EUT Congress News - Sunday 26 March by European Association of Urology (EAU)

European Urology Today

EUT Congress News

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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 ties across borders

‘Sleepless Nights’ session offers insights on legal pitfalls

By Erika de Groot By Joel Vega

dock’ as he presented his arguments for performing a renal tumour biopsy (RTB). Leigh, who specializes in medical negligence, pressed Bex on his rationale for RTB, to which Bex conceded that there are no reliable approaches for diagnosing an oncocytoma before surgery.

Insights into the legal pitfalls and challenges of offering balanced and optimal treatments to kidney cancer patients were explored and debated in Plenary Session 1, a newly introduced format where a legal veteran subjected three urologists to intense cross-examination regarding their surgical strategies. In a well-attended and applauded session, expert medical litigation lawyer Bertie Leigh (GB) put Professors Alex Bex (NL), Karim Bensalah (FR) and Vsevolod Matveev (RU) under intense questioning to elicit insights into the crucial decisions they made for kidney cancer patients. ‘’Each of these cases, in different ways, raises questions about the conventional ways of treating patients. As a lawyer I am particularly concerned about consent counseling and how patients are handled because these are very difficult positions for urologists to take,” said Leigh, as he stressed that

Leigh emphasized that despite the low statistics on risks and complications, patients view the matter in an altogether different way. The loss of a kidney or suffering the consequences of complications is traumatic for patients. Prof. Karim Bensalah faces intense cross-examination by lawyer Bertie Leigh (seated) as Mr. Tim O’Brien moderates

doctors should be “recording their uncertainties in the way in which they communicate with patients.” Mr. Tim O’Brien, as moderator, presented three cases with the first case involving a small renal mass (less than 3cm) in an elderly patient. Bex was first ‘in the

“Doctors should offer patients alternatives which are realistic to them, all of the options available to them, and must relay the information in a form that patients can understand,” added Leigh. “You must make records of the advice you give them. Doctors are diligent in recording the results of their investigations, but when it comes to recording their advice, they write nothing. If it’s not written down, it won’t stand up in court,” said Leigh.

Cutting-edge techniques at Live Surgery ESUT, ERUS, EULIS pull out all the stops in Live Surgery session By Joel Vega

A five-member panel composed of Mr. Chris Anderson (GB), Dr. Alberto Breda (ES), Dr. Rafael Sanchez-Salas (FR), Prof. Peter Tenke (HU), and Dr. Patricia Zondervan (NL) gave additional commentary and asked the surgeons to explain the preparations and steps they took for the crucial surgical maneuvers.

Maintaining the EAU’s tradition of presenting Live Surgery sessions, yesterday three section offices presented the newest techniques in robotic and minimally invasive surgeries used in aggressive prostate, bladder and kidney diseases as well as stone treatment. The EAU Section of Uro-Technology (ESUT) collaborated with the EAU Robotic Urology Section (ERUS) and the EAU Section of Urolithiasis (EULIS) to organise a full-day series of simultaneous surgeries and pre-recorded videos that showed advances in surgical techniques and approaches including as, amongst many others, 3D-4K nerve-sparing radical prostatectomy (RP), bipolar bladder tumour resection with photodynamic diagnosis (PDD), and robotic neobladder reconstruction. “This complex programme aims to show the current advances in imaging and the new instruments and

Live Surgery audience use 3D glasses to follow the wide-screen transmission from Guy’s Hospital

techniques that are necessary,” said ESUT chair Prof. Evangelos Liatsikos. With the live broadcasts transmitted directly from Guy’s Hospital in London to the eURO Auditorium at the congress venue, the audience were guided by actual commentary from the participating surgeons.

Professors Alexander Haese (DE), Jens-Uwe Stolzenburg (DE) and Peter Wiklund (SE) were the first three surgeries broadcasted from Guy’s Hospital with Haese demonstrating his technique in robotic neurosafe RP. Stolzenburg took the audience through the crucial steps in performing a nerve-sparing approach that involved meticulous dissection. Despite intermittent disruptions in satellite connections the panel provided insightful commentary and audience questions were also directed to the surgeons.

The EAU’s engagement with the European Union (EU), the different EAU Offices’ new projects, and the announcement of newly elected officers topped the agenda yesterday at the annual General Assembly. EAU Members As of March 2017, there are a total of 15,409 EAU members, the majority of whom are active members (7,397), alongside 3,608 junior members, 2,441 active international members, and 531 junior international members. New appointments New roles were announced during the meeting. Prof. Jens Sønksen (DK) was elected as the new EAU Adjunct Chapple discusses EAU-EU engagement Secretary General – Clinical Practice with 92% 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 through the EAU Junior Ambassadors.” Other appointments included Prof. Anders Bjartell (SE), a member of the Guidelines Office Board who took on the role of EAU Research Foundation Chairman, succeeding Prof. Peter Mulders (NL). Assoc. Prof. Christian Gratzke (DE), Associate Editor of European Urology and member of the EAU Guidelines panel on BPH/male LUTS, is the new Editor-in-Chief of European Urology Focus. Prof. Alberto Briganti (IT), member of the Scientific Congress Office and the EAU Guidelines Office Board, is the Editor-in-Chief of the new publication European Urology Oncology. EU engagement The EAU cited stronger links with Members of the European Parliament (MEPs) and other EU partners via the advisory tasks it has fulfilled. EAU Secretary General Prof. Chris Chapple (GB) said the EAU raises not only its own profile but also that of urology, as well as building relationships, by providing scientific advice to MEPs and the European Commission through initiatives such as the EAU white paper on Prostate Cancer and the strategic relationships with the EU Joint Action on Cancer Control (CANCON) and MEPs Against Cancer (MAC).

EAU-RF thanks Mulders By Loek Keizer Saturday afternoon saw the EAU Research Foundation hold its Special Session, giving delegates an update on currently-running research projects, trials and registries. The session also featured a presentation by Dr. Alvaro Aytes (ES), the EAU-RF’s newest career track fellow. Prof. Peter Mulders (NL) chaired the session, having been succeeded as chairman of the EAU-RF by Prof. Anders Bjartell (SE) at the General Assembly earlier that morning. Looking back at his eight years as Chairman of the EAU-RF, Mulders reflected on the uniqueness of the Foundation. “The EAU is the only professional association with its own clinical trial office. In that respect, we’ve had a lot of opportunities for conducting trials in prostate, bladder and kidney cancer.” All ongoing EAU-RF projects were presented Sunday, 26 March 2017

at the session. Mulders pointed to NIMBUS as one of the studies that generated a huge international database, which will allow the foundation to present data for many years to come. “A real achievement of the Foundation is the establishment of the career track fellowship for non-urological researchers. This helps us attract such researchers to the EAU to work on urological projects.” “I’ve always said that the Research Foundation depends on its activities. I will continue to advise the EAU-RF and should I initiate any new projects in the future that could be facilitated by the EAU-RF, that would of course be my first choice.” For further coverage of projects of the EAU-RF, See pages 20 and 29

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MEDICAL

EUT Congress News

Today’s Industry Sessions

A long history of British contributions to urology

Industry sessions and Workshop, all starting at 17:45 hrs

EAU History Office explores early developments

Navigating the world of OAB: Lightening the load, staying on track ASTELLAS - Room Copenhagen, North Hall (Level 1) Checkpoint inhibitors: Summary of latest data in GU cancers BRISTOL-MYERS SQUIBB - Room London, North Hall (Level 1) A multidisciplinary forum: How can we improve management of hormone-sensitive prostate cancer? FERRING PHARMACEUTICALS - Room Vienna, North Hall (Level 1) Overcoming obstacles in medical management of BPH patients GSK - Room Berlin, North Hall (Level 1) Multidisciplinary perspectives on managing bladder cancer: Hope is on the horizon PEERVOICE - Room Stockholm, North Hall (Level 1) Novelty in premature ejaculation RECORDATI SPA - Room Amsterdam, North Hall (Level 1) New light on prostate cancer STEBA BIOTECH - Room 7, Capital Suite (Level 3) Revealing Moses: Revolutionary new Holmium technology Industry workshop by LUMENIS - Room 9, Capital Suite (level 3)

European Urology Today Editor-in-Chief Prof. M. Wirth, Dresden (DE) Section Editors Prof. T. E. Bjerklund Johansen, Oslo (NO) Mr. Ph. Cornford, Liverpool (GB) Prof. O. Hakenberg, Rostock (DE) Prof. P. Meria, Paris (FR) Dr. G. Ploussard, Paris (FR) Prof. J. Rassweiler, Heilbronn (DE) Prof. O. Reich, Munich (DE) Dr. F. Sanguedolce, London (GB) Dr. S. Sarikaya, Ankara (TR)

By Loek Keizer

Truly international While intending to serve as an overview of British urology, British history being what it is made the morning session more international than one might initially expect. The profiles of the 19th and early 20th century urological surgeons created a veritable atlas of the once global British Empire.

Prof. Paul Weindling presenting detailed new research on urologists and other medical professionals who were forced to flee to the UK when the Nazi party came to power in Europe.

being born on the Indian subcontinent, serving within the Empire or, in the case of Thompson, treating 19th century global high society.

Britain and European Refugees The second part of the session focused on the Mr. Michael Dinneen (GB) presented a detailed publication Urology Under the Swastika, the end of a biography of Sir Peter Freyer (1851-1921), beginning “seventeen-year process” for its editors Prof. Dirk Schultheiss (DE) and Dr. Friedrich Moll (DE). with his childhood and education in Ireland shortly after the Great Famine. Freyer signed up for the Schultheiss gave an introduction to the topic, as well Indian Medical Service (IMS), serving in India for as an overview of the book’s major findings. He introduced one of its contributors, medical historian many years before joining the staff at St. Peter’s Hospital for the Stone in London in 1897. He pioneered Prof. Paul Weindling (GB), who proceeded to explain the role Britain had in accepting medical his eponymous technique for total enucleation of the professionals (including urologists) who escaped the prostate, popularizing its implementation. emergence of National Socialism on the continent. As war broke out in Europe in 1914, Freyer rejoined Between 1930 and 1945, 6000 medical professionals the IMS, having remained fluent in Hindustani from (of which 4258 were physicians) entered the United his earlier stretch with the service. Freyer was Kingdom, the largest single group coming from knighted in 1917, and in 1920, he was elected the first president of the section of urology of the Royal Society Poland. Other sizeable groups were Germans, of Medicine. This cemented his reputation as “the first Austrians (including Sigmund Freud and his family and staff in 1938) and Czechoslovakians. leader of British Urology”. Freyer passed away in 1921, and was buried in Clifden, Ireland. Mr. Dinneen showed a picture of Freyer’s gravestone, which is due to be restored in 2021 for the centenary of his death. Freyer’s was just one of the biographies presented at the session, which had serious international connections with several of the profiled urologists

Founding Editor Prof. F. Debruyne, Nijmegen (NL)

A new study, coming from the Dutch part of the European Randomised study for the Screening of Prostate Cancer (ERSPC) has found that MRI-based screening can reduce overdiagnosis by 50% and reduce unnecessary biopsies by 70%, potentially changing the equation for prostate cancer (PCa) screening.

Many of the biggest names in the history of British Urology echoed through the ExCel London venue yesterday morning, as their contributions to the field were presented and analysed from a historic perspective. Sir Henry Thompson, Sir Peter Freyer and Terrence Millin were extensively eulogized, as were more recently departed pioneers like John Blandy and John Fitzpatrick. Thanks to many contributions from historicallyminded BAUS members, the History Office’s annual thematic session was expanded into a three-hour “Special Session” on Saturday morning. In addition to presenting some highlights from local (insofar as the British Empire can be considered “local”) urology, the session also gave time to two contributors to this year’s Congress Gift: Urology Under the Swastika.

MRI: A game changer in PCa screening?

Many entered Britain as a first step to emigrating to the United States or beyond, but several “concessionary schemes” were introduced to re-qualify physicians, nurses and dentists. These immigrants were able to find employment after the establishment of the National Health Service shortly after the Second World War, as there was a demand for qualified specialists.

