ETS ERG-induced transcriptional reprogramming in Collectively, our data provide advance on defining the 10.50-11.10: Thematic Session 1: Personalised factors contribute to their specific properties and prostate epithelial cells. As supporting evidence, we epigenetic network connected with TMPRSS2-ERG medicine in urological oncology, Personalised regulatory functions and are reflected in their diverse found that ERG-induced transcriptional activation and gene fusion and the role of ERG and EZH2 in prostate approach to antagonising ERG in prostate cancer roles in tumorigenesis1,2. In normal development the repression are both reduced upon depletion of EZH2, cancer progression. Importantly, these findings define ETS transcription factor ERG has a critical role in the underlying the functional relevance of the interaction. formation of the vascular system, urogenital tract and Furthermore, these events were enhanced by PTEN bone development. ERG is also expressed at high levels deficiency providing for the first time a direct in embryonic neural crest cells during migratory phase. mechanistic explanation of the synergistic effects of PTEN loss and ERG gene fusion on progression of ERG Come and meet with Peyronie’s experts ERG expression regulates the pluripotency of positive tumors. hematopoietic stem cells, endothelial cell homeostasis and angiogenesis. In the adult mouse ERG is expressed We have observed that ERG and EZH2 form a complex TAKE THE CHANCE – TALK TO EXPERIENCED in endothelial tissue including adrenal, cartilage, heart, that is detected by immuno-precipitation in VCaP spleen, lymphatic endothelial and eosinophil cells. ERG cells, an ERG fusion positive prostate cancer cell line, COLLAGENASE USERS has been shown to have a major role in cell response to and in samples from ERG fusion positive human vascular inflammation and cell adhesion, normal tumors, confirming the clinical relevance of our hematopoietic stem cell function and the maintenance findings (Figure1). Moreover, analysis of CHIP-seq Booth #H02 of normal peripheral blood platelet numbers. data in VCaP cells revealed the localization of ERG and EZH2 complexes at a number of genomic sites, March 25, Saturday Gene rearrangements involving ERG are very frequent including promoters and enhancers. Interestingly, in prostate cancers. These events link the ERG gene to many of the ERG-EZH2 co-occupied genes are 10.00-10.30 Mr Amr Raheem the promoter of the androgen-regulated gene over-expressed in ERG fusion positive cells and their 15.30-16.00 Mr David Ralph TMPRSS2 providing a mechanism for over-expression expression depends on both ERG and EZH2 and is of ERG in androgen-stimulated prostate epithelial significantly reduced after knockdown of either ERG cells. Aberrant overexpression of ERG due to the or EZH2. Furthermore, ERG/EZH2 co-occupied genes March 26, Sunday TMPRSS2 translocation in prostate epithelial cells, a are deregulated more prominently in prostate tumors 13.00-13.30 Mr David Ralph cell context inappropriate for ERG, results in with concomitant ERG fusion and PTEN loss compared significant alterations and broad transcriptional to the others, consistent with cooperation between March 27, Monday reprogramming. However, more than 10 years since the two events in driving clinical progression of the discovery of the TMPRSS2-ERG gene prostate cancer. 10.00-10.30 Mr Amr Raheem rearrangement in prostate cancer, its clinical impact is still unclear. Uncertainty persists regarding the From one hand, these results confirm that EZH2 is an molecular determinants of ERG-induced oncogenesis ERG co-factor in gene silencing by mediating histone XIAPEX® Abbreviated Prescribing Information (Peyronie’s Disease): (See XIAPEX Summary of Product Characteristics for full Prescribing Information). and its role in tumor progression. While aberrant methylation at the promoters of repressed genes. On Presentation: Powder and solvent for solution for injection. The vial of powder contains 0.9 mg collagenase clostridium histolyticum. Indications: The treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. Dosage: Xiapex expression of ERG does not lead to invasive the other hand, our data show that EZH2 together must be administered by a physician appropriately trained in the correct administration of the product and experienced in the diagnosis and treatment of male urological diseases. The recommended dose of Xiapex is 0.58 mg per injection administered into a Peyronie’s plaque. The volume of reconstituted Xiapex to be carcinomas in mouse models, aggressive castration- with ERG forms also activating complexes on a administered into the plaque is 0.25 ml. If more than one plaque is present, only the plaque causing the curvature deformity should be injected. A treatment resistant human prostate tumors are ERG- positive, distinct set of gene promoters, which is consistent course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Xiapex injections and one penile modelling procedure. The second Xiapex injection is administered 1 to 3 days after the first injection. A penile modelling procedure is performed 1 to 3 days after the second injection of each supporting a role for ERG in disease progression. with the recently identified activating function of treatment cycle. The interval between treatment cycles is approximately six weeks. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Treatment of Peyronie’s plaques that involve the penile urethra, due to potential risk to this structure. Warnings and Precautions: Allergic 15 EZH2 . Thus, these data provide novel insights about reactions – Following Xiapex injection, severe allergic reaction could occur, and patients should be observed for 30 minutes before leaving the clinic in order to monitor for any signs or symptoms of a serious allergic reaction Patients should be instructed to consult a doctor immediately if they experience any of these The emerging view is that ERG requires additional non-canonical functions of EZH2, showing that this signs or symptoms. Emergency medication for treatment of potential allergic reactions should be available. Corporal rupture was reported as a serious adverse event after Xiapex injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials. In other Xiapex-treated patients (9 of 1044; cooperating factors to fully exert its oncogenic effects function in ERG-positive cancer cells involves direct 0.9%), a combination of penile ecchymoses or haematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in and drive tumor progression. In human cancers ERG cooperation with ERG. Drugs directed to EZH2 and these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile haematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%). Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile gene fusions are often concomitant with other genetic other epigenetic targets are undergoing clinical haematoma. Use in patients with coagulation disorders – Xiapex must be used in caution in patients with coagulation disorders or those taking anticoagulants. See SmPC for details. Immunogenicity – As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. 21 events. Co-occurrence of ERG gene fusion and PTEN testing in various tumor types . Special penile conditions/diseases not studied in clinical trials – Xiapex treatment in patients having a calcified plaque that could have interfered with the 3 injection technique, chordee in the presence or absence of hypospadias, thrombosis of the dorsal penile artery and/or vein, infiltration by a benign or malignant loss are associated with more aggressive disease . mass resulting in penile curvature, infiltration by an infectious agent, such as in lymphogranuloma venereum, ventral curvature from any cause and isolated hourglass deformity of the penis has not been studied and treatment in these patients should be avoided. Long-term safety – Long-term safety of Xiapex is Furthermore, both pre-clinical and clinical evidence The efficacy of EZH2 inhibitors is generally attributed to not fully characterised. The impact of treatment with Xiapex on subsequent surgery, if needed, is not known. Drug Interactions: Use of Xiapex in patients who suggest that cross-talks and cooperation between the inhibition of histone H3K27 methylation and reversal have received tetracycline antibiotics e.g. doxycycline, within 14 days prior to receiving an injection of Xiapex is not recommended. Pregnancy & Lactation: Peyronie’s disease occurs exclusively in adult male patients and hence no relevant information for use in females. Driving and operating machinery: Minor multiple signaling pathways are involved in the of epigenetic gene silencing21. We found that inhibition influences on the ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache. Patients must be instructed to avoid potentially hazardous tasks. Side Effects: Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate progression of ERG-positive tumors. However, the of EZH2 has also a direct impact on ERG functions severity, and most (79%) resolved within 14 days of the injection. Very common (≥1/10): Penile haematoma, swelling, pain, ecchymosis. Common (≥1/100 to <1/10): Blood blister, Skin discolouration, Penile blister, Pruritus genital, Painful erection, Erectile dysfunction, Dyspareunia, Penile erythema. Injection site molecular details of these interactions are not defined inhibiting ERG/EZH2 promoter occupancy and vesicles, pruritus, Localised oedema, Nodule Suprapubic pain, Procedural pain. For further information refer to summary of product characteristics. Legal Category: POM. Marketing Authorisation Holder: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden. Package Quantities, Marketing yet. Understanding these mechanisms could greatly transcription of co-regulated genes. Consistently, EZH2 Authorisation Numbers and UK Basic NHS Price: XIAPEX 0.9mg powder and solvent for solution for injection, EU/1/11/671/001, £650. Further information impact on development of new therapeutic inhibition reversed in vitro and in vivo the malignant is available on request from: [email protected], Tel: +46 8 697 20 00. Date of Preparation: February 2017. approaches for prostate cancer. phenotype of ERG fusion positive cancer cells. Adverse events should be reported to your local regulatory authority and to Sobi at [email protected]