This work, the first to confirm that the use of MRI in a population-based screening setting may be viable, was presented at this congress. Dutch researchers have compared the outcomes from the TRUS-biopsy approach with an MRI-based screening approach in a group of heavily pre-screened men. They took 6-core TRUS-biopsy samples from 177 men, and 12-core TRUS-biopsy samples from 158 men: the 158 men who received a 12-core TRUS-biopsy had first been given an MRI scan. If the MRI showed a suspicious area, then further MRI- targeted biopsy samples were taken. “This could change the balance of the equation” said lead author Dr. Arnout Alberts (Erasmus Medical Centre, Rotterdam). “It means that population-based prostate cancer screening with MRI instead of TRUS-biopsy has a significantly better risk/benefit ratio and could offer real benefits to men at risk of prostate cancer. Now we have shown that MRI screening has potential, we need confirmatory studies in a true screening setting to allow us to get a better handle on the statistics and costs.” The researchers found that the 6-core TRUS-biopsy, 12-core TRUS biopsy and MRI-targeted biopsy method all had a similar detection rate for more dangerous (high-grade) cancers; however using the MRI-targeted biopsy method the majority of men (70%) did not need a biopsy at all as the MRI scan had shown no suspicious areas. In addition to potentially eliminating 70% of biopsies, the MRI-targeted biopsy only approach meant that the number of men who were overdiagnosed with non-aggressive cancer was reduced by half. Alberts said MRI screening for prostate cancer will be more expensive than the currently used approach, but introducing mammography screening a generation ago was also expensive. “ We have to decide if it’s worthwhile. In this study we achieved a 70% reduction in biopsies and a 50% reduction in overdiagnosis of insignificant prostate cancer: if larger studies can reproduce these results it will mean a considerable saving further down the line,” explained Alberts.

Editing and Coordination J. Vega

Breakthroughs in andrology

Onsite Reporting and Editing E. de Groot L. Keizer T. Parkhill J. Vega

Plenary Session 2 explores ‘hot’ topics in andrology

Communications and Promotion J. Bloemberg M. van Gurp I. Moerkerken P. Pigmans

By Erika de Groot New insights into the gold standards, developments and controversies within andrology were deliberated today in the state-of-the-art lectures of the “Hot topics in andrology” session chaired by Prof. Dr. Francesco Montorsi (IT) and Prof. Hein Van Poppel (BE).

Advertising L. Schreuder

EUT Editorial Office PO Box 30016 6803 AA Arnhem The Netherlands T +31 (0)26 389 0680 F +31 (0)26 389 0674 communications@uroweb.org Disclaimer No part of European Urology Today (EUT) may be reproduced without written permission from the Communication Office of the European Association of Urology (EAU). The comments of the reviewers are their own and not necessarily endorsed by the EAU or the Editorial Board. The EAU does not accept liability for the consequences of inaccurate statements or data. Despite of utmost care the EAU and their Communication Office cannot accept responsibility for errors or omissions.

EUT Congress News

Colophon

Lay-Out/Printing D. Blom G. Smit

The Plenary Session commenced with the presentation of Dr. Peter B. Østergren (DK) on testosterone therapy in men with prostate cancer (PCa). He stated that high endogenous T levels are not associated with an increased risk of PCa, and that testosterone replacement therapy (TRT) is not associated with an increased risk of aggressive PCa but may increase the risk of being diagnosed with low-risk PCa due to more vigorous monitoring. He added that TRT appears safe in men curatively treated for low-risk PCa but there are only few available studies with small sample sizes. Østergren emphasised that TRT is not recommended in men with untreated PCa.

Mr. David John Ralph (GB) discussed that as priapism duration increases, the success for conservative therapy decreases and surgical management increases. Early insertion of a penile prosthesis in priapism maintains penile length, aids easy insertion, and treats the condition. Alternatively, late insertion of penile prosthesis result in penile shortening and difficult implantation. Ralph mentioned the pre-requisites of penile implants for patients with Peyronie’s disease such as refractory erectile dysfunction, distal flaccidity, significant hinge effect, ossified/calcified plaque or, for example, those who cannot have a grafting procedure due to vascular disease

Dr. Ulla N. Joensen (DK) stated that male reproductive development depends on normal early feotal testicular function. She said normal germ cell development in feotal life determines later reproductive capacity, and that timing is everything with reference to the masculinization programming window. Joensen said translation to clinical recommendations of the According to Dr. Yacov Reisman (NL), large multicentre, advancements in understanding how these processes well-conducted trials are essential for establishing work are difficult because this is a system that cannot evidence to facilitate a standard algorithm to approach be interventionally studied. scrotal pain. He said that reversible causes should be ruled out before any treatment, and testicles should be Men should not be considered infertile until they have spared whenever possible. A multidisciplinary a microTESE and are found to be infertile according to approach that includes psychological, sexual and Mr. Majid Shabbir (GB). MicroTESE should be the gold physical therapy modalities, should be considered. standard survival sperm retrieval (SSR) technique for

“Normal germ cell development in fetal life determines later reproductive capacity”

patients with irreversible non-obstructive azoospermia (NOA). Compared to the conventional TESE, microTESE almost doubles the chance of successful SSR. Dr. Ferdinando Fusco (IT) discussed that male contraception remains an important area of research, and introduction of new forms of male contraception based on both hormonal and non-hormonal paradigms are wanted and needed. Sunday, 26 March 2017

Imaging and prostate cancer Imaging technologies have still some way to go Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1 By Tom Parkhill At the 2015 conference we asked, “Is the train of prostate imaging gathering speed?” Well now we can say it is not only gathering speed, it is roaring ahead”. With these words, Prof. Jochen Walz introduced the session addressing the hottest topics in urological imaging “How to get the most out of prostate cancer imaging” organized by the EAU Section of Urological Imaging (ESUI) in cooperation with the EAU Section of Urological Research (ESUR) and the European Society of Nuclear Medicine (EANM).

ESUI, Prof Georg Salomon (DE), who will take the group forward to the winter meeting in Barcelona.

still need to study the ability of images to rule out significant diseases”.

Congress highlights . . . . . . . . . . . . . . . . . . 2/3

Prof. Nicolas Mottet (FR), Chairman of the EAU Prostate Cancer Guidelines Panel confirmed the evidence base. “Can we use an MRI to rule out biopsy, the answer is probably ‘no’, certainly not yet”. He stated that imaging is only useful if it can change the outcome, but noted that we don’t yet have clear data to justify routine MRI use; and it still needs to be used in conjunction with other diagnostic techniques – it can add information, rather than replace other techniques.

Walz summed up the session: “We learned that we probably get less benefit than we should for the money which we spend. The technology should only be used if it changes how we treat the patient, not just because we have the technology. Some would like to do MRI before any biopsy, as happens with mammography, but the comparison isn’t completely valid. In France for example, a mammography costs around €80, and whereas an MRI costs €350. In addition, the infrastructure needed is still significantly different.

Robot-assisted RP: Managing inguinal hernias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

But despite this progress, the session concluded with considerable caution about the distance yet to be travelled before imaging becomes routine.

Mottet noted that just about all the published reports come from expert centres, with high levels of expertise and strong teams, so it is not yet a routine technique.

The meeting heard that the growth in the field has been impressive, with 1400 published papers in the last year. Walz also introduced the new chair of the

Prof. Alberto Briganti (IT) confirmed the cautious approach “Imaging is here to stay, and we are looking forward to the next developments, but we

Update on hereditary prostate cancer. . . . . . . 4

Is every man fertile?. . . . . . . . . . . . . . . . . . . . 7 Photodynamic therapy for prostate cancer. . . 8 Benign Prostatic Enlargement (BPE). . . . . . . . 9 PS3: Debate on low-risk BCa . . . . . . . . . . . . 10 Non-muscle invasive bladder cancer (NMIBC). . . . . . . . . . . . . . . . . . . . . . . . 11

Do not miss this today:

Clinical Guidelines. . . . . . . . . . . . . . . . . . . . 12

Posters & Videos - The Prize Winners

Biomarkers for immune checkpoint inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Special presentations on stage at the e-Poster Area at 11.00 hrs.

Filling the GAP. . . . . . . . . . . . . . . . . . . . . . . 13

Ureterocutaneostomy. . . . . . . . . . . . . . . . . . 15 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: I. Ahmad (Glasgow, United Kingdom)

Best Paper on Clinical Research: J. Steinestel (Muenster, Germany)

First Prize Best Abstract (Oncology): R. Seiler (Bern, Switzerland)

First Prize Best Abstract (Non-Oncology): H. Langenhuijsen (Nijmegen, The Netherlands)

Second Prize Best Abstract (Non-Oncology): M. Ilg (Chelmsford, United Kingdom)

Third Prize Best Abstract (Oncology): N. Fossati (Milan, Italy)

Best Scientific Paper Fundamental Research in European Urology: A. Ross (Baltimore, United States of America) Sponsored by ELSEVIER

Best Scientific Paper Clinical Research in European Urology: J. Weinreb (New Haven, United States of America) and J. Barentsz (Nijmegen, The Netherlands) Sponsored by ELSEVIER

Best Scientific Paper in European Urology: E. Baco (Oslo, Norway) Sponsored by ELSEVIER

Best Scientific Paper on Robotic Surgery in European Urology: K. Ghani (Ann Arbor, United States of America) Sponsored by VATTIKUTI FOUNDATION

Best Booth Award 2017: STEBA BIOTECH Bertrand Gaillac MD, Prof. Chris Chapple, Dr. Stefan Spaniol, John Rewcastle PhD, Silvestre de Lima Neto, Prof. Avigdor Scherz

Sunday, 26 March 2017

EUT Congress News

Update on hereditary prostate cancer Family history- a major risk factor for prostate cancer development Dr. Patrick C. Walsh University Distinguished Service Professor Emeritus The James Buchanan Brady Urological Institute Baltimore, Maryland (USA)

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

Genome-wide association studies to search for complex disease Next, investigators became excited about the influence of SNPs, and the possibility that a large number with each having a very small effect would be the answer. These studies led to the successful identification of over 100 SNPs associated with prostate cancer risk. 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 highwith 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 The next step was to determine whether this familial prostate cancer. However, it was only within the last 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 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 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 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? patients with advanced RCC after prior therapy in adults Two major genetic influences: Monogenetic and No one knows for sure, but based on the recent 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 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, Uxbridge UB8 1DH, United Kingdom. Tel: 0800-731-1736. contrast, complex disease is caused by common genetic 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 Medical Information on 0800 731 1736 or medical.information@bms.com. of them to cause disease, like Type 2 diabetes mellitus. the disease. The history should include age at 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 The identification of germline mutations in hereditary cancers is of great importance. These mutations make it possible to identify individuals who are at high risk for developing the disease (e.g. BRCA1/2 in breast cancer) and to develop targeted therapeutic approaches directed at events that drive tumor initiation and progression (e.g. renal cancers).

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Sunday, 26 March 2017

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Sunday, 26 March 2017

EUT Congress News

Robot-assisted RP: Managing inguinal hernias Experienced and skillful robotic repair of inguinal hernias Prof. A. Erdem Canda Yildirim Beyazit University School of Medicine Ankara Ataturk Training & Research Hospital Department of Urology Ankara (TR) Robotic-assisted radical prostatectomy (RARP) is increasingly being performed for the surgical management of localized prostate cancer and, to some extent, some patients might have preoperatively detectable or intraoperatively identified inguinal hernias (IHs) (Photo 1). It was reported that 33% of the patients had incidental IHs during radical retropubic prostatectomy (RRP) (1). In a study carried out at Karolinska University Hospital, 1,411 consecutive patients who underwent RRP or RALP were included (2). The cumulative risk of IH development at 48 months was 12.2%and 5.8% for RRP and RARP groups, respectively (p<0.05) suggesting that RARP leads to a decreased risk of IH development (2). It is important to make a proper physical examination preoperatively to identify asymptomatic and subclinical inguinal hernias before the RARP procedure. A preoperative abdominal computed tomography or ultrasound might also be helpful in identifying asymptomatic inguinal hernias before surgery. It might be difficult to diagnose inguinal hernias preoperatively particularly in obese patients. It was suggested that men with preoperative lower urinary tract dysfunction have an increased risk of a hernia at RARP and should be counseled about the potential need for concurrent hernia repair (3). Therefore, due to the preoperative evaluation if the inguinal hernia(s) is/are diagnosed before RARP the patients could then also be preoperatively counseled and informed about the possibility of repairing hernia at the same session.

Before starting the rTAPP procedure, it is important to obtain a watertight urethro-vesical anastomosis that is confirmed by distending the bladder intraoperatively with sterile saline solution (Photo 2). In addition, it is also important to have a good hemostasis that could be tested by decreasing the intra-abdominal pressure to 5 mmHg before starting the hernia repair. Likewise, a preoperative sterile urine culture should also be confirmed. Our technique of rTAPP inguinal hernia repair was reported and presented previously at the EAU ERUS 2016 Meeting (9). During the transperitoneal RARP procedure a large peritoneal incision is made on the lateral sides of both medial umbilical folds, below the level of umbilicus opening the preperitoneal space. If bilateral extended pelvic lymph node dissection is also performed then the lymphatic tissues around external iliac arteries and veins up to the ureters are all cleared giving the console surgeon a good anatomical exposure of the important vascular structures. It is important to include the peritoneal dissection lateral to the internal inguinal ring. It is also important to particularly pay attention to vascular and pain triangles during dissection. Vascular triangle includes external iliac vein, external iliac artery, femoral branch of genitofemoral nerve and femoral nerve, whereas pain triangle includes femoral branch of genitofemoral nerve, femoral nerve and lateral cutaneous nerve of thigh.

Mesh materials Before repairing the inguinal hernia defect with a mesh material, lateral and superior edges of the peritoneum are freed creating a space to locate the mesh. There are different mesh types available on the market to use for hernia repair. In addition to the polypropylene mesh materials, bio-absorbable coated permanent mesh materials are also available to cover the defect. Mesh size could be adjusted according to the size of the defect. Before inserting the mesh material through the assistant port into the abdominal cavity, the bedside surgeon and the nurse always change gloves before handling and manipulating the mesh material to decrease the risk of contamination. Thereafter, the mesh material is introduced into the abdomen through the 11 mm sized assistant port (Photo 3). Rarely, omentum, bowel segments or even urinary bladder could be found as herniated into the hernia sac and these structures should be carefully decompressed. Following the application of the mesh material over the defect, laparoscopic applied tacks (absorbable or non-absorbable) could be used to secure the mesh over the hernia defect (Photo 4). Alternatively, a suture material could be also used for this purpose. Attention should be paid not to injure spermatic cord, testicular artery, genitofemoral nerve, epigastric artery or external iliac vessels during mesh application and securing.

In published literature, many colleagues reported that inguinal hernias are a common intraoperative finding during RARP, and concurrent hernia repair with the use of a mesh material is a safe and effective Photo 1: Appearance of an inguinal hernia during RARP additional procedure with reasonable increased (Courtesy of Author’s Photo Archive). operative time (4-8). If the inguinal hernia is not 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.

If a bio-absorbable coated permanent mesh is used, peritoneum could be left open otherwise it should be closed over the mesh by using a running absorbable suture (Photo 5). An abdominal drain is introduced and is removed during the postoperative follow-up. On postoperative Day 7, urethral catheter is removed following a confirmation of no leakage on cystography. Robotic repair of the inguinal hernias by using mesh materials following

the completion of the RARP seems to be a safe and easy procedure to perform by taking specific precautions and having the proper training and knowledge to avoid a further operative procedure for the patient. References 1. Nielsen ME, Walsh PC. Systematic detection and repair of subclinical inguinal hernias at radical retropubic prostatectomy. Urology 2005;66:1034-7. 2. Stranne J, Johansson E, Nilsson A, Bill-Axelson A, Carlsson S, Holmberg L, Johansson JE, Nyberg T, Ruutu M, Wiklund NP, Steineck G. Inguinal hernia after radical prostatectomy for prostate cancer: results from a randomized setting and a nonrandomized setting. Eur Urol. 2010 Nov;58(5):719-26. 3. Sánchez-Ortiz RF, Andrade-Geigel C, López-Huertas H, Cadillo-Chávez R, Soto-Avilés O. Preoperative International Prostate Symptom Score Predictive of Inguinal Hernia in Patients Undergoing Robotic Prostatectomy. J Urol. 2016 Jun;195(6):1744-7. 4. Lee DK, Montgomery DP, Porter JR. Concurrent transperitoneal repair for incidentally detected inguinal hernias during robotically assisted radical prostatectomy. Urology. 2013 Dec;82(6):1320-2. 5. Kaler K, Vernez SL, Dolich M. Minimally Invasive Hernia Repair in Robot-Assisted Radical Prostatectomy. J Endourol. 2016 Oct;30(10):1036-1040. 6. Teber D, Erdogru T, Zukosky D, Frede T, Rassweiler J. Prosthetic mesh hernioplasty during laparoscopic radical prostatectomy. Urology. 2005 Jun;65(6):1173-8. 7. Finley DS, Rodriguez E Jr, Ahlering TE. Combined inguinal hernia repair with prosthetic mesh during transperitoneal robot assisted laparoscopic radical prostatectomy: a 4-year experience. J Urol. 2007 Oct;178(4 Pt 1):1296-300. 8. Finley DS, Savatta D, Rodriguez E, Kopelan A, Ahlering TE. Transperitoneal robotic-assisted laparoscopic radical prostatectomy and inguinal herniorrhaphy. J Robot Surg. 2008;1(4):269-72. 9. Canda AE, Atmaca AF, Bedir F, Ozer M, Ardicoglu A. Concurrent robotic trans-abdominal pre-peritoneal (TAPP) inguinal herniorrhaphy during robotic-assisted radical prostatectomy. ERUS Video abstract. European Urology Supplements, Volume 15 Issue 7, September 2016.

Monday 27 March 10.30-10.50: Thematic session 18, Masterclass RARP Semi-Live; Management of inguinal hernias during robot assisted radical prostatectomy

A first-generation cephalosporin is administered for antibiotic prophylaxis. Following completion of the RARP procedure, a robotic trans-abdominal preperitoneal (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 the RARP procedure (Author’s Photo Archive ).

Photo 4: Application of titanium tacks on the sides of the mesh material to secure it over the defect by laparoscopic applier (Author’s Photo Archive).

Photo 3: Appearance of the introduced and located mesh material covering the inguinal hernia defect in the abdomen (Author’s Photo Archive).

Photo 5: Peritoneum is closed over the mesh using a running absorbable suture and a drain is introduced (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 as indirect hernia. 6

EUT Congress News

Sunday, 26 March 2017

Is every man fertile? Pharmacological and surgical ways to fertility in young men hormonal parameters. The management strategy depends on the level and nature of the obstruction, as summarized in the figure below. Effective reversal of obstruction allows restoration of normal fertility, with the advantage of allowing natural conception for the first and subsequent children. Analyses have shown reconstructive techniques can achieve live birth rates comparable to IVF/ICSI, but with better costeffectiveness. 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. households long since passed and the trials of King Henry VIII. Mr. Majid Shabbir Consultant Urologist Specialist in Andrology and Genito-urethral Reconstruction, Guy’s and St Thomas’ Hospital London (GB)

Henry VIII and his first wife, Catherine of Aragon, had problems with fertility. Their marriage bore six children, including three male heirs, but all were either stillborn or died in the first two months, except their daughter Mary. Catherine’s inability to produce a male heir led Henry to annul this marriage in favour of his wife’s lady-in-waiting, Anne Boleyn. This move led to a break with the Catholic Church and Rome, the development of the Church of England and the dissolution of the Monasteries.

Developments in reproductive techniques have transformed the landscape of infertility management. The advent of intracytoplasmic sperm injection (ICSI) just over two decades ago provided the greatest boost to severe male factor infertility management. By allowing single sperm cells to be injected directly into viable oocytes, this technique opened up a world of possibility to those previously considered infertile. While this has been an undoubted success, it has lead to a shift away from understanding and correcting the underlying cause of male factor infertility, to one that simply overcomes it with assisted reproductive techniques. When considering the causes of male infertility, the problem can be primarily divided into: 1. Issues with spermatogenesis, or 2. Issues with sperm delivery. Detailed assessment of the patient including examination of the testes and scrotal contents, assessment of hormone profile and semen analysis allow the urologist to pinpoint where the underlying issue may be.

Medical and Surgical Options for Obstructive Azoospermia (OA) 1. Ejaculatory duct obstruction –surgical management with Transurethral resection of the ejaculatory ducts (TURED) 2. Retrograde ejaculation –pharmacotherapy aimed at bladder neck (Pseudoephedrine, Imipramine) or urine alkalinisation) 3. Vasal or Epididymal obstruction – microsurgical reconstruction by vasovasostomy or epididymovasostomy 4. Testicular obstruction – surgical sperm retrieval (TESA)

Non-obstructive azoospermia Non-obstructive azoospermia accounts for approximately 60% of all azoospermia cases, and remains the most challenging scenario in male factor infertility. Apart from the few cases of hypogonadotrophic hypogonadism, who respond extremely well to hormonal stimulation to recover their fertility potential, this group of infertile men fare less well with medical and surgical intervention. Challenging and controversial areas of management are discussed below. Surgical sperm retrieval- MicroTESE Surgical sperm retrieval (SSR) is the primary option in those with irreversible NOA. Of all the available SSR techniques, microTESE has the greatest chance of success. Compared to conventional TESE, microTESE almost doubles the chance of successful SSR (weighted means 33% vs. 54% in meta-analysis1), allowing considerably more men the chance to progress to ICSI. MicroTESE is also successful in those men with previous failed conventional TESE.

In our series, 65% of men deemed infertile by conventional TESE had sperm found on subsequent microTESE, including azoospermic men after previous chemotherapy. Similar findings have been described in The most challenging situation is azoospermia, where other series. This finding has lead to the conclusion that men should not be considered infertile until they no sperm are seen in the ejaculate. Azoospermia have a microTESE and are found to be infertile. Using affects approximately 10-15% of infertile men. Even in this extreme, infertility can be effectively managed and hormonal stimulation with HCG/HMG prior to redo surgery may further enhance these success rates, restored. While not every man with azoopsermia is although the best regime and combination of drugs fertile, more have fertility potential than one would expect and they may achieve fatherhood using a variety remains unclear at present and an area that requires better coordinated multi-centre trials. of techniques. Obstructive azoospermia In approximately 40% of cases, azoospermia is due to a structural, or ‘functional’, obstruction in the sperm pathway. Problems may occur at any point from its inception in the seminiferous tubule to its delivery at the external urethral meatus. In obstructive cases, the testicular structure and function is normal, with normal Sunday, 26 March 2017

A: Ex-vivo dissection of the removed testis. B: Tumour (right) is reflected to one side. C: Lower power assessment of seminiferous tubules (left) away from tumour (right). D: Identification of individual dilated tubule (circled) from which sperm is successfully extracted.

Testis cancer and oncofertility Approximately 40-50% of men with testis cancer have impaired fertility at presentation, of which up to 10% are azoospermic (NOA). Currently patients with testis cancer are recommended to consider fertility preservation prior to orchidectomy, although this is not considered essential at this step. In most units, semen cryopreservation is performed after surgery, but prior to subsequent chemotherapy, despite the negative impact of surgery on overall fertility potential.

Fortunately, issues with fertility don’t shape history and nations in the same way in the modern era! However, the impact of such problems can significantly affect relationships and lead to feelings of inadequacy and detachment in men unable to produce offspring. Male factor infertility Male factors account for approximately 50% of issues with a couple’s fertility. While there are a few rare genetic conditions where a man may have no fertility potential at all, in the main, environmental factors and health issues are the most common causes of male factor infertility. As such, a man’s fertility potential is often a barometer of his health, and infertility a symptom of underlying disease.

Oncological microsurgical testicular sperm extraction (Onco-microTESE)

When one considers the significantly lower complication rates of microTESE compared to conventional TESE, despite its more invasive nature2, it becomes clear that microTESE should be the gold standard SSR technique in NOA. Despite this, there are still more fertility centres worldwide undertaking a conventional rather than microsurgical SSR.

In our unit, we have taken a proactive approach to fertility preservation, assessing all patients’ testicular function and hormones prior to orchidectomy, with cryopreservation of semen at first presentation. This allows detection of those with unexpected NOA, in whom we offer an onco-microTESE (See above). This procedure allows the safe oncological removal of the testis via an inguinal approach, with subsequent ex-vivo microTESE dissection of sperm from the removed testis to allow maximal fertility preservation from adjacent tissue that would have been resigned to the ‘scrapheap’ of the pathology specimen. This approach has allowed successful fertility preservation in 60% of cases without having to involve the contralateral testis. A proactive drive to improve fertility preservation in cancer patients at first presentation may prevent subsequent disappointment once the irreversible iatrogenic effect of treatment has been inflicted. Varicoceles This has been an area of controversy for many years, based on the flawed analysis of Evers and Collins published in the Lancet in 20033. Subsequent review of the original data a decade ago found that confining the analysis to only those with clinically significant varicoceles and infertility resulted in a significant improvement in pregnancy rates after correction of the varicocele4. Despite this, most reproductive medicine specialists still do not treat varicoceles pro-actively. There are a number of ways in which a varicocele may affect fertility, from the effects of the increased temperature, to its effect on hormones, spermatogenesis, and DNA fragmentation. Metaanalyses have shown correction of varicoceles can lead to significant improvements in sperm counts and motility. Other studies have shown reduced DNA fragmentation and spontaneous miscarriage rates after correction. Randomized control trials have also shown that treatment of clinically significant varicocoles can improve the chance of spontaneous pregnancy with an odds ratio of 3.04, and NNT 5.27 in men with oligozoopsermia5. In those with NOA and clinically significant varicoceles, treatment can lead to sperm recovery in the ejaculate in up to 32%6. Even in those who remain azoospermic, subsequent SSR after varicocele repair significantly increased the chance of SSR by 2.67. Despite its inclusion into EAU and AUA guidelines, a proactive approach to the management of clinically significant varicoecles is still slow on the uptake.