SE-112 76 Stockholm While numerous genetic alterations have emerged in The ERG co-regulatory network has been matter of Phone: +46 8 697 20 00 prostate cancer, epigenetic events clearly cooperate in investigation in the recent years. ERG can form www.sobi.com determining malignant transformation and tumor complex with AR and is able to disrupt AR signaling PP-2089

Sunday, 26 March 2017 EUT Congress News 23 New Endoscopic Stone Treatment EST-s1: A “Made in the EAU” novel basic training curriculum for endoscopic stone therapy

Dr. Domenico endourological techniques was essential. As opposed place in Athens, during Veneziano to E-BLUS, the EST s1 (Endoscopic Stone Treatment, the ESUT16 congress. Member, YAU Working step 1) protocol has been completely developed in the Data collection for Group European Association of Urology, under the validation took place Endourology & coordination of the European School of Urology (ESU)/ during EUREP16 in Urolithiasis EAU Section of Uro-Technology (ESUT) training Prague and involved 134 Ospedali Riuniti, Dept. research group, and thanks to the close collaboration participants with different of Urology & Kidney of these groups with the EAU Section of Urolithiasis expertise. All trials have Transplant (EULIS). The team involved experts in simulation and been DVD-recorded for Reggio Calabria (IT) stone treatment: Domenico Veneziano, Bhaskar re-evaluation and quality Somani, Kamran Ahmed, Alberto Breda and many feedback sheets have others. The “full life cycle curriculum development” been used to score Dr. Bhaskar Somani template, as described by Richard Satava was several aspects of the Member, YAU followed along the process, which started in 2014 procedure. Working Group with a Cognitive Task Analysis of the RIRS (Retrograde University Hospital Intra-Renal Surgery) procedure, operated by the The training curriculum is Southampton NHS FT YAUWP (Young Academic Urologist Working Party) composed of four tasks Olivier Traxer (middle) gives comments during the EST s1 validation in Prague Dept. of Urology Endourology & Stone Treatment group. This initial and requires mastering of Southampton (GB) research, based on a broad literature review, was the four different instruments to solid base behind the development process. successfully complete the test. The first two tasks ability with the flexible ureteroscope. The original focus on flexible and rigid cystoscopy. In these, the K-Box was slightly modified to correctly meet the EST-s1, as suggested by its name, is the first of a participant needs to touch (with the guidewire) a assessment requirements. During the task the scope three-step process and is focused on the simple skills sequence of 3mm-balls placed in a synthetic bladder, needs to be navigated to 10 numbered pre-marked of endoscopic stone treatment: navigation and basic following the instructions of the tutor. This is to points in the simulator, mimicking rotation, deflexion The last few years have seen a fast growth in the use of the operative channels. After several consensus demonstrate an understanding of the proper and in-out movements, in a standardised fashion. field of urological education and simulation, meetings and test sessions, the preliminary trials took taxonomy, to move the guidewire in and out when particularly with the aid of hands-on-training. In needed and to correctly Assessment has been designed to rely not only on 2013, the E-BLUS exam was delivered for the first manoeuver the time taken, but also on a questionnaire on the quality time during the European Urology Residents cystoscope. of trainee performance, to be filled out by the proctor. Education Program (EUREP). This year, we are finally Based on the literature research made upfront, the ready to deliver the novel EST-s1. After Task 2, the safety examination sheet contains a list of critical aspects guidewire is left in one of related to basic endoscopic skills, such as positioning E-BLUS, the renowned basic laparoscopy exam, was the ureters. Task 3 and use of the scope, handling the access sheath, and born from an analysis and integration of the American consists of simulating a correct navigation based on technical needs. All tasks FLS (Fundamentals of Laparoscopic Surgery) project. semi-rigid ureteroscopy, will be available for hands-on training sessions In time, the curriculum was slightly modified to meet with a working guidewire during this congress, while the first official exam the specific needs of urology. Over the last few years, placement. This task ends session is planned for September this year, during the E-BLUS has spread the European teaching standards with a successful EUREP17 course. to even outside European borders, reaching as far as placement of an access Indonesia and beyond. sheath. Task 4 takes place With step 2 already in the works, we are sure that the on the K-Box, a EST-s1 curriculum will allow once again the sharing With a recent surge in endourology and stone low-fidelity simulator of surgical standards, contributing to an improved treatment, a development of dedicated protocol- designed by Olivier educational system for residents and better based training and assessment relating to Author Veneziano explains the modifications applied to the K-Box Traxer, and tests trainees’ healthcare.

ADVERTORIAL New Compact SWL Solution for Urological Workstations STORZ MEDICAL presents a new versatile lithotripter: The MODULITH® SLK »intelect«

Since more than 25 years STORZ MEDICAL is an urological workstation, C-arc or ultrasound device. enhancing the technology of shock waves. The set-up of the lithotripter in combination with an With the new compact MODULITH® SLK »intelect« X-ray system and the focus adjustment during the a lithotripter has been developed which can be therapy are assisted by this navigation system. perfectly adapted to different imaging modalities. Once the stone is visualised, it only has to be marked The device features a fully motorized positioning of in the ultrasound image and the automatic positioning the therapy source making it easy to set up the system LITHOPOS® moves the shock wave focus on the lithotripter or to target stones in the urinary tract. stone for the treatment. The same smart function works with X-ray systems as well. The Companion for Urological Workstations Urological X-ray workstations are an important part of The Lithotripsy Module for C-arcs equipment in urological departments. They can be The MODULITH® SLK »intelect« in its basic version can used for diagnosis and interventional procedures. be combined with various surgical C-arcs and OR-tables But they are often lacking in the possibility of with lateral cut-out. The motorised movements of the performing instantly an SWL when a stone is detected therapy source facilitate the focus alignment for a fixed in the KUB of a patient. therapy head position. In-line ultrasound can be used for targeting radiolucent stones. “The versatile shock wave solution.” The MODULITH® SLK »intelect« can optionally be This gap is now filled with the MODULITH® SLK linked to C-arc and ultrasound device via the optical »intelect«. It allows treating patients lying on the navigation system LITHOTRACK®. This version allows table of the workstation. There is no need to move maximum flexibility in set-up and use. No dedicated them to a separate SWL room. table is needed to perform a SWL, normal surgical OR-tables are sufficient. MODULITH® SLK »intelect« with X-ray In this combination the superior image quality of the workstation’s X-ray can be used for localising the Smart Features stone and in-line X-ray control of the therapy success The lithotripter can be folded easily to a space saving controllable. The smart control concept guarantees a navigation system. It can be used with C-arcs and during the treatment. transport position for storage or transport. Safe and short learning curve. urological workstations like the PRIMERA ST360®. simple handling is ensured through the integrated After the therapy the lithotripter can easily be moved brake which fixes the device securely for operations. Hospital owned C-arcs can be used without any The MODULITH® SLK »intelect« - Great flexibility has away from the urological workstation and be stored The integrated focal gauge allows re-aligning the mechanical modifications for localisation. Virtually no never been so easy. without using much space. system or checking the focus alignment within installation is necessary and set-up is easy thanks to seconds. It’s appealing design was already awarded the small foot print of the device. The MODULITH® SLK »intelect« is the ideal complement twice, once by the International Design Award and to urological workstations like the PRIMERA ST360®. latest by the iF Design Award. The modular concept of the new MODULITH® SLK »intelect« allows easy future updates at any time. LITHOTRACK® Navigation System Economic Solution The lithotripter can be configured according to needs LITHOTRACK® is an optical navigation system The long service life of the proven shock wave and budget, from the economic solution without Olaf Gleibe comfortably linking the MODULITH® SLK »intelect« to components makes the investment economic and navigation up to a high-end setup with LITHOTRACK® Product Manager Urology