Genetics A number of genetic conditions are known to be associated with infertility. Screening of patients with NOA allows detection of recognizable chromosomal anomalies, which occur in <10% of cases. In the majority of NOA patients, no clear abnormality can be found. It may be that while the larger structural chromosomes are normal, smaller genomic abnormalities may exist. One such example is the presence of certain anomalies on the Y chromosome, such as the AZFa or AZFb micro-deletions. These are present in only a very small number of cases, but are known to be associated with no spermatogenesis, and if detected no surgical sperm retrieval should be offered. Screening therefore allows selection of this very small group with no fertility potential. Those with other abnormalities may have successful SSR, and can be offered genetic counseling and pre-implantation genetic diagnosis. The detection of novel biomarkers in NOA is an area of great interest. Genomic and proteomic analysis of infertile men will be one of the most important steps in the future to identify single nucleotide changes and markers which may predict fertility potential with more accuracy, and allow a clearer understanding of ‘idiopathic’ male factor infertility. The ideal would be the identification of markers such as those used in cancer diagnosis and follow up, which may guide infertility diagnosis and management with more accuracy. Ongoing investigations in this field may lead to the biggest changes and refinement in the management of infertile men since ICSI, but given the vastness of the task, this remains some way off at present. Final thoughts In those who cannot achieve fertility, alternatives such as donor sperm and adoption remain alternative routes to fatherhood. UNICEF estimate approximately 13 million children are without parents worldwide, while WHO estimated approximately 48 million couples were unable to have a child in 2010. In a utopian society, neither should exist. As such the question should change from one asking ‘Is every man fertile’, to one, which asks ‘Is every man able to be a father?’ As I discovered when I became a father myself, there is certainly much more to it than just passing on your genetic code. New techniques and developments in the management of male factor infertility continue to allow us to reduce the proportion of infertile men who are considered beyond assistance. Thankfully, the fate of nations no longer hangs in the balance! References 1. 2. 3. 4. 5. 6. 7.

Deruyver Y et al Andrology 2014 2:20-24 Okada H et al. 2002 J Urol 168, 1063–1067. Evers J & Collins J. Lancet. 2003 May 31;361(9372):1849-52. Ficarra V et al Eur Urol. 2006 49(2):258-63. Abdel-Meguid TA et al Eur Urol 2011 59(3):455-61 Abdel-Meguid TA J Urol. 2012 187(1):222-6 Esteves SC et al Asian J Androl. 2016 18(2):246-53

Saturday 25 March Plenary Session 2, Hot topics in andrology

EUT Congress News

Photodynamic therapy for prostate cancer Treatment strategy in low-risk PCa may change with photodynamic therapy Prof. Arnulf Stenzl Dept. of Urology Eberhard-KarlsUniversity Tuebingen Tuebingen (DE)

The principles of photodynamics, i.e., light-induced activation of intracellular or extracellular photosensitizers which can be used for diagnostic and/or therapeutic purposes in non-muscle invasive bladder cancer have been well-known to urologists. It has also been used for many years in the treatment of neurosurgical tumors as well as upper respiratory tract, gynecologic and dermatologic lesions with variable success. Its use for prostate cancer is relatively new. There have been many in-vitro and in-vivo studies using Padeliporfin as the sensitizer, activated by intraprostatic laser light omitting fibers. The wave length and dosage in humans was set at 753nm with a fixed power setting of 150mW/cm leading to an energy dose of 200J/cm. The time necessary to achieve this fixed dosage is 22min 15sec. Many photosensitizers have been tested for photodynamic diagnosis and treatment. Some photosensitizers such as aminolaevulinic acid and its derivatives use an enzyme defect in the hem synthesis which only occurs in certain tumour cells. The subsequent accumulation of protoporphyrin IX can be made visible with monochromatic light at a wave length of 428 nm. In a more concentrated form or by using different sensitizers a singlet oxygen formation is provoked leading to cell destruction and necrosis. The photosensitizer Padeliporfin used in the prostate

cancer study is a vascular – acting photosensitizer consisting of water – soluble, Palladium – substituted bacteriochlorophyll derivative. If activated with low-power monochromatic (laser) light at 753nm, a 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 where a monochromatic light source can reach it, which means the laser fibers have to be placed in or near lesions made visible by imaging. Vascular-targeted photodynamic therapy Several weeks ago a prospective randomized study including 413 patients from 47 institutions throughout Europe and a minimum follow-up of 24 months has been published, comparing vascular-targeted photodynamic therapy with active surveillance in patients with low-risk prostate cancer. This is to date the only prospective randomized study comparing any approved or experimental focal therapy with active surveillance.

“Nevertheless, the remarkable results of this study may change the strategy in low-risk and maybe even low/intermediate-risk patients with prostate cancer. It may be a tool for a tissue-sparing form of treating prostate cancer which will benefit patients...”

anesthesia consisted of an intraprostatic placement of optical fibres through a perineal raster followed by intravenous application of the photosensitizer Padeliporfin. After 12 and 24 months the prostate was re-biopsied. Twenty-four months after the initial treatment a negative biopsy result was observed in 49% of the vascular-targeted photodynamic therapy group versus 14% in the active surveillance group, being highly statistically significant.

Several facts have changed since this study was initiated several years ago. The technique and quality of a prostatic MRI have improved and a multiparametric MRI is in some centers nowadays used as a selection criterion for the initial biopsy as well as a marker for active surveillance. Active surveillance is a The majority of those patients included in this study more widely accepted strategy for low-risk prostate (86% and 87% in the vascular- targeted photodynamic cancer despite the fact that under-staging may occur therapy and active surveillance group, respectively) and some patients with a long life expectancy cannot were stage T1c. The two-hour treatment under general accept the psychological burden.

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Nevertheless, the remarkable results of this study may change the strategy in low-risk and maybe even low/ intermediate-risk patients with prostate cancer. It may be a tool for a tissue-sparing form of treating prostate cancer which will benefit patients that may have an “under-staged” disease, and the small number of patients that may develop metastases despite an initially proven Gleason 3+3=6 score disease. And it might help men who are seeking non-surgical treatment despite different advice because they can´t live with subjective uncertainty of living with a malignant disease. Recent developments in imaging including multiparametric MRI, PSMA-PET- MRI and navigationassisted tools/MRT biopsy will further make focal therapy more accurate by improving prediction of prognosis, better targeting of relevant tumor lesions, and aiming re-biopsies at the previous sites of biopsy put in storage.

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Sunday, 26 March 2017

Benign Prostatic Enlargement (BPE) Evaluation, drugs, surgery or new interventional treatment Mark J Speakman Taunton & Somerset NHS Foundation Trust Dept. of Urology Musgrove Park Hospital Taunton (GB)

The majority of our patients still present because of bothersome LUTS although a significant and important minority present because of either acute or chronic retention. Most guidelines agree on the important issues for the clinical history, examination and evaluation and it is good to see that more and more guidelines are correctly promoting the frequency 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 role of inflammation in LUTS/BPE pathogenesis by retention and more recently in an analysis of the 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 value of urodynamics in LUTS/BPE evaluation and Urodynamics treatment planning, chaired by Henry Woo (AU) Most of us would agree that formal urodynamics can and debated by Matthias Oelke (DE) and Nikesh add useful information to the comprehensive workup Thiruchelvam (GB), taking the pro and con of men with LUTS, particularly those being positions, respectively. This debate is likely to be considered for surgical intervention. It is however an ‘won’ by the better proponent of their case invasive test that some patients find unpleasant. although it is hoped that the results of the Those surgeons who do routine urodynamics tend to ongoing UPSTREAM study will answer this advocate that surgery should only be performed in uncertainty in the relatively near future. those men with proven bladder outlet obstruction. Advocates for restricted use stress the lack of 3. Next there will be patient cases in three different evidence of better outcomes after urodynamics and clinical scenarios presented by Andrea Tubaro (IT) of course the associated costs. Do the benefits and we hope to identify how to select appropriate therefore outweigh the disadvantages? The UPSTREAM7 trial has addressed this very question in surgical interventions and agree when it is not appropriate to offer surgical intervention a systematic and randomised way and it is hoped (Discussants Alexandre De La Taille [FR] and Mark that Marcus Drake (GB) and co-workers will provide Speakman, [UK]) us with a definitive answer in 2018. 4. Most of us now fully accept the importance of high-quality Guidelines in the evaluation and management of our patients and particularly their value to our juniors in training. Dr Stavros Gravas (GR) will present the essentials of what matters in these documents and educate us on the strengths and perhaps some of the weaknesses of their different forms. 5. Over the last few years there has been a plethora of new technologies in the surgical management of LUTS/BPO and the next section chaired by Christian Gratzke (DE) describes the latest developments in surgical progress using three fundamentally different modalities; Electricity (presented by Thomas Herrmann, DE), Light (Cesare Marco Scoffone, IT) and Water (Neil Barber, GB). This should be a highly illuminating programme. 6. Many of us have patients who are still bothered with symptoms even after what appears to be good case selection, a seemingly complete work-up and apparently successful surgery. Therefore a state of the art presentation by Karel Everaert (BE) follows which will update us on the latest thinking and provide important tips about how to avoid or deal with these problems if they occur. 7. The session finishes with the ‘blockbuster’ presentation from Claus Roehrborn (US), the ‘Emperor’ of LUTS/BPE who will give us his valuable personal explanation of, to borrow from Donald Rumsfeld, …the known and unknown (by many of us) unknowns of the diagnostic and therapeutic pathways. Terminology Since the seminal BMJ paper1 by Paul Abrams over 20 years ago we have gradually moved away from ‘prostatism’ and hopefully everywhere, except the USA, also stopped using the term ‘BPH’ as a clinical syndrome, as BPH is first and foremost a pathological definition. We now recognise that using LUTS is the correct terminology as it is neither gender nor organ- specific. The UK NICE guideline2 and that of the EAU3 and many others have correctly moved to this terminology to define the storage, voiding and post-micturition symptoms. Sunday, 26 March 2017

When to operate? This is not an easy decision and certainly not as easy as many of us thought it was when we were junior registrars. Surgery can often be highly beneficial but if patients get results below those they had expected, or if they get complications they can subsequently be very difficult patients to manage. If at all possible therefore, patients should always be encouraged to have a trial of medical or conservative therapies before proceeding to surgery. The only strict exception would be high pressure chronic retention. In reality patients need to ‘earn’ their operation and be demanding surgery before plans are made. They need to be made fully aware of all the possible alternative therapies and the potential for complications and symptom failure for each of them. It can be better to do what we may believe is the second-best solution if that is the well informed choice of the patient. Understanding and managing patients’ expectations is now an important and time consuming part of our role. We are now much more knowledgeable on which patients require mono-therapy with drugs and which require combination therapies, and Claus Roehrborn and others have highlighted the importance of identifying which of our patients are at a greater risk of LUTS progression and those more likely to develop complications of their disease. The reasonable question is, are we as thoughtful about which surgical modality to offer our patients as we are with the drugs? Should this be based on prostate size or on the type of LUTS that they suffer? Do storage and voiding symptoms behave differently after surgery? Is there a value in offering more minimally invasive therapies to our younger patients wishing to avoid ejaculatory problems? Whilst accepting that there is a greater probability that they will require further surgery in the future or should we promote a more definitive procedure as first choice? Clearly patient choice and the limitations of the local health care organisation will strongly influence these decisions. Guidelines Clinical Practice guidelines addressing the management of men with LUTS/BPH began appearing in the urological journals in the early 1990s and the number and quality of these have increased year on year. Most national urological associations publish