24 EUT Congress News Sunday, 26 March 2017 Male contraception: Where are we going? Future genomics can lead to new and innovative fertility products

Dr. Ferdinando Fusco testosterone alone showed that it is very effective with Gossypol could act on male fertility both effectively and Azienda Ospedaliera few adverse effects. Addition of a progestin acting Gossypol is a compound found in cotton seed oil. reversibly because inhibition of PPP3CC/PPP3R2 targets Universitaria synergistically increases the rate and extent of Effectively suppresses spermatogenesis. In a clinical spermatozoa in the epididymis. Federico II suppression of spermatogenesis. However, the fact study carried out in China, gossypol rendered 98.5% Center of Preclinical & that supernormal testosterone levels are necessary to of volunteers infertile at an oral dose of 20 mgr per Manipulation of cellular junctions in the Clinical Research In achieve the desirable suppression of spermatogenesis day for 75 days as the initial dose, followed by a seminiferous epithelium Sexual Medicine has raised concern over the long-term effects of maintenance dose of 40-50 mgr per week, but its The testis is a unique organ with complex junction Naples (IT) contraceptive treatment on men’s health, especially as effects are not consistently reversible, and it causes arrangements in the seminiferous epithelium7. Cell concerns the cardiovascular system and prostate hypokaliemia and myoparesis15. junction dysfunction in the seminiferous epithelium is associated morbidity2. The focus of MHC development one of the many causes of male infertility7. Recent in recent years has been the development of novel Immunization findings in different animal models support the androgens that may be more potent than testosterone GnRh vaccination involves the injection of GnRH hypothesis that cell junction may be one of the prime Co-Authors: Massimiliano Creta (IT), in the suppression of gonadotropins and with fewer conjugated to a foreign protein such as ovalbumin, targets for male fertility regulation7. Adjudin, for Nikolaos Sofikitis (GR) potential side effects6. and combined with an adjuvant, to induce anti-GnRH example, a compound able to perturb germ cell antibody formation. The antibodies bind to adhesion in the seminiferous epithelium7. Fertility control represents a global health issue as The ideal steroid for therapeutic androgen endogenous GnRH within the hypothalamic-pituitary overpopulation and unintended pregnancy have both replacement would be a potent testosterone agonist portal vessels and prevent it from binding to receptors The epididymis as a contraceptive target major social and personal consequences1. To date, a that does not undergo 5a-reduction to DHT but can be on the pituitary gonadotropes, thereby removing the When the maturing spermatozoa leave the testis, they large percentage of births remain undesirable with aromitized to an estrogen. In this regard, the synthetic stimulus to gonadotropin secretion. As a result, they are non-motile and unable to fertilize the oocyte in about 80-90 million unintended pregnancies androgen 7a-methyl-19-nortestosterone (MENT) has decrease steroid hormone secretion and reduced vivo. Their full maturation, including potential to occurring annually2,3. been developed. MENT cannot be 5-alpha -reduced to spermatogenesis in the male. display motility, takes place during transit through the dihydrotestosterone like steroids and may have less epididymis. The use of small molecule Many men wish to take active responsibility for family stimulating effects on the prostate gland6. Initial Spermatogenic germ cell-specific proteins pharmacological inhibitors to target epididymal planning2-7. According to some authors, the ideal male studies using MENT as an implant in men showed Several agents that inhibit the sperm-specific or proteins necessary for the sperm maturation process contraceptive should have the following characteristics2: very effective suppression of spermatogenesis with testis-specific targets have been identified and studies represent an attractive choice for non-hormonal male 1. At least as effective as the corresponding female four MENT implants6. in animals have shown promising results. To date, contraception. Despite the existence of multiple methods; however, most methods are still in experimental potential epididymal targets, the major difficulty in 2. Be acceptable by both partners; Another androgen, dimethandrolone undecanoate stages, since both toxicity and reversibility data are delivering the drugs to epididymis is represented by 3. Have quick results; (DMAU), is being developed as an oral preparation as discouraging2. Bromodomain, testis-specific (BRDT) is the blood–epididymis barrier. 4. Have not significant adverse effects, especially in well as an intramuscular injection. In the body, DMAU is a tissue-restricted, chromatin-associated protein relation to virility, libido and erectile function; converted to dimethandrolone (DMA) which is the active expressed in spermatocytes and round spermatids. The New and innovative products will come from our 5. Not affect the offspring; entity6. In in vitro studies, DMA showed dose-dependent feasibility of targeting human BRDT with acetyl-lysine knowledge of the unique physiology and genetics of 6. Be reversible with regards fertility; and androgenic and progestational activities6. The dual competitive small molecules (JQ1), which blocks the reproduction, as well as by exploiting existing and 7. Be readily available and affordable. activities on the androgen and progesterone receptors interactions of bromo and extra terminal (BET) proteins future genomics, proteomics and protein network may create a single agent capable of suppressing (BRD2, BRD3, BRD4 and BRDT) with histones has been platforms. Based on their target of action, male contraceptive spermatogenesis while maintaining androgenic activity tested16. Sperm-specific calcineurin represent a further methods are classified into three main categories2: in men1. A single-dose escalation study in healthy male potential target. Genetic disruption of either the Editorial Note: Due to space constraints the reference 1. Methods that hinder the transport of sperm in the volunteers has shown that DMAU appears to be a safe catalytic subunit (PPP3CC) or the regulatory subunit list has been omitted. Interested readers can email at female reproductive system; and well-tolerated contraceptive agent6. (PPP3R2) of sperm-specific calcineurin or short-term in [email protected] for a complete listing. 2. Methods that suppress spermatogenesis; and vivo pharmacological inhibition with calcineurin 3. Methods that disrupt the maturation or fertilizing Role of anti-androgens inhibitors (cyclosporine A or FK506) leads to complete Saturday 25 March ability of spermatozoa. Cyproterone acetate (CPA), is an antiandrogen with male infertility, with reduced sperm motility owing to 09.45-10.00: Plenary Session 2, Hot topics in progestational action. In men, CPA has been widely an inflexible midpiece during sperm maturation in the Andrology Currently, in the clinical practice, three options for used for the treatment of hypersexuality and prostatic epididymis. Inhibitors of sperm-specific calcineurin male-based contraception exist: coitus interruptus, cancer. Moderate dose cyproterone aceteta (CPA), vprobeQuarterAdEUTFinal_Layout 1 2/14/17 10:14 PM Page 1 condoms and vasectomy. However, these methods are induces progestational/anti-gonadotropin effects at acknowledged as inadequate1. the hypothalamo-pituitary level in addition to its antiandrogenic action at the testicular level10,11. The main disadvantage of condoms is the high failure Addition of cyproterone acetate to testosterone is CRYOABLATION OF THE PROSTATE rates, which in “real life” conditions concern up to considered effective to suppress spermatogenesis and 19% of couples during the first year of use2. On the is based on the hypothesis that the synergistic action other hand, usage of condoms in sexual activities of these compounds can induce a more profound offers a protection against sexually transmitted suppression of gonadotropins than either compound diseases. administered alone and that cyproterone acetate can act directly at the gonadal level to block the It should be mentioned that vasectomy is poorly stimulation effect of androgens on spermatogenesis12. reversible and male reproductive potential post- ™ vasectomy reversal depends on the technique/ Role of progestins equipment used for this procedure. The loupe- Nestorone is a potent progestin that has minimal assisted group had a 72% patency and a 28% androgen or estrogen activity6. Nestorone applied pregnancy rates, whereas the microsurgical group transdermally has been used in combination with had a 96% patency and a 40% pregnancy rates8. testosterone gel for hormonal contraception clinical • Adjustable Up To Moreover, vasectomy is associated with considerable trials in men. In a six-month study, a combined gel 5 Different Iceball Settings short and long-term complications2. Finally, concerns (testosterone 100 mg/day and nestorone 8 mg/day on have been raised regarding a potential association skin) suppressed sperm output to <1 million/ml in 89 • Precise Isotherms between vasectomy and a modestly increased % of men compared to 23 % of those who applied • Integrated Thermocouple incidence of high-grade prostate cancer2. It should be testosterone gel alone. There were minimal adverse emphasized that there is no association between effects6. • Insulated Shaft vasectomy and risk of developing aggressive prostate cancer. Men who had undergone a vasectomy were at Role of GnRH analogues or GnRH antagonists an increased risk for nonaggressive prostate cancer9. There are two different approaches to male contraception that are presently based on two distinct Consequently, male contraception remains an types of derivatives of luteinizing hormone releasing important area of research and introduction of new hormone (LH-RH), the antagonistic and agonistic forms of male contraception based on both hormonal analogues. GnRH agonistic analogs were originally and non-hormonal paradigms are wanted and developed as longer acting therapeutic agents to treat needed1. This need is becoming recognized by both GnRH deficient patients, and given chronically, they the public and private sectors1. had paradoxical inhibitory actions on LH and FSH secretion13. GnRH antagonists, block the pituitary Male hormonal contraception (MHC): Role of GnRh receptors, and have been shown to be among androgens the promising additives to testosterone14. The overall Normal sperm production is maintained by high effect of the administration of either GnRH agonists or intratesticular testosterone concentrations. Very low GnRH antagonists on male reproductive tract is the intratesticular testosterone levels result in few or no development of azoospermia. However the For more information about detectable sperm, irrespective of circulating requirement of daily or weekly injections and the high how to acquire this and other testosterone levels. MHC clinical trials began in the costs of the currently available preparations have cryoablation devices, please 1970s. The mechanisms of action of MHC- hindered the futher development of GnRH antagonists phrmaceutical agents is based on the suppression of for hormonal male contraception. visit us at booth I12. the secretion and production of the gonadotropins, both luteinizing and follicle stimulating hormone, Non-hormonal contraception methods from the pituitary by exogenous sex steroids Non-hormonal targets of contraception include sperm TM (androgens with or without progestins) or production at the testicular level, sperm maturation at 6 Endocare is a wholly-owned subsidiary gonadotropin-releasing hormone analogues . the level of epididymis and development of sperm of HealthTronics,Inc., Austin, TX 78717 TM motility. Selectivity, specificity and lesser side effects healthtronics.com The ultimate goal of MHC is to reduce the number of compared to hormonal methods make these approaches sperm in the ejaculation so drastically that it is attractive so non-hormonal contraception methods © 2017 HealthTronics, Inc. All Rights Reserved. E ENDOCARE EXTENDING LIFE EVERY DAY AND V-PROBE are trademarks of Endocare, Inc. registered in the U.S. and other countries. The HT HEALTHTRONICS logo is a trademark of HealthTronics, Inc. registered in the U.S. and other countries. impossible to achieve fertilization2. Studies using represent the most promising field of research2.