UroLift system delivery steps: (a) release safety lock, (b) deploy needle, (c) retract needle, delivering capsular tab and tensioning monofilament, (d) attach urethral end piece and trim monofilament. Photo: Thomas McNicholas, et al, European Urology Archives

their own guidelines and larger organisations like the EAU provide their high-quality guidelines free for members and non-members alike. In the early days these were often based on the ‘ex cathedra’ statements of senior urologists but they are now predominantly based on evidence-based medicine and therefore of a much higher quality, although there are methodological issues that vary between them and thereby affect the quality. In addition, the uptake and utilisation of these guidelines by their members is less than it should be; a good example would be the underutilisation of frequency volume charts (bladder diaries) even though they are recommended in all good guidelines. Emerging technologies Surgical interventions for LUTS/BPO have evolved considerably over the last 10 to 15 years and the pace of development is showing no signs of Table 1: Treatment Options for LUTS/BPO • Conservative measures • Medical Treatments; 0 single or combinations • Surgery 0 Conventional; - TURP(mon & bipolar), TUIP, TUVP, Open 0 Minimally invasive surgery - laser techniques - prostate injection treatments8 - stents - prostatic urethral lift (Urolift® System)9 - prostate artery embolization10 - transurethral RF water vapor thermaltherapy (Rezum® System)11 - robot-guided water ablation (PROCEPT Aquablation™)12 - Histotripsy - Robotic assisted simple prostatectomy

slowing. The principal surgical options have been resection, enucleation and/or vaporization and these have led to generally acceptable long-term outcomes with reasonable safety. Most of these procedures are operator dependent and we tend to believe that success depends upon the degree of relief of obstruction of the bladder outlet. Whilst some of these procedures have required hospitalization the latest developments are focused on trying to achieve an outpatient / daycase or office-based procedure without the need for general anesthesia. There has also been greater awareness amongst patients of some of the sexual and ejaculatory dysfunctions from some of the more traditional approaches. This has led to even more minimally invasive therapies such as intra-prostatic injections (still undergoing clinical trials) and innovations such as the Neotract Urolift™ device that have been introduced after a well-structured investigational clinical trials process (unlike some of the innovations in the past). There have also been a variety of ablation techniques ranging from the use of high frequency ultrasound to water vapor (Rezum and Procept aquablation). Within the realm of interventional radiology there has also been increasing success with prostate artery embolization. It is unlikely that robotic assisted simple prostatectomy will be cost-effective. A comprehensive list of treatments is provided in Table 1. Editorial Note: Due to space constraints the reference list has been omitted. Interested readers can email at EUT@uroweb.org for a complete listing. Sunday 26 March 8.45-9.15: Plenary Session 4 : Benign Prostatic Enlargement (BPE): Evaluation, drugs, surgery or new interventional treatment

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PS3: Debate on low-risk BCa Mr. Hugh Mostafid Consultant Urologist and Senior Lecturer Royal Surrey County Hospital The University of Surrey Guildford (GB)

The current EAU guidelines on non-muscle invasive bladder cancer (NMIBC) recommend cystoscopic follow-up for five years in patients with low- grade NMIBC but this is only a Grade C recommendation as there is little high quality evidence in this area. Indeed the EAU guidelines themselves state that ‘tumour recurrence in the low-risk group is nearly always low stage and LG/G1. Small, Ta LG/G1 papillary recurrence does not present an immediate danger to the patient and early detection is not essential for successful therapy’ (LE:2b). The UK National Institute for Health and Care Excellence (NICE) develops practice guidelines for the National Health Service (NHS) in England and the NICE Bladder Cancer Guidelines were developed by a panel of 15 experts and published in 2015. One of the most notable recommendations was that patients with low grade NMIBC could be discharged at one year as long as they had been free of recurrence at both their three and 12 month cystoscopies. It is known that the outcome of cystoscopy at three months is a strong predictor for future recurrence and patients who are free at three months form a particularly low-risk group of patients with a recurrence rate between years one to five of only 12% none of which developed progression (Mariappan and Smith 2005). Given the lack of high quality evidence and costs and workload implications of cystoscopic surveillance in this group the NICE guidelines group developed a model to assess the clinical and economic impact of a reduced one-year follow-up in patients

with low-risk NMIBC compared with a standard five-year surveillance schedule. The results of this model showed that a reduced surveillance protocol was associated in a reduction of nearly 50% or 4000 pounds per patient in costs with only a negligible reduction in clinical effectiveness. Based on this, NICE recommended that in the UK patients with low risk/grade NMIBC with no recurrence at 12 months should be discharged back to primary care and importantly their primary care physician should not perform regular investigations such are urine cytology to monitor for recurrence. However patients were to report any visible haematuria immediately. The guidelines were published in February 2015 and in the two years since, the majority of urology departments in the UK have adopted this strategy. Although as yet no scientific literature has been published on outcomes following this change, the British Association of Urological Surgeons (BAUS) have been monitoring the situation closely and as yet no concerns have been raised by UK urologists. Many departments report a significant easing of their cystoscopic workload following the change which has enabled them to focus on faster cystoscopic investigation of new haematuria referrals. Interestingly, there is anecdotal evidence that new low-risk NMIBC patients are happy to be discharged at one year, whereas patients with established LR NMIBC who are between years one to five seem more reluctant to be discharged, which suggests that what the patients are told at the outset about their disease follow-up has a strong influence in how acceptable reduced surveillance is for patients. Reference 1. A surveillance schedule for G1Ta bladder cancer allowing efficient use of check cystoscopy and safe discharge at 5 years based on a 25-year prospective database. Mariappan P, Smith G. J Urol. 2005 Apr;173(4):1108-11.

Dirk Schultheiss Friedrich Moll

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UROLOGY under the

S WA S T I K A

Urology Under the Swastika Edited by Dirk Schultheiss and Friedrich Moll The rise of national socialism and fascism and the subsequent occupation of the continent during the Second World War dramatically influenced and destroyed the careers of urologists and the development of the young specialty of urology. This new publication by the EAU History Office documents the fates of urologists in this period and explores the effects of the war on our field.

Sunday 26 March 09.00-09.15: Plenary Session 3, Redefining and optimising contemporary bladder cancer care, Debate

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Sunday, 26 March 2017

Non-muscle invasive bladder cancer (NMIBC) Where should we focus future efforts? Prof. Marko Babjuk Department of Urology Hospital Motol and 2nd Faculty of Medicine Charles University Prague (CZ)

Bladder cancer is the 11th most common diagnosed cancer and significant cause of tumour-related deaths worldwide. Although we observe global reduction of bladder cancer mortality in recent years, its more positive trend is not possible without new achievements and comprehensive research activities. There are several areas, which seems to be critical to achieve better clinical results. Improve efficacy of primary prevention Several etiological factors in bladder cancer were identified and confirmed many decades ago, which brought unique opportunities for primary prevention and reduction of disease incidence and mortality. Unfortunately, not all expectations and promises were accomplished. There is no doubt that the most important risk factor for bladder cancer development on a population basis is, at present, tobacco smoking. Recently published meta-analysis of cohort and case-control studies estimated pooled relative risk of bladder cancer between current and former smokers of 3.47 and 2.04, respectively. Moreover, both current smokers (RR 1,53) and former smokers (RR 1,44) have a higher risk of bladder cancer mortality compared to non-smokers1.

tract. For this reason their contribution in daily practice is limited. Typical observation has very low reproducibility of achieved results. The reason is not only extremely high variability of bladder cancer antigen characteristics, but also difficulties with standardization of samples collection as our group demonstrated in presented studies3. Apparently, non-invasive bladder cancer detection remains a significant challenge for future research activities. Improve results of transurethral resection (TURB) The treatment strategy of NMIBC is based on complete TURB, individually followed by intravesical chemotherapy or immunotherapy instillations. TURB represents the critical step in the management of NMIBC. The aim of the procedure is to establish the histological diagnosis, determine the tumor stage and grade and achieve complete removal of papillary non-muscle-invasive tumors. Unfortunately although TURB is a frequently performed procedure which should be familiar to all urologists, its results are far from optimum and both the diagnostic and therapeutic purposes are not always completed. Indeed, tumors are frequently overlooked and left behind during initial resection or, more importantly and dangerously, their depth of invasion can be underestimated. To overcome these limitations, the second resection (second TURB) performed after two to six weeks was incorporated in our treatment algorithms. The current version of European Association of Urology (EAU) Guidelines recommends considering a second TURB if there is a suspicion that the initial resection was incomplete and when the pathologist reported no muscle tissue in the specimen, with exception of TaG1/ LG tumours and primary CIS. Furthermore, it should be performed when a T1 tumour was detected at the initial TURB. The second TURB can detect residual tumour in 33 to 55% of cases staged as T1 by initial resection. More importantly, the likelihood that muscle-invasive disease is detected by second resection of initially T1 tumour ranges from 1.3-25%, and it increases to 45% if there was no muscle in the initial resection. It has been demonstrated that a second TURB can increase recurrence-free survival and improve outcomes after BCG treatment.

Figure 1-A: White Light

How effective are we in smoking prevention? According to recent data, global modeled agestandardized prevalence of daily tobacco smoking in the population older than 15 years decreased from 41.2% in 1980 to 31.1% in 2012 for men and from 10.6% to 6.2% for women. Because of population growths however the number of daily smokers increased from 721 million in 1980 to 967 million in 2012 worldwide. Moreover, the decrease of the prevalence was less pronounced in last two years of the analysis compared to previous period2.

We should not forget, however, that a second TURB is just the “rescue” procedure. The recommendation to repeat surgery in a significant number of patients with NMIBC must be critically discussed and our effort should be concentrated on improvement of the quality of the first TURB. How to perform the optimal initial TURB? The essential requirement is modern equipment and surgery performed by well trained surgeon.

beneficial effect of HAL FC on recurrence rate in patients with TURB was confirmed by a multicentre, prospective, randomised trial and by a raw-databased meta-analysis of controlled trials. A metaanalysis reported in the HAL arms showed an increase in detection of tumour lesions across all-risk groups and an absolute reduction of 9% in recurrence rates within 12 months5.

“Our research must be focused also on improvement of patients´ selection for a second TURB. We should concentrate on characteristics achieved by initial resection...” In NBI, the contrast between normal urothelium and hyper-vascular cancer tissue is enhanced by selection of specific wavelength of light. Initial studies have demonstrated improved cancer detection by NBI-guided biopsies and resection and also the reduction of recurrence rate for low-risk tumours if NBI is used during TURB6.

More attention is also paid to the technique of resection. It was demonstrated that the method of “en-bloc” resection performed with monopolar or bipolar current, Thulium-YAG or Holmium-YAG laser provides high quality of achieved specimen even in tumours over 1 cm7. Its definitive role in daily practice should be specified in the future. Our research must be focused also on improvement of patients´ selection for a second TURB. We should concentrate on characteristics achieved by initial resection, like T1 sub-staging or lymphovascular invasion, which could specify the risk of tumour persistence or under-staging. Interestingly, in a retrospective evaluation of a large multiinstitutional cohort of 2,451 patients with BCGtreated T1G3/HG tumours, the second resection improved recurrence-free survival (RFS), progression-free survival (PFS) and overall survival (OS) only in patients without muscle in the specimen from initial resection8.

Although the first warning report on the health effects of smoking was released more than 50 years ago, we are apparently not very successful in reducing smoking prevalence. More intensified efforts will be needed, to my opinion, and not only in less developed countries. Moreover, to implement more effective preventive measures we need to understand in more details molecular principles of cancerogenesis. Improve non-invasive bladder cancer detection The detection of both primary and recurrent bladder cancer is based on endoscopic examination, which is time-consuming, expensive and, particularly, bothersome for patients. Desirably, at least some cystoscopies could be replaced with less invasive methods.

Major problems represent patients with high-risk tumours, which progress in a significant number of cases. The only treatment modality which can reduce the risk of tumour progression is BCG intravesical immunotherapy9. We understand today that to achieve optimal efficacy, BCG must be used including the maintenance schedule.

Sunday, 26 March 2017

Figure 1-B: Photodynamic Diagnosis

It was confirmed that with this method we can detect significantly more tumor lesions comparing to standard white light investigation and reduce the number of residual tumours. Moreover, our group presented several years ago that 5-ALA induced fluorescence cystoscopy used during TURB can reduce the recurrence rate in Ta T1 bladder UC4. Until now, this observation was confirmed by further trials. The

What is new in adjuvant treatment? Promising data have been presented on enhancing the efficacy of MMC using microwave-induced hyperthermia in patients with high-risk tumours. In one RCT comparing one year of BCG with one-year MMC and microwave-induced hyperthermia in patients with intermediate and high-risk bladder cancer, a reduced RFS at 24 months in the MMC group was demonstrated. There are available several technologies which increase the temperature of instilled MMC. They are based on different principles than microwave-induced hyperthermia and must be evaluated separately. The data about their efficacy in prevention of recurrences are however still lacking.

SPIES is based on a new software platform, which uses the different light wavelengths to produce images with different contrast specifications. Its clinical benefit however needs to be confirmed.