Sunday, 26 March 2017 EUT Congress News 25 Testosterone therapy in men with prostate cancer Long-term safety is uncertain but TRT is an option for well-informed patients

Dr. Peter B. Østergren Testosterone replacement therapy after curative- Department of intended treatment Urology It is intuitive to state that if the patient is cured from Herlev and Gentofte his PCa, i.e. the patient does not harbor any cancer University Hospital cells, then TRT is as safe for the man with a previous Herlev (DK) PCa as it is for any other man. However, a considerable proportion of men, undergoing curative treatment (radiotherapy or radical prostatectomy) will have residual disease. For these patients it is unknown if TRT affects time-to-metastatic disease or cancer-specific survival.

Treatment of testosterone deficiency in the ageing Only a few studies have addressed this issue and the male has gained interest as several studies have available studies have all been small with short follow- demonstrated a beneficial effect of testosterone up. One cohort study reported on 103 hypogonadal replacement therapy (TRT) especially on sexual men undergoing TRT after radical prostatectomy and health. found no increased risk of PCa recurrence compared with 49 eugonadal men7. Both men with high and The combination of testosterone deficiency and low-risk PCa were included in the analyses. A second clinical symptoms in the ageing male are referred to retrospective study of 57 hypogonadal men with mainly as late onset hypogonadism and the prevalence low risk PCa (4 men had gleason ≥ 8) treated with increases with age1. Among men 40 to 49 years of age radical prostatectomy and subsequent TRT found no the prevalence is estimated to be 0.1% using data increases in PSA during a median follow-up of 13 from the European male Ageing study (EMAS)1. This is months from TRT commencement8. Similarly, no Vials of injectable anabolic-androgenic steroids that contain natural androgens like testosterone and synthetic substances, Photo: using the definition of late onset hypogonadism: increased risk of disease recurrence has been WIkipedia/US DEA Serum total testosterone < 11.0 nmol/L and having demonstrated after radiotherapy in the currently decreased frequency of morning erection, decreased available small retrospective cohort studies9. However, frequency of sexual thoughts, and erectile TRT seems contra-intuitive after radiotherapy at least in risk of developing PCa. Similarly, TRT does not appear References dysfunction. Among men 70 to 79 years of age the men with locally advanced PCa. In this setting there is to increase the risk of developing PCa, but the 1. Wu FCW, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, prevalence increases to around 5%. Thus a sizeable substantial evidence demonstrating improved survival follow-up time of the currently available trials is too et al. Identification of Late-Onset Hypogonadism in proportion of men will, with increasing age, have when combining androgen deprivation therapy with short to convincingly answer this question. Middle-Aged and Elderly Men. N Engl J Med impaired sexual function associated with low external beam radiotherapy. Monitoring with digital rectal examination and PSA 2010;363:123–35. testosterone. measurements is therefore still recommended in men 2. Bell KJL, Del Mar C, Wright G, Dickinson J, Glasziou P. “The long-term safety of TRT commencing TRT. In patients previously treated with Prevalence of incidental prostate cancer: A systematic At the same time the risk of being diagnosed with curative intend for PCa and thought not to harbor review of autopsy studies. Int J Cancer 2015;137:1749–57. prostate cancer (PCa) increases with age. A recent is uncertain. Current evidence residual disease, TRT may be an option in the systematic review on autopsy studies estimated the does not support an association well-informed patient under close monitoring. TRT is Editorial Note: Due to space constraints the age specific prevalence of PCa for men >79 years of not recommended in patients with active PCa. reference list has been shortened. Interested age to be 59% (95% CI 48-71%)2.The timing of being between high levels of endogenous readers can email at [email protected] diagnosed with late onset hypogonadism may serum testosterone and the risk of Acknowledgement: I would like to thank Prof. Jens to request for the full list. therefore coincide with a diagnosis of PCa. Previously, Sønksen, Dr. Mikkel Fode and Dr. Christian Fuglesang an active or previous PCa diagnosis was a developing PCa.” S. Jensen from the Urological Research Unit, Herlev Saturday 25 March contraindication for starting TRT. However, the and Gentofte University Hospital, Denmark, for their Plenary Session 2, Hot Topics in Andrology available evidence challenges this paradigm and Overall, TRT has mainly been investigated after contributions and scientific sparring for this article. current recommendations state that TRT may be a curative treatment in men believed not to harbor possibility in selected well informed patients with PCa residual disease. Currently, the EAU guidelines after curative treatment. But what is the rationale for propose that TRT is restricted to men who have been this change of mind? treated for low-risk cancers, i.e. gleason grade <8, pathological pT1-2 and preoperative PSA < 10. Endogenous and exogenous testosterone and Furthermore, TRT should not be started earlier than PCa risk one year after the end of PCa treatment. Huggins and Hodges discovered the association between androgens and PCa in 1941 by observing Testosterone replacement therapy during active changes in serum phosphatases in men with PCa and disease proven bone metastases when they were androgen- Reports on TRT in men with active PCa are limited. deprived (orchiectomy or estrogen injections). Since Men diagnosed with a low-risk PCa have excellent then, serum testosterone has been investigated cancer specific survival and not all will require active extensively as a potential risk factor for PCa without treatment even after long-term follow-up. Clinical any studies convincingly demonstrating this. An trials therefore require a very large sample size and explanation may be found in the proposed saturation long-term follow-up to address safety of TRT in men model, which states that maximal androgen undergoing active surveillance. stimulation of healthy prostate- and PCa tissue already happens at low testosterone levels3. As such, Morgentaler et al. reported results from 13 men with further increases in testosterone do not affect PCa PCa undergoing TRT and found no association between development or progression. TRT and PCa progression10. Twelve of these men had gleason 6 PCa and one had a gleason 7 PCa and the A recent meta-analyses demonstrated that an increase median duration of TRT was 2.5 years. Kacker et al. in endogenous serum testosterone of 5 nmol/L was came to similar conclusions11. These authors not associated with an increased risk of PCa investigated biopsy progression in a retrospective (summary relative risk 0.99 (95% CI 0.96; 1.02))4. Most analysis of 28 men undergoing active surveillance while participants in the included trials of the analysis were receiving TRT compared with 96 testosterone deficient relatively young men under the age of 65 years and men also on active surveillance who did not receive they may not be representative of those with the TRT. There was no difference in biopsy progression highest risk of developing PCa. However, based on between the groups; in fact, a numerically larger available evidence it seems safe to state that high percentage of men in the non-TRT group had biopsy endogenous serum testosterone levels do not increase progression. While these data suggest it may be safe in the risk of PCa. In fact, studies have demonstrated that certain patients with low-risk PCa to prescribe TRT, the low serum testosterone, as opposed to high serum data are too limited to draw any conclusions. testosterone, at diagnosis is associated with more aggressive PCa5. In addition, the REDEEM trial demonstrated a 38% reduction in PCa progression for men treated with While high endogenous serum testosterone does not dutasteride, a 5α-reductase inhibitor, compared with seem to impact on the risk of developing PCa, it is placebo12. In this trial 302 men with PCa on active unknown if TRT does. Several meta-analyses have surveillance were randomized to dutasteride or been published and none of them find that TRT placebo. Dutasteride reduces the intracellular levels of increases the risk of PCa4,6. This is reassuring, but it is the highly potent androgen dihydrotestosterone. While important to note that none of the trials included in the endpoint of PCa progression, either pathological these analyses were designed to address PCa safety progression on biopsy or start of medical treatment, and none of the larger studies included had a has been criticized the data indirectly suggest a follow-up over one year. Men starting TRT must continued role of androgens in PCa progression and therefore still be counseled on the lack of evidence on support caution with TRT even in men with low-risk long-term safety. For this reason prostate monitoring PCa. with digital rectal examination and PSA measurements is recommended for all men starting Conclusion TRT. However, one can speculate that the extra The long-term safety of TRT is uncertain. Current screening with PSA may lead to over-diagnosis of evidence does not support an association between otherwise ‘insignificant’ cancers. high levels of endogenous serum testosterone and the

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Sunday, 26 March 2017 EUT Congress News 27 Today’s European Urology Events

• Introduction by Jim Catto Social Media • Source for scientific research by Stacy Loeb Course • Dissemination of content by Stacy Loeb

• Measurement & Analytics by Hendrik Borgmann

• Reputation Management by Matt Cooperberg

• Guidelines in the use of social media by Inge van Ooort

• Interaction with patients - discussion March 26th To be held in room 13 from 11.45 - 14.15

10:45 - 11:15 Male cystectomy Surgery in Motion 11:15 - 11:45 Female cystectomy

11:45 - 12:15 Ileal conduit

12:15 - 12:45 Neobladder

Peter Wiklund, Stockholm (SE), Jim Catto, Sheffield (GB), March 26th Alex Mottrie, Aalst (BE), Joan Palou, Barcelona (ES)

To be held in Room Copenhagen, North Hall (Level 1), 10.45 to 12.45

We would like to invite you to attend the Platinum Hour drinks reception to meet and greet the Editors, Authors and Reviewers of The Platinum Journal. Platinum hour Please join us daily to toast the success of European Urology, “Your” Platinum Journal.

To be held at the European Urology booth #B02. Daily from 17.00

March 24th - 26th

europeanurology.com

28 EUT Congress News Sunday, 26 March 2017 Patient selection for adjuvant treatment of high-risk NMIBC EAU Research Foundation NIMBUS Project

Today’s European Prof. Marc Colombel Adverse effects of BCG therapy are also a limiting Hôpital Edouard factor in adhering to treatment and patient selection. Herriot BCG systemic toxicity may be life-threatening and Dept. of Urology and local toxicity may cause major loss of urinary Transplantation function14. It is recommended that BCG therapy should Lyon (FR) not be used in case of active tuberculosis and immune deficiency. The immune-dependent response in these Urology Events patients is impaired and the risk of complication can have dramatic consequences even if BCG does not proliferate. Finally, patient’s adherence to treatment may be decreased for social reasons: patients in precarious situations (which is common in urothelial Bladder cancer is the ninth leading cause of cancer in carcinoma), severe disability, and old age. Regarding the world with a higher incidence in Western Europe age, current data show that in a group over 75 years Figure: NIMBUS study • Introduction by Jim Catto and North America and the eight leading cause of there is benefit from BCG therapy because the risk of cancer death1,2. While most cancers have an incidence cancer recurrence and progression is higher15. Social Media that is either increasing or decreasing, bladder cancer However, a correct geriatric evaluation is needed Guerin for primary stage T1 grade 3 bladder cancer: weekly instillations of mitomycin C followed by monthly • Source for scientific research by Stacy Loeb has a very stable epidemiology in incidence and whenever patient’s frailty is observed16. recurrence, progression and survival. J Urol, 2003. 169(1): bacillus Calmette-Guerin (BCG) or alternating BCG and mortality2. p. 96-100; discussion 100. interferon-alpha2b instillations: prospective randomised Course Although the choice of treatment is simple in the case 12. Kamat, A.M., et al., Expert consensus document: FinnBladder-4 study. Eur Urol, 2015. 68(4): p. 611-7. • Dissemination of content by Stacy Loeb Another data that does not evolve over time is the of a primary tumor, the decision to continue with Consensus statement on best practice management 19. Marttila, T., et al., Intravesical Bacillus Calmette-Guerin tumor stage at the time of the diagnosis, with adjuvant therapy may be difficult for recurrent tumors. regarding the use of intravesical immunotherapy with Versus Combination of Epirubicin and Interferon-alpha2a • Measurement & Analytics by Hendrik Borgmann superficial non-muscle invasive bladder carcinoma The severity of recurrences after BCG therapy must be BCG for bladder cancer. Nat Rev Urol, 2015. 12(4): p. in Reducing Recurrence of Non-Muscle-invasive Bladder (NMIBC) remaining the most frequent (80%) as well measured: radical cystectomy must be proposed 225-35. Carcinoma: FinnBladder-6 Study. Eur Urol, 2016. 70(2): p. compared to muscle invasive disease2. The main risk in case of early recurrences or even recurrences during 13. Herr, H.W. and S.M. Donat, A re-staging transurethral 341-7. • Reputation Management by Matt Cooperberg of NMIBC is tumor recurrence, which affects 40 to the cure of BCG therapy. Otherwise, when recurrence resection predicts early progression of superficial 20. Rexer, H., [A study of non-muscle-invasive bladder 60% of patients within five years of the primary occurs after one year, BCG must be restarted from the bladder cancer. BJU Int, 2006. 97(6): p. 1194-8. cancer therapy : Treatment of high-grade non-muscle- tumor resection. On the medico-economic level, this six-weekly induction course. 14. Lamm, D.L., et al., Incidence and treatment of invasive urothelial carcinoma of the bladder with the • Guidelines in the use of social media by Inge van Ooort translates into a high cost of care3, and impairment of complications of bacillus Calmette-Guerin intravesical standard number and dosage of intravesical BCG quality of life with a psychological impact4. Although maintenance therapy with BCG therapy is therapy in superficial bladder cancer. J Urol, 1992. 147(3): instillations versus a reduced number intravesical BCG • Interaction with patients - discussion considered the standard for patients at high-risk of p. 596-600. instillations at the standard dosage: A European The decreasing recurrence rate should therefore be recurrence, the optimal rate of instillation and the 15. Joudi, F.N., et al., The impact of age on the response of Association of Urology Research Foundation randomized March 26th the main objective in the care of the NMIBC. This duration of maintenance therapy is still debatable. patients with superficial bladder cancer to intravesical phase 3 study - NIMBUS - AB 37/10 of the AUO]. Urologe To be held in room 13 from 11.45 - 14.15 depends on the histo-prognostic group that Several BCG regimens have been tested in randomized immunotherapy. J Urol, 2006. 175(5): p. 1634-9; A, 2016. 55(4): p. 528-31. determines the rate of endoscopic monitoring and the studies, including the decrease of BCG dose or the discussion 1639-40. 21. Colombel, M., et al., The effect of ofloxacin on bacillus indication of an adjuvant treatment that includes introduction of norfloxacin to decrease side-effects17,21, 16. Herr, H.W., Age and outcome of superficial bladder calmette-guerin induced toxicity in patients with chemotherapy (MMC) or BCG intravesical therapy5. and more recently the rate of instillations and types of cancer treated with bacille Calmette-Guerin therapy. superficial bladder cancer: results of a randomized, Today, urological societies recommend adjuvant maintenance treatment18,19. The NIMBUS study, Urology, 2007. 70(1): p. 65-8. prospective, double-blind, placebo controlled, treatment by intravesical instillation for intermediate promoted by the EAU research foundation, proposes 17. Martinez-Pineiro, J.A., et al., Improving the safety of BCG multicenter study. J Urol, 2006. 176(3): p. 935-9. 10:45 - 11:15 and high-risk patients. For both groups, randomized the reduction in the number of instillations, keeping immunotherapy by dose reduction. Cooperative Group studies have confirmed the superiority of BCG therapy the general scheme of induction and one-year CUETO. Eur Urol, 1995. 