There were several modalities presented which could improve visualization of the tumour lesion and can be categorized as PDD (flouorescence cystoscopy), NBI (narrow band imaging) and SPIES. The principle of PDD is based on selective accumulation of protoporphyrin IX in tumor tissue after intravesical Figure 2-A: White Light instillation of 5-aminolevulinic acid (5-ALA) or, preferably, hexaminolevulinate (HAL). Protoporfyrin IX emits intensive red fluorescence after illumination Improve efficacy of adjuvant treatment after TURB with blue light. The principles of the adjuvant treatment are individually tailored intravesical chemotherapy or immunotherapy instillations. The indication is based on patients´ stratification into three risk groups, which is specified in EAU guidelines (EAU guidelines on NMIBC).

During recent decades, several tests which detect either soluble or cellular -based markers of urothelial carcinoma in urine have been introduced. The most promising of them are prepared for routine application and some of them (UroVysion (FISH), Immunocyt/uCyt +, Nuclear matrix Protein 22, BTA stat and BTA TRAK) received FDA approval. These methods have, according to various authors, greater sensitivity in bladder cancer detection than cytology. However, their disadvantage is the high rate of false positive results in patients with other diseases of the urinary

for patients with BCG failures and, even more importantly, more effective treatment which could replace BCG as a primary treatment option after TURB.

In spite of that, we are aware of several limitations. BCG fails in a not negligible subgroup of patients it was demonstrated that in T1G3 tumours the five-year disease-related death rate reaches 11.3% despite BCG therapy. BCG has several side-effects and is not tolerated by all recipients; moreover, we are facing today the enormous market shortage of the drug, worldwide. Moreover, after failure of BCG treatment there is no reliable bladder-sparing option which could prevent patients from radical cystectomy. Apparently, we need effective treatment

Figure 2-B: Narrow Band Imaging

References 1. Cumberbatch MG, Rota M, Catto JWF, La Vecchia C. The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks. Eur Urol in press. 2. Marie Ng, PhD1; Michael K. Freeman, MPH1; Thomas D. Fleming et al. Smoking Prevalence and Cigarette Consumption in 187 Countries, 1980-2012 JAMA 2014;311:183-192. 3. Brisuda A, Pazourkova, E. Soukup V, Horinek A, Hrbácek J, Capoun O, Svobodova I, Pospisilova S, Korabecna M, Mares J, Hanuš T, Babjuk M. Urinary Cell-Free DNA Quantification as Non-Invasive Biomarker in Patients with Bladder Cancer. Urol Int 2016, 96(1):25-31. 4. Babjuk M, Soukup V, Petrik R et al.: 5-aminolaevulinic acid induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta /T1 bladder cancer. BJUI, 2005, 96, 798-802. 5. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 2013;64:846-54. 6. Naito S, Algaba F, Babjuk M, et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscleinvasive Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol 2016;70:506-15. 7. Kramer MW, Rassweiler JJ, Klein J, et al. En bloc resection of urothelium carcinoma of the bladder (EBRUC): a European multicenter study to compare safety, efficacy, and outcome of laser and electrical en bloc transurethral resection of bladder tumor. WJU 2015;33:1937-43. 8. Gontero P, Sylvester R, Pisano F, et al. The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guerin. BJUI 2016;118:44-52. 9. Sylvester RJ, van der MA, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964-70. 10. Arends TJ, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. European urology 2016;69:1046-52.

Sunday 26 March 8.00-8.15: Plenary Session 3, Redefining and optimising contemporary bladder cancer care

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Clinical Guidelines Aren’t we all stakeholders? Prof. Dr. James N’Dow Chairman, EAU Guidelines Office Dept. of Urology, University of Aberdeen, Aberdeen (UK)

The EAU Guidelines Office (GO) has been expanding their activities over the past years, supported by a number of designated Committees including: the GO Methodology Committee, chaired by Prof. Dr. Richard Sylvester and the GO Guidelines Associates Committee, chaired by Prof. Dr. Thomas Knoll. The GO, together with both committees, have made great strides in improving the methodological quality of the EAU Guidelines. However, one area that will require particular attention in future update cycles is stakeholder engagement in the EAU guidelines development process. Stakeholder participation is an established feature of high-quality clinical guidelines development. The GO’s anticipation is that inclusion of all key stakeholders in the development process will result in better guidelines, better adherence by patients and clinicians and improved care whilst potentially increasing cost-effectiveness. What are ‘stakeholders’, a definition may be: ‘any group or individual who can affect or is affected by the achievement of the organisation’s objectives’.

Whilst there is agreement regarding the importance of stakeholder involvement in the guidelines development process, effectively incorporating all key stakeholders in this process is a considerable challenge. ‘Consideration must be given on how to manage and optimise involvement of all these groups in a formalised guidelines development process which includes: • Guidelines topic selection; • Panel development; • Decision on the remit (the scope of a guideline – what needs addressing?); • Development of recommendations; and • Review of results. The UK National Institute of Clinical Excellence (NICE) have a very robust methodology in place for stakeholder involvement, which serves as a model for many other guidelines developers. However, translating such models to an international setting is challenging. In particular, meaningful engagement of patients in clinical guidelines development has posed a challenge to the EAU GO. Some EAU Guidelines Panels include a patient advocate, but a sustainable method on how to progress this further across all of our Panels, has been lacking. However, with the assistance of Prof. Dr. Rachel Giles (Patient Advocate in the EAU Renal Cell Cancer Guidelines Panel on behalf of the International Kidney Cancer Coalition) a potential model has been developed. Recently, a scientific paper mapping out the various aspects of this process was accepted for publication1. The authors consider that transparency, accountability and harmonisation of patient care based on the best available scientific evidence are core elements of this process.

In addition, the GO recently carried out a prioritisation exercise to identify and rank clinical topics that should be addressed in the 2018 EAU Guidelines. This was done through a process of structured consultation of a large stakeholder base. While it is still early days, this may become a standard element of EAU guidelines methodology. Over the past two years, the EAU GO has heavily invested in the development of systematic reviews as a means to ensure that guidelines recommendations are based on the best available scientific evidence. Whilst this has been highly successful, and will continue into the future, a number of important clinical questions elude this process since either no high level evidence has been published, or the available publications do not allow for a clear conclusion because they present contradictory findings. Having a transparent process in place, which can address such questions in a structured fashion, will be hugely beneficial. In this situation formalised consensus finding will allow all stakeholders to reach agreement on such controversial subjects. For this reason an EAU consensus group, chaired by Prof. Dr. Axel Bex, has been set up to develop a protocol to guide this process. The GO firmly believes that in order to maximise outcomes for this consensus process, stakeholder engagement is key. Another future project for the GO is public review of all pre-publication guidelines documents. Other organisations are already following such an approach with highly positive result. Ultimately, all these processes rely on transparency as well as the management of all stakeholders’ potential

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conflicts of interest (COI). To address the issue, Prof. Dr. Anders Bjartell and a team of EAU GO Panel Chairs have developed a policy document addressing the handing of potential conflicts. The GO sincerely hope that when we reach out to you to learn your views, you will enthusiastically engage with us since all EAU members are key stakeholders in all of the activities of the organisation. Reference 1. MacLennan SJ, et al. Eur Urol prior to print. Changing current practice in urology: improving guideline development and implementation through stakeholder engagement.

TP 59 1.0 02/2017/A-E

This involves all individuals and groups that ‘use’ clinical guidelines, are subjected to them, or are contributors to their content. Obviously, all of you, at EAU17 are our stakeholders, without exception. Other stakeholders in clinical guidelines development include, but are not limited to: patients, their carers and families, patient

organisations/stakeholder groups, medical professionals and their associations (also from bordering specialties), healthcare funders, industry, politicians and charity organisations.

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Sunday, 26 March 2017

Filling the GAP How to include MRI for active surveillance of low-risk prostate cancer Prof. Chris Bangma Chairman, Department of Urology Erasmus University Rotterdam (NL)

still improving, the new kid on the block is genetic profiling. All of the technologies mentioned have their individual diagnostic and prognostic value, and their relative importance varies over time. Here we focus on MRI as part of a multiparametric risk evaluation in men with newly diagnosed and low risk cancers.

Ivo Schoots Associate professor, Radiology Erasmus University Medical Centre Rotterdam (NL)

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 screening because he has a first-degree relative (a father or brother) or a female relative with breast cancer, we need to live with the uncertainty that over time a symptomatic prostate cancer can surface. And the longer the period for our predictions is, the larger the uncertainty will be. This means that we better refrain from looking ahead more than 10 to 15 years (with the likely exception from having a very low serum 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 biopsies.

Sophie Bruinsma Postdoctoral researcher, Department of Urology Erasmus University Medical Centre Rotterdam (NL)

Now we hope of course, that histologic biopsies will become unnecessary to diagnose prostate cancer, and if by non-invasive testing with imaging, urine and blood tests we can claim that a person will not be affected by symptomatic prostate cancer, that would be ideal. That, however, is unlikely to happen during our careers. What might happen is that an individual can be provided with a likelihood of not having a relevant cancer for the next 10 years, based on urine and blood tests, enriched with information obtained by imaging when needed. And this in combination with an individualised advice for re-screening in case there is a low-risk. Also it is reasonable that in case of an increased risk on prostate cancer an adjusted scheme for diagnostic biopsies will be provided, sometimes with systematic biopsies, sometimes with targeted biopsies only, to minimize the number of unnecessary diagnostic biopsies.

Figure 2: The care path for active surveillance (A.R.Alberts, Erasmus MC). The top line depicts current Active Surveillance PRIAS-MRI study protocol. Confirmatory MRI with targeted biopsies within 12 months of diagnosis may add to the earlier diagnosis of low-risk tumours (or to upgrading), but at the cost of missing some upgraded tumours compared to systematic confirmatory TRUS biopsies. Offering systematic biopsies in case of negative MRI to men with increased risk by PSA-density or genomic profiling may optimize the care path (blue path).

targeted biopsies and additional upgrading of low-risk tumours towards intermediate or even high-risk tumours in ca. 10% of cases, not detected by systematic TRUS guided biopsies. This is on top of the value of repeated systemic TRUS directed biopsies itself, which already corrects grading in ca. 20% at confirmatory biopsies. However, would the diagnosis be dependent on targeted biopsies only, then 10 % of relevant tumours would be missed upfront due to the lack of systematic biopsies.

low-volume studies so far. Still, the number of men being followed for at least five years needs to grow, since at the moment sufficient imaging data is available in less than 5% of the 14,000 participants. To assess the value of MRI for the future management of AS, from 2017 to 2019, the database will be retrospectively complemented and prospectively extended with data of more modern patients diagnosed by MRI.

Where there is no MRI Active surveillance has turned out so far as a safe This means that MRI can reduce the upfront treatment option for men with low-risk cancers, as less misclassification by correction of targeted biopsies in than 3% of men develop metastases due to missing men that were selected with low-risk tumours tumour progression during the follow-up of 15 years The public awareness on prostate cancer has (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 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 reason for reclassification within one year in AS This means that the use of MRI aims at improving the cancer incidence has changed profoundly. protocols currently is an upgrading by confirmatory outcome of follow-up, reduce the initial 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 underestimating the size of the lesion. Correction of this number of unnecessary biopsies needed for the societies (Torre 2012), statistics show the steepest 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 PSAMovember 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 Foundationsâ&#x20AC;&#x2122; 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 menâ&#x20AC;&#x2122;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, EUT@uroweb.org 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

Biomarkers for immune checkpoint inhibitors A key concern: Identify patients who may benefit from new strategies Prof. Shahrokh F. Shariat Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna (AT)