27 Suppl 1: p. 13-8. Saturday 25 March Male cystectomy as long as the induction course continues with maintenance20 (Figure). The hypothesis of this study is 18. Jarvinen, R., et al., Long-term outcome of patients with Special Session, EAU Research Foundation Surgery in Motion maintenance6. The alternative in case of that the suppression of instillations of weeks 3,4,5 frequently recurrent non-muscle-invasive bladder Meeting 11:15 - 11:45 contraindication or intolerance is intravesical during induction and of week 2 during maintenance carcinoma treated with one perioperative plus four chemotherapy5,7. In the absence of maintenance with does not alter the frequency of recurrence. Female cystectomy BCG, treatments are comparable, with a risk of recurrence equivalent to 50 to 60% at two years. We believe this is an important study for several 11:45 - 12:15 reasons: a reduction in the number of instillations will Despite recommendations, it is estimated that 30% of improve tolerance and therefore treatment adherence; Ileal conduit patients will not be treated8,9. The non-prescription this treatment will be prescribed and followed by a Prostate enucleation using low energy factors of BCG are numerous; they include the greater number of patients. On the other hand, in the pulsed Thulium laser with preservation of 12:15 - 12:45 reluctance of the practitioners to carry out the current context of BCG shortage a decreased number of treatment for fear of complications, lack of confidence instillations will improve our capacity to treat a larger Neobladder in the effectiveness of BCG ; financial issues given the number of patients, and finally, this European study is ejaculation low valorization of BCG instillations. Another a good opportunity for a new cost efficacy study. Peter Wiklund, Stockholm (SE), Jim Catto, Sheffield (GB), non-prescription factor is the refusal of the patient to receive treatment that requires repeated weekly References Dr J.B Roche March 26th Alex Mottrie, Aalst (BE), Joan Palou, Barcelona (ES) instillations and exposure to serious adverse events. 1. Antoni, S., et al., Bladder Cancer Incidence and Mortality: Previous studies have shown that non-prescription or A Global Overview and Recent Trends. Eur Urol, 2017. Groupe Urologie Saint-Augustin – Bordeaux (Fr) To be held in Room Copenhagen, North Hall (Level 1), 10.45 to 12.45 discontinuation of treatment is a factor in recurrence 71(1): p. 96-108. with significant socio-economic consequences10; the 2. Miller, K.D., et al., Cancer treatment and survivorship In this session, consultant urological surgeon Jean-Baptiste Roche enucleates a cost of recurrence or progression of cancer being statistics, 2016. CA Cancer J Clin, 2016. 66(4): p. 271-89. 130g prostate using the 200W Hemera® Laser from Rocamed. much higher than the cost of bladder instillations3. 3. Yeung, C., T. Dinh, and J. Lee, The health economics of We would like to invite you to attend the Platinum Hour drinks reception to bladder cancer: an updated review of the published Harnessing the latest in laser technology, this low-energy pulsed device provides The effectiveness of adjuvant therapy for bladder literature. Pharmacoeconomics, 2014. 32(11): p. 1093-104. meet and greet the Editors, Authors and Reviewers of The Platinum Journal. carcinoma depends on a careful selection of patients 4. Heyes, S.M., et al., The relative contributions of function, excellent results in terms of post-operative urinary function, minimizing the risk of Platinum hour Please join us daily to toast the success of European Urology, “Your” and adapted timing to start bladder instillations. At perceived psychological burden and partner support to incontinence, pelvic discomfort, and storage-related symptoms. Platinum Journal. the level of a urological unit, this means that a cognitive distress in bladder cancer. Psychooncology, dedicated nurse will have a central role to informing 2016. 25(9): p. 1043-9. When combined with an anatomically precise application, this type of dissection the patient, organizing and delivering treatments, and 5. Babjuk, M., et al., EAU Guidelines on Non-Muscle- affords the maximum level of protection to the patient’s ejaculatory function, and To be held at the European Urology booth #B02. Daily from 17.00 detecting adverse events. In our case, a meticulous invasive Urothelial Carcinoma of the Bladder: Update greatly reduces the risk of recurrence. management has considerably decreased the rate of 2016. Eur Urol, 2016. treatment drop-out and grade III toxicity. 6. Oddens, J., et al., Final results of an EORTC-GU cancers The presentation gives a clear, accessible, step-by-step insight into laser-based group randomized study of maintenance bacillus prostate enucleation, showing all phases of the procedure, from dissecting the apex Patient selection Calmette-Guerin in intermediate- and high-risk Ta, T1 of the prostate through to nal morcellation. Apart from patients with allergies or with a papillary carcinoma of the urinary bladder: one-third contraindication to BCG therapy (persistent hematuria, dose versus full dose and 1 year versus 3 years of active tuberculosis, history of complication with BCG maintenance. Eur Urol, 2013. 63(3): p. 462-72. therapy) and for whom conservative treatments must 7. Lamm, D.L., et al., Maintenance bacillus Calmette-Guerin Pre-recorded video Session be adapted, patients at very high-risk of progression immunotherapy for recurrent TA, T1 and carcinoma in must be rapidly identified and oriented towards situ transitional cell carcinoma of the bladder: a March, 25th March 24th - 26th radical treatment11. Criteria include the size (> 3cm), randomized Southwest Oncology Group Study. J Urol, the multifocality, diffuse carcinoma in situ, lympho 2000. 163(4): p. 1124-9. vascular invasion and finally tumors that progress 8. Snyder, C., et al., Patterns of care for the treatment of 16:55 during BCG12.This justifies that all high-risk tumors bladder cancer. J Urol, 2003. 169(5): p. 1697-701. including those not invading the basal membrane 9. Witjes, J.A., et al., Current clinical practice gaps in the eURO Auditorium (Level 0) (pTa) have endoscopic and biopsy control before treatment of intermediate- and high-risk non-muscle- Procedure performed with receiving a course of bladder instillations. invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guerin (BCG): results of an 200W Hemera® Thulium Rocamed Laser In a recent retrospective study, 30% of high grade international individual patient data survey (IPDS). BJU tumors (Ta and T1) had a positive histology at the Int, 2013. 112(6): p. 742-50. second TUR increasing the risk of early recurrence and 10. Takeda, T., et al., Discontinuance of bacille Calmette- stage progression despite intravesical therapy13. Guerin instillation therapy for nonmuscle-invasive Here again, in daily practice, there is great reluctance bladder cancer has negative effect on tumor recurrence. europeanurology.com to perform a second-look TUR; considering that a Urology, 2009. 73(6): p. 1318-22. Visit Us Booth I26 visually complete resection is a fair criteria or because 11. Shahin, O., et al., A retrospective analysis of 153 patients of the patient’s refusal of a new surgical procedure. treated with or without intravesical bacillus Calmette-