The field of immuno-oncology has witnessed unprecedented success in recent years, with several programmed cell death 1 (PD-1) and PD-L1 inhibitors obtaining US FDA and EMA registration and breakthrough drug therapy designation in multiple tumor types such as bladder and kidney cancers. Immune checkpoint blockade activates cellularmediated immune response against tumor cells. Preclinical studies have shown that blockade of either PD-1 or its ligands improve T-cell effector function, and blockade of PD-L1 increased infiltration of tumor-reactive CD8+ T cells in mouse models. Besides the PD-1/PD-L1 pathway, another immunomodulatory mechanism that has been exploited in the clinical setting is cytotoxic T-lymphocyte antigen-4 (CTLA-4), a surface receptor on effector T cells that interacts with antigen-presenting cells, leading to T-cell arrest. Other new targets of immunomodulation that are under active investigation include TIM3, an immune checkpoint molecule frequently co-expressed with PD-1, and LAG3, a co-stimulatory receptor that decreases cytotoxic T-cell function. These breakthroughs are reaching us in an age where cancer treatment strategies are evolving from an all-comer approach with cytotoxic chemotherapies to biomarker-driven strategies with molecular targeted agents where patients with potentially actionable mutations/molecular alterations are matched with rational antitumor therapies. Despite showing promising efficacy, immune checkpoint inhibitors fail in a substantial percentage of patients in addition to causing toxicities and substantial financial burden. It is, therefore, critical to identify patients likely to benefit from such therapies and develop strategies to differentiate responders from non-responders early during treatment. Unfortunately, to date, the search for robust analytically and clinically validated biomarkers that can accurately and reliably predict response to immune checkpoint inhibitors has been without success. A specific problem for immune checkpoint inhibitors is that conventional treatment response criteria to immunotherapies using standard imaging techniques are not optimal assessment strategies. They may sometimes be misleading due to the tumor flare phenomenon which represent a pseudoprogression of tumor due to inflammatory cell infiltration or necrosis of tumor due to treatment response. This is further compounded by the poor correlation between response rates and overall survival as evidenced by the subgroup of patients who achieve durable long-term responses despite not developing an objective radiological response. As such, in addition to predictive biomarkers, there is a need to seek biomarkers that can reflect treatment response more accurately and to serve as surrogate intermediate end-point markers. PD-1 and PD-L1 have been assessed as predictive markers of response to PD-1/PD-L1 inhibitors. While PD-1 expression may be the most intuitive choice as a predictive biomarker of response to PD-1 inhibitors, early studies indicated that PD-L1 expression showed better correlation with antitumor response. Nonetheless, correlation with clinical outcomes has not been consistent. PD-L1 can be expressed both constitutively due to oncogene activation and the dysregulation of signaling pathways, or induced in an adaptive fashion by pro-inflammatory factors such as IFN-γ. Tumors with constitutive PD-L1 expression have also been linked to specific oncogenes, such as phosphate and tensin homolog loss, EGFR activation and the janus kinase/signal transducers and activators of transcription pathway in T-cell lymphoma. However, the majority of other tumors, which express PD-L1 appear to have dynamic levels of PD-L1 expression, which are influenced by the tumor microenvironment and a host of inflammatory factors. The upregulation of PD-L1 leads to increased binding to T cells through PD-1, creating an overall 14

EUT Congress News

dampening effect on immune feedback, permitting tumor cells to escape immune surveillance. PD-L1 protein expression Early studies have shown promising results when testing pretreatment tumor biopsy specimens for cell surface PD-L1 protein expression using immunohistochemistry. The preferred expression cutoff for PD-L1 positivity was set at 5%. Meanwhile this candidate predictive biomarker has been tested in various anti-PD-1 and anti-PD-L1 therapeutic studies with varying degrees of success. In general, while increased PD-L1 expression correlates with improved response to PD-1/PD-L1 inhibitor treatment, it has also become clear that there is a proportion of patients withPD-L1-negative tumors who still respond to therapy. Currently, the only companion diagnostic for PD-L1 expression approved by the FDA is the pharmDx test of PD-L1 IHC 22C3 to assess PD-L1 expression prior to pembrolizumab use, which has been FDA- approved for bladder cancer. Nivolumab has been FDA-approved with a complementary but not mandatory PD-L1 IHC 28–8 PharmDx diagnostic. It is important to realize that while PD-L1 positivity may potentially correlate with improved response rate and survival, multiple studies have repeatedly shown that there is a small but definite proportion of patients with PD-L1-negative tumors who continue to benefit from treatment. Excluding such patients from potentially life-prolonging treatments on the basis of immunohistochemical expression thus remains a clinical and ethical dilemma. This, together with the biological and technical complexities of PD-L1 expression using immunohistochemistry, limits PD-L1’s utility as a predictive biomarker. Multiple tumor factors contribute to the challenge of assessing PD-L1 expression of an isolated tumor specimen at a single time point as a critical indicator in determining if a patient may benefit from anti-PD-1 or anti-PD-L1 therapy. Due to the adaptive nature of PD-L1 and its upregulation by pro-inflammatory conditions, PD-L1 expression levels tend to be dynamic rather than stagnant, raising questions as to whether a single tumor sample that may have been taken at the time of a patient’s original diagnosis is truly reflective of the current state of disease, especially after multiple lines of antitumor therapy. PD-L1 expression also tends to be focal, mainly bordering areas of tumor cells and lymphocytes, leading to concerns of sampling error by missing the tumor-immune interface and thereby rendering false negative results. Indeed, in a study that assessed matched patient samples from primary and secondary sites of disease from patients with RCC, there was discordant tumor cell PD-L1 staining in 20.8% of patients, raising concerns that inter-tumor immunologic heterogeneity may confound the accuracy of overall tumor PD-L1 expression status. Additionally, PD-L1 is expressed not only on tumor cells but other components in the tumor microenvironment, such as macrophages and lymphocytes. Determining if positive PD-L1 expression is actually meaningful on such cells is currently an area of active research. Candidate predictive biomarkers Emerging alternative candidate predictive biomarkers include the tumor’s mutational load, neo-antigens, tumor infiltrating immune cells and the tumor microenvironment. While correlation of response to immune checkpoint inhibitors with driver mutations has been largely unsuccessful, there is mounting evidence that mutational load may correlate with response to immune checkpoint inhibitors. Melanoma, lung and bladder cancers – malignancies in which PD-1 and PD-L1 inhibitors are now approved – ranked as the tumors with the highest median mutational load. Most recently, a Phase II study of atezolizumab in patients with advanced bladder cancer evaluated the mutational load of enrolled patients, and showed that the median mutational load was significantly higher in responders compared with non-responders (12.4 vs 6.4 per megabase; p < 0.0001), independent of The Cancer Genome Atlas subtype or immune cell subgroup1. While costs of genomic sequencing has been steadily decreasing over the past decade, whole exome and whole genome sequencing and their respective data analyses remain challenging in terms of the associated relative financial costs and time implications as well as bio-informatic challenges, limiting their large-scale application in the routine clinical setting. \While PD-1 inhibitor trials in colorectal cancer have been disappointing, patients with mismatch-repair

deficient tumors –determined by microsatellite instability analysis – had an improved objective response rate (62 vs 0%) and disease control rate (92 vs 16%)2. This is interesting for us urologists since upper tract urothelial carcinoma carries a significant alteration rate in mismatch repair genes. While further studies are needed, these data suggest that targeted next-generation sequencing panels or microsatellite instability analyses may potentially be a more time and cost–effective surrogate of the mutational load of tumors. The link between mutational load and response to immune checkpoint inhibitors is likely to be due to the production of neo-antigens by tumor cells compared with somatic cells. Single nucleotide mutations may lead to changes in peptide sequences producing T-cell neo-antigenic peptides that are prone to immune attack. A greater mutational load may thus translate to a higher number of neo-antigens, which may potentially lead to greater T-cell dependent cytokine production and tumor cell kill when immune checkpoint blockade is lifted. In advanced melanoma treated with ipilimumab, a neo-epitope signature was correlated with survival3. In urologic cancers, there are no such studies yet. The inherent challenges in the study of neo-antigens are that not all may elicit a T-cell response. While there may be shared antigens present in the majority of tumors, it may be the unique antigens present within each patient that are necessary to elicit immunogenicity. While the correlation of mutational load and neo-antigens may be scientifically promising as a tool for the prediction of response to immune checkpoint inhibitors, further investigation is still required to confirm their clinical utility. Finally, there is a complex host of factors in the tumor microenvironment, which collectively influence immunomodulatory effects to either promote or combat tumor growth. Strong lymphocytic infiltration has been shown to be associated with improved patient outcomes in bladder cancers4. While the

prognostic value of tumor-infiltrating immune cells has consistently been shown in various tumor types, its predictive role is still under investigation. Today, the era of truly personalized immunotherapy is well within reach – heralding further acceleration and innovations in patient care. Two future areas that sound promising are molecular imaging with radionuclides tagged to antibodies like anti-cytotoxic T-lymphocyte antigen-4 or anti-PD-L1 and immune surveillance with monitoring of the T-cell receptor repertoire in both tumor tissue and peripheral blood samples. Building on the significant benefits that have already been demonstrated in multiple tumor types, the incorporation of state-of-the-art high-throughput predictive or response biomarkers will improve our ability to select patients for stratified immunotherapy, identifying those who are most likely to respond to treatment while minimizing the risks of immunerelated toxicities. References 1. Rosenberg JE, Hoffman-Censits J, Powles T et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, Phase II trial. Lancet 387(10031), 1909–1920 (2016). 2. Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372(26), 2509–2520 (2015). 3. Snyder A, Makarov V, Merghoub T et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371(23), 2189–2199 (2014). 4. Sharma P, Shen Y, Wen S et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc. Natl Acad. Sci. USA 104(10), 3967–3972 (2007).

Sunday 26 March 11.10-11.25: Thematic Session 6, Immunooncology: Changing treatment paradigms in renal and urothelial cancer

ChM in Urology PART-TIME ONLINE MASTER OF SURGERY DEGREE PROGRAMME

This two year part-time Masters programme in Urology, taught entirely online, is offered by the Royal College of Surgeons of Edinburgh and the University of Edinburgh, and leads to the degree of Master of Surgery (ChM). Based on the UK Intercollegiate Surgical Curriculum, the programme provides the opportunity for advanced trainees in Urology to study modules relevant to their declared specialty and supports learning for professional urology examinations FRCS(Urol) and FEBU. “I found the experience of this degree rewarding and informative, with the benefit of seeing the quality of my practice improve. “

For futher information please email: chminfo@rcsed.ac.uk

www.urochm.rcsed.ac.uk Sunday, 26 March 2017

Ureterocutaneostomy UUCS is a good option for frail and elderly patients • Pull through both ureters at least 1.5 cm above skin level • Observe arterial capillary bleeding from both ureter stumps and spontaneous urine ejaculation • The greater omentum is brought through the gap, completely wrapping both ureters • The omentum is fixed with single stitches Vicryl 3/0 to the rectus fascia at the outer and the inner side • Both ureters are spatulated on a length of at least 1.5cm • A single stitch Monocryl 6/0 unites both ureters in There are two epidemiological phenomena, which the middle on the deepest point (knot to the 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 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 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 associated with a significant rate of postoperative after 90 days and was followed by an endovenous 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 maximising the patient‘s benefits. We present a diversion. Intestinal complications after an end-tomodified 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 Indications, limits, risks and contraindications group with 34.5% the colon conduit group had 5.8% 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 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. (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 Operative technique step by step: reproducibility. • Landmarks are: xyphoid, 12th rib, umbilicus, superior anterior iliac spine and symphysis However, patients with primary muscle invasive • 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 the retroperitoneum (cave: the mesoslit has to be complications in RC is to avoid intestinal surgery. The 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 Prof. Armin Pycha Sigmund Freud University Medical School Vienna (AT) Department of Urology General Hospital of Bolzano Bolzano (IT)

Sunday, 26 March 2017

patients a ureterocutaneostomy is a good option and will experience a renaissance, as age alone can not be an exclusion criteria for cure or palliation. However, only simple and reproducible approaches will stand the test of time. Figures 8: Pull-through maneuver completed

Editorial Note: Due to space constraints the reference list has been omitted. Interested readers can email at EUT@uroweb.org for a complete listing. Sunday 26 March 11.30-11.45: Thematic Session 8, Challenges in urinary tract reconstruction

Figures 9: Pull-through maneuver completed

Figure 1: The stoma position

Figure 10: Both ureters fixed and wrapped by the greater omentum

Figure 2: The cross-over maneuver completed

Figure 3: Circular excision of the skin in former marked stoma region

Figures 11 and 12: Stoma construction

Figure 4: Incision of the fascia in a cross-like fashion

Figure 13: Stoma completed Figure 5: The length of both ureters after the cross-over maneuver is checked

Figure 6: The greater omentum is divided and an omentum flap is created

Figure 15: Stoma examples

Figure 7: he size and the length of the omentum flap is checked

Figure 14: Stoma 36 months after construction

EUT Congress News

Congenital lifelong urology Multidisciplinary team: Best suited for patients needing care for congenital anomalies Mr. Dan Wood Institute of Urology at University College London Hospitals London (GB)