Sunday, 26 March 2017 EUT Congress News 29 Overcoming obstacles in patient communication Things patients do not ask or do not dare to ask their doctors

Ms. Corrine Tillier Patients are satisfied when they estimate the length of 7 Netherlands Cancer the visit > 20 minutes . In the institute where I work, Institute the visit length for new patients is 20 minutes for the Antoni Van urologist and for a follow-up visit, 10 minutes. When Leeuwenhoek patients complain over the fact that the urologist was Hospital too busy or had to rush, it concerns usually follow-up Dept. of Urology and routine visits. They indicate that the time they Amsterdam (NL) have is too short for asking questions. I am convinced that the solution is not in giving more time for each patients but in making consultations more efficient, thanks to a time management course for doctors.

Communication between patients and health There are some disturbing factors as a phone call to professionals is nowadays one of the most important the urologist during the consultation. It is very aspects of the support given to the patients and annoying for the patient when the conversation with contributes to the high quality of healthcare. the urologist is interrupted by a phone call. Another disturbing factor could be the attitude of some This fact has led to the introduction of courses at physicians during the consultation. Some physicians medical schools and universities to improve the are so busy to type in the digital file that there is no communication skills of medical students. Future eye contact with the patient. This attitude doesn’t physicians learn techniques in listening, explaining, encourage patients to ask questions. questioning, counseling, and motivating. Compared to previous decades, patients today are less passive than In addition, there are things patients don’t dare to ask 50 years ago. They want to be informed, they play an the doctor. It concerns psychological needs or the use active role in their health process, they use the of complementary and alternative therapies. Patients internet to search medical information about their very often think that doctors are disinterested about A doctor still has to make efforts to improve tcommunication with the patient by encouraging the patient to ask questions symptoms, illness, etc. But still there are things that psychological matters and only talk about medical patients do not ask or do not dare to ask their doctors. matters. Patients talk easily with the nurse about The question is not only what they do not ask the non-medical matters. Nurses play a unique role by 5. Andersson SO, Mattsson B. Length of consultations in 9. Eisenberg DM, Kessler RC, Foster C, et al. Unconventional doctor, but why. monitoring patients and can provide psycho-social general practice in Sweden: views of doctors and medicine in the United States: prevalence, costs, and support in adult oncology patients8. More and more patients. Fam Pract. 1989;6:130–4. patterns of use. N Engl J Med. 1993;328(4):246–252. As a clinical nurse specialist, I am a contact person for hospitals or institutions have understood this unique 6. Watanabe J, Schulman K, Sulmasy D. The changing 10. Sanders K., Moran Z., Shi Z. , Paul R., Greenlee H. patients. It happens very often (almost daily) that role of nurses and provide nurse consultations beside times: patient visit duration with internists, 1980-1996 Natural Products for Cancer Prevention: Clinical Update patients call me the day after the consultation with the doctor consultations. [abstract]. Paper presented at: 1998 National Research 2016. Seminars in Oncology Nursing, Vol 32, No 3 the urologist to ask things they didn’t ask to the Service Award (NRSA) Trainees’ Research Conference July (August), 2016: pp 215-240 doctor. When I question them about the reason not A bridge 20, 1998 Washington, DC 11. Quilliam, Susan (April 2011). “’The Cringe Report’: why asking the doctor, I hear several reasons, such as: Nurses are a privileged interlocutor. Patients often do 7. Chen-Tan Lin, MD; Gail A. Albertson, MD; Lisa M. patients don’t dare ask questions, and what we can do not dare to say that they use natural products or Schilling, MD; et al. Is Patients’ Perception of Time Spent about that”. J Fam Plann Reprod Health • After the consultation with the urologist the complementary therapies to their doctor, but dare to With the Physician a Determinant of Ambulatory Patient patient realized that he/she should have asked tell the nurse. Seventy five percent of cancer patients Satisfaction? Arch.Intern.Med/Vol 161, June 11, 2001 Friday 24 March more details. It could be about the diagnosis, using complementary and alternative medicine (CAM) 8. Melanie Jane Legg. What is psychosocial care and how Special Session Patient Information, EAU Patient treatment or about results of the pathology report; do not inform the physician about their CAM use9. It can nurses better provide it to adult oncology patients? Information Project: Setting standards in • Patient’s perception of the physician’s being could have some serious consequences, as we know Australian Journal of Advanced Nursing Volume 28 cooperation and care rushed or busy; that that some herbal remedies or vitamins interact Number 3, 2011 • The information given by the urologist is with traditional medications. For example, there are misinterpreted by the patient; possible harmful interactions between vitamin C and • A medical treatment or surgery was proposed to anticoagulants and contraceptives. Furthermore, the the patient but the consequences or side effects physician and the nurse should know the scientific of the treatment were not clear to the patient. In evidence of natural products and vitamins10. Please join us for a casual case of minor surgery or prostate biopsies, the procedure and the possible complications were Other factors which can influence the patient not Q&A session to Meet the vague to the patient; and asking the doctor are: Expert on phi featuring: • The patient didn’t understand/forgot the Want to information given by the urologist about a new • Uncomfortable or intimate subjects in the prescription. presence of a conjoint or accompanying person, Dr Massimo Lazzeri and learn more Istituto Clinico Humanitas, Milan, Italy Patients remember about 20% of the verbal medical • The patient didn’t understand what the doctor information the physician gives1. Different reasons said and didn’t dare to ask more explanations. Saturday, March 25 could explain this issue: the physician use medical about the 10:00-11:00 & 15:30-16:30 terms the patient do not understand, the mode of Patients come very often to the doctor with an information given (spoken or written) and factors attendant. The accompanying person gives support to 2 Dr. Vincent Gnanapragasam related to the patient such as low level of education . the patient during the consultation, can ask questions Addenbrookes Hospital, Cambridge, UK But since patients are more confident and become but another person present can influence the phi more active or involved in their own health issues, the communication between the patient and the doctor. (Prostate Health Index) Sunday, March 26 physician gives more and more information. Patients then don’t dare to ask the doctor particularly 10:00-11:00 & 15:30-16:30 about sexual issues11 or uncomfortable subjects. The patient cannot assimilate the great amount of information given during the consultation. It is also Finally, without paying attention the doctor can use test? difficult for the patient to have an objective view of a medical jargon the patient does not understand. It situation that involves him directly. Emotion and happens that the patient doesn’t dare to ask what the stress play an important role during the consultation doctor means. As healthcare providers we have to be and the level of distress increases if the physician careful to use vocabulary the patient can understand. makes a worried impression; hence patients will remember less information3. In conclusion, the doctor still has to make efforts to improve the communication with the patient to Older adults have more difficulty to encode and encourage the patient to ask questions. At the end of remember medical information and their memory the consultation, it is often sufficient to just ask Dive into the also fades more rapidly. We have to consider this patients if everything was clear, or if they have other given the fact that majority of urology patients are questions. With the permission of the physician the older than 70 years. patient can record the consultation. Doctors and history of Annual nurses have complementary roles with regards the Consultation hours communication with patients, and they can both EAU Congresses! To help patients to remember the information, we can motivate patients to ask questions. invite the patient to record the conversation with the doctor, which is now very easy with a mobile phone. References Or the physician can give written information to complete or support the spoken information given. 1. Kessels R.P.C. Patients’ memory for medical information. www.eaucongresshistory.org Patients often indicate that the reason for them not J R Soc Medv.96(5); 2003 MayPMC539473 asking the urologist is the impression they have that 2. Ley P. Memory for medical information. Br J Soc Clin the physician is too busy, or there is the lack of Psychol 1979;18: 245-55 consultation’s time. The average visit length for 3. Shapiro DE, Boggs SR, Melamed BG, Graham-Pole J. The general practitioners is between five to eight minutes4 effect of varied physician affect on recall, anxiety, and in Great Britain and 10 to 20 minutes in Sweden5. perceptions in women at risk for breast cancer: an analogue study. Health Psychol 1992;11: 61-6 Visit length can vary by specialist. A new patient visit 4. Groenewegen PP, Hutten JBF. Workload and job YEARS AWARDS PRESIDENTS HIGHLIGHTS with an internist takes between 29 and 17 minutes satisfaction among general practitioners: a review of the and a follow-up visit between 19 and 16 minutes6. literature. Soc Sci Med. 1991;32:1111–9.

30 EUT Congress News Sunday, 26 March 2017 Current issues in urological nursing care Changes in urological nursing include diversity in roles and practices

Mrs. Paula Allchorne benefits as a result. There is also increasing evidence EAUN Board member that nurses bring a different dimension to patient care Guy’s and St Thomas’ that other clinicians are unable to provide, as nurses NHS Foundation are more holistic in their approach to a patient’s Trust problems. Dept. of Urology London (GB) This is amply demonstrated in a UK initiative, discussed in the session which prepares patients better for survival after cancer treatment. The “Recovery Package” aims to identify all the patients’ needs that develop either as a result of the cancer or as sequelae of the cancer treatment that has taken Nursing is evolving at an accelerated pace. In some place. These holistic needs are assessed by the countries this is happening more quickly than others specialist cancer nurses during various stages of a and the EAUN is making sure that it can encourage patient’s treatment pathway and then are addressed and support advanced nursing practitioners at the in a timely manner, allowing earlier discharge to forefront of change as well as the many urological primary care. nurses undertaking more traditional roles. National concerns It is now seen in many countries as ‘normal’ for Most of us have our own national concerns with urology nurse specialists to undertake advanced regards to healthcare; economic constraints, practices in diagnostics such as urodynamics, flexible workforce shortages and an increasing demand in cystoscopies and transrectal and transperineal biopsy. patient activity. Assigning nurses in advanced roles As well as developing nurse-led follow-up in are cost-efficient, effective, patient-centred and outpatient clinics, and treating patients using flexible provide much needed continuity of care to patients. laser cystoscopy, intravesical therapy and port But nurses undertaking these roles still need the Majority of healthcare models endorse collaborative approaches to delivering care to patients such as multi-disciplinary teams insertion in laparoscopy. support of urological colleagues and work in a department that encourages innovation and the This collaborative session at the EAUN conference will attainment of high standards. value the access to the published EAUN guidelines and European countries. Encouraging a nurse from each describe nursing developments in many areas of the EAUN conference. At the EAU Square in the department to join the EAUN would allow the urology using presentations from the British Realising the important contribution that nursing Exhibition (EAUN counter) more information is standardisation of urological nursing within the EU Association of Urology Nursing (BAUN) in the UK, makes to urology, the Secretary General of the EAU available as well as instant membership registration. and nursing innovation to be shared more easily and Denmark and the Netherlands. and the EAUN launched the Plus One campaign to more quickly through the regions. We welcome you to promote membership of the EAUN; an initiative to Many years ago, when the fledgling EAU was the collaborative EAUN-BAUN session to get a The majority of healthcare models endorse encourage every department across Europe to evolving, the standards of urology across Europe were glimpse of what are the Current issues in Urological collaborative approaches to delivering care to patients support urological nursing in their locality by very varied. But slowly by exemplary leadership, by Nursing and what is achievable with a bit of vision, and multidisciplinary team-working is accepted as the sponsoring at least one urology nurse in their setting attainable standards and by publishing support, enthusiasm and hard work. gold standard in the majority of specialities. department to become a member of the EAUN. evidence-based guidance, urological surgery has grown from strength to strength across all countries Sunday 26 March As each different discipline (surgeons, pathologists, The main reason behind this was that although the of Europe. 16.30 – 17.30: 18th International EAUN Meeting, radiologists, nurses and allied healthcare EAU membership across Europe is high the nursing Thematic Session 11: Joint EAUN-BAUN session: professionals) bring its own unique skill set, the effect membership of the EAUN in many countries is quite Urology nursing, however, is in a similar situation to Current issues in urological care of each individual is cumulative, so that ‘The whole is low in comparison. The membership fee is exceedingly urological surgery decades ago. There often appears Location: Room 1 (Level 3) greater than the sum of its parts’ and the patient good value at only 30 euros a year and nurses greatly to be diversity in roles and practice in different

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Sunday, 26 March 2017 EUT Congress News 31 32 EUT Congress News Sunday, 26 March 2017