Children born with congenital anomalies of the genitourinary tract receive the highest level of care in their paediatric life. This has led to a dramatic improvement in outcomes. Survival is now regarded as normal – even in the face of major anomalies. This is as a result of surgical innovation and excellence in specialist centres combined with proactive care (such as intermittent self catherisation) early in life. Surgical developments, alongside other specialties, such as intensive care have led to a realistic rise in expectations. Parents and, latterly, patients now anticipate reasonable urinary function and as a profession we aim to offer this. These are combined with expectations relating to sexual and reproductive function all contributing to an expectation for a quality of life comparable to their peers1,2. The paediatric urological community has cared for a group of patients who have and are continuing to reach adolescence and adulthood. Despite excellent care many of these patients continue to need long-term surveillance and revision surgery. Many will have concerns about normality, function, cosmesis and significant fears relating to anaesthesia, needles and further surgery. These teenagers are knowledgeable (and some expert), they quickly recognize healthcare staff who are not familiar with their condition or prior

treatment. Anecdotally, it is common for them to report negative experiences if they are seen in a setting that appears not to cater for their needs. In some, this is because their expectations may be unreasonably high – naturally this needs to be managed so that all parties are realistic but that patients have excellent care maintained. In short – it will depend on the staff involved and the environment but if these patients are seen in a busy general clinic it may be much more difficult to tackle some of their needs. The importance of this is that teenagers can be very difficult to engage with - this is most obvious in young men3. Published data suggests that some specialties are running transition well4 and that as a result, health outcomes may be improved5. With support from both the European Society of Paediatric Urology and the European Association of Urology, we have formed a working group. The aim of this group is to promote the care of these patients by contributing to both annual meetings. The potential for further innovation such as joint meetings with specialist groups such as ESGURS, ESAU and ESFFU exists and the work of Prof. Piet Hoebeke and his team in organizing the first joint meeting between ESGURS and the ESPU in 2015 demonstrated the potential to be found in such projects. We have welcomed support from the ESPU, EAU, SIU and BAUS in supporting educational sessions within their meetings. We have collaborated with colleagues, as part of the AUA, and contributed to sessions in the American meetings too. The value of this is to establish a means by which these teenagers and young adults can receive lifelong care, when it is needed. There is no one model that works in all settings. The principles are based on preparation and transition where the child develops their own understanding of their diagnosis, treatment and takes responsibility for their healthcare needs. As they develop this

da Vinci

independence, the healthcare relationship shifts away from their parents or carers, taking responsibility to the patient themselves. This can be difficult for a variety of reasons relating patient, parents, politics and finance. Above all, the service needs energy and expertise from a multidisciplinary team who have dedicated time for these patients. This allows investment and development of the service in the first instance and specialist clinics and surgery in the long-term. We know that some conditions are vulnerable to late renal failure – these include posterior urethral valves – whilst important, early changes can be subtle and awareness is important to allow detection and understanding risk factors becomes important6. Whilst many have worked hard to produce information on outcomes some conditions appear to have complication rates potentially worse than originally published. It is important to emphasise that this is not because of bad surgery – many factors appear to play a part – not least the underlying disease and puberty. However, to take hypospadias as an example we have no clear understanding about the denominator, standardization of the condition and the surgery. This means that in the current environment it is a huge challenge to produce data that gives the real outcomes for complications such as stricture, fistulae and re-operation rates7,8. Other patients need monitoring following complex reconstruction – looking for factors such as metabolic change, stones and infection. Others will need reconstruction in adolescence and adulthood whilst around 60% of those who have had bowel incorporated into their urinary tract in childhood will need further surgery in adulthood. There is a huge range of potential interest. This is a field that is early in its development and the population of patients needing care will inevitably grow – creating a wide range of clinical and academic opportunities9,10.

Some of the work will involve controversial decisions and thus needs to be dealt with as part of multidisciplinary teams. In some groups the timing and nature of surgery or the increasing development of patient understanding and their own questions around existing standards of care provide clinical, surgical, moral, ethical and intellectual challenges that clinicians must confront11. By definition, paediatric urologists are passionate about these patients and have a strong desire to see that they have good ongoing care. This needs to be comparable to their previous care. Whilst there are pockets of interest - the aim of the working group is to educate and encourage adult urologists to develop an interest in these patients and provide specialist care as part of their practice. We hope that this stimulus will enliven interest in the adult urological community. In the long-term the working group hopes to see the development of wider academic work, the ability for interested clinicians to communicate and network with similarly interested colleagues. This can only help with providing clinical support for those working in this field and, as a result, improve care for all patients across the board. Ultimately, with the engagement of a wider group of clinicians all will benefit. In the long-term the development of educational programs, fellowships and guidelines may ensue. We would welcome interest from any clinicians and would be delighted to support those who have interest and aptitude for the care of these patients. Editorial Note: Due to space constraints the reference list has been omitted. Interested readers can email at EUT@uroweb.org for a complete listing. Sunday 26 March 11.30-11.45: Thematic Session 7, Paediatric urology

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

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Sunday, 26 March 2017

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Meta-analysis re-reviews the current body of evidence 1

New insights and recommendations on decreasing the risk of progression in bladder cancer Blue-light cystoscopy (BLC) has shown promise in improving detection of bladder tumours and is increasingly becoming a standard in clinical practice.1 Just recently, the first meta-analysis showing the impact of hexaminolevulinate-guided bladder cancer Transurethral Resection of the Bladder (TURB) on reducing progression rates was published.1 At the same time, the new 2016 French National Guidelines2 (AFU) for the management of bladder cancer (BC) have been presented, in which blue-light cystoscopy is recommended for the first TURB in the majority of the BC patients. Clinical trials have shown that hexaminolevulinate (HAL) fluorescence cystoscopy improves the detection of bladder tumours compared with standard white-light cystoscopy (WLC), resulting in more efficacious treatment.3 A meta-analysis of raw data had previously revealed an increase in the detection rate of carcinoma in situ (CIS) by 40%, and there were almost 25% patients with at least one additional Ta/T1 tumour seen with BL only (p < 0.001).4 Despite improved detectability of bladder cancer with BLC, literature has not reported a beneficial impact on progression in non-muscle-invasive bladder cancer (NMIBC). However, progression is one of the most important clinical outcomes in non-muscle-invasive bladder cancer as it indicates a worsening of disease.5 A working group compared the results of HAL- vs. white-light guided TURB and found out that rate of progression was significantly lower in patients in whom a TURB was performed with BLC versus WLC alone.1 This recently published meta-analysis by Gakis et al. included NMIBC studies published between 2000 and 2016 reporting on progression after HALand WL-based TURB. Eligible studies were identified via PubMed search and a manual search of publications in journals not listed in PubMed. The selection excluded non-English articles, non-original articles (i.e. review articles with or without systematic review or meta-analysis), editorials or case reports, studies on 5-aminolevulinic acid (ALA)-based TURB, and repeated publications on the same cohort to avoid publication bias. Overall more than 1,300 patients studied The review covered a total of 294 studies, of which five were considered for final analysis (Figure 1). Of the 1,301 patients in these five studies, 49.5% (n=644) underwent BL TURB and 50.5% (n=657) had a WL TURB. Progression was found in 6.8% of BL patients, (44/644) and 10.7% of WL patients (70/657), which was statistically significant (median odds ratio: 1.64, 1.10–2.45 for HAL vs. WL; p = 0.01). Progressionfree survival was reported in a single study and was longer after BL TURB and showed a trend towards improved survival (p = 0.05). The primary objective of the analysis was the rate of progression due to the fact that a beneficial impact of HAL-guided TURB on progression of NMIBC has not been confirmed in meta-analyses until now1. One reason may be that so far, clinical trials have used varying definitions or have failed to define disease progression altogether.5 Therefore, the International Bladder Cancer Group (IBCG) suggests a new definition that goes beyond the commonly used increase in stage from non-muscle-invasive to

UKHEX00164 February 2017

Sunday, 26 March 2017

muscle-invasive bladder cancer.5 The largest and most recent publication included in the review re-analysed the dataset of a phase III randomised trial on HAL- vs. WL-TURB with regard to progression using the new IBCG definition.5 “This is the first meta-analysis which shows a significant beneficial impact of NMIBC detection and resection with HAL-guided TURB on progression. Patients should therefore receive hexaminolevulinaterather than white-light-guided TURB [alone] at their first resection as this might allow more patients at risk of progression to be treated timely and adequately.” Professor Gakis from the Department of Urology, University Hospital Tuebingen, Germany, summarised the result of the review1. Diagnoses with BLC was also associated with decreased risk of recurrence of non-muscle-invasive bladder cancer versus WLC in another recently References published meta-analysis.6 This publication included 1. Gakis G, Fahmy O Systematic review and meta-analysis stratified analyses by use of 5-ALA and HAL. Findings on the impact of hexaminolevulinate- versus white-light were similar when looking at short-term, guided transurethral bladder tumour resection on intermediate-term and long-term recurrence risk. progression in non-muscle invasive bladder cancer. Effects on short-term and long-term recurrence were Bladder Cancer 2016;2:293–300. DOI: 10.3233/BLC-160060 statistically significant in trials that used HAL, and were 2. Rouprêt M et al. CCAFU French National Guidelines not statistically significant in trials that used 5-ALA.6 Diagnostic with Blue-light cystoscopy for the first resection Today, BLC is mentioned and recommended in the majority of Guidelines (Figure 2), including the recently updated American Urological Association (AUA), Association Française d’Urologie (AFU) and Deutsche Gesellschaft für Urologie (DGU) Guidelines from 2016. On November 17th, 2016, during the national meeting of the Association of French Urologists (AFU) in Paris, France, the new 2016 French National Guidelines for the management of Bladder Cancer were presented.7 The purpose of the Comité de Cancérologie de l’AFU (CCAFU) was to propose updated French Guidelines for non-muscle-invasive and muscle-invasive (MIBC) bladder cancers. In order to evaluate references and their levels of evidence, a Medline search had been conducted covering diagnosis, treatment and follow-up of bladder cancer between 2013 and 2016.

2016-2018 on bladder cancer. Prog Urol 2016;27 (Suppl 1):S673–S91. DOI: 10.1016/S11663–7087(16)307043–7. 3. Di Stasi SM et al. Hexaminolevulinate hydrochloride in the detection of non muscle invasive cancer of the bladder. Ther Adv Urol 2015;7(6):3393–50. DOI: 10.1177/ 1756287215603274 4. Burger M et al. Photodynamic diagnosis of non-muscleinvasive bladder cancer with hexaminolevulinate cystoscopy: A meta-analysis of detection and recurrence based on raw data. European Urology 2013;64(5):846–54.

DOI:10.1016/j.eururo.2013.03.059 5. Kamat A et al. The impact of blue light cystoscopy with hexaminolevulinate (HAL) on progression of bladder cancer – a new analysis. Bladder Cancer 2016;2(2):2733– 278. DOI: 10.3233/BLC-160048 6. Chou R et al., Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis or surveillance of bladder cancer on clinical outcomes: systematic review and meta-analysis. J Urol. Article in press. DOI: http://dx.doi.org/10.1016/j.juro.2016.10.061 7. Rouprêt et al. CCAFU French National Guidelines 2016-2018 on bladder cancer. Prog Urol 2016;27 (Suppl 1):S673–S91. DOI: 10.1016/S11663–7087(16)307043–7 8. Rouprêt et al. Cost effectiveness of TURBT of the bladder with blue light in patients with non-muscle invasive bladder cancer in France. Progres en urologie (2015) 25, 2563–264.

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 hydrochloride as a powder and one 50mL polypropylene or glass vial containing solvent. After reconstitution in 50mL of solvent, 1mL of the solution contains 1.7mg hexaminolevulinate which corresponds to an 8mmol/L solution of hexaminolevulinate. Indications: This medicinal product is for diagnostic use only. Hexvix blue light fluorescence cystoscopy is indicated as an adjunct to standard white light cystoscopy to contribute to the diagnosis and management of bladder cancer, in patients with known or high suspicion of bladder cancer. Dosage and Method of Administration: Hexvix cystoscopy should only be performed by healthcare professionals trained specifically in Hexvix cystoscopy. The bladder should be drained before the instillation. Adults (including the elderly): 50mL of 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 The new French Guidelines recommend blue-light should start within approximately 60 minutes. The cystoscopic examination should not be performed more than 3 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 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 many patients. This facilitates the most correct staging identified making examination non-informative. For optimal visualisation it is recommended to examine and map the entire bladder under both white and blue light before any surgical measures are initiated. Biopsies of all and grading, which is crucial for the optimal 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 to blue light. Only CE marked cystoscopic equipment should be used, equipped with necessary filters to allow both to the former version of the Guideline the update standard white light cystoscopy and blue light (wavelength 380-450nm fluorescence cystoscopy). Children and includes the situations in which diagnosis with BLC adolescents: There is no experience of treating patients below the age of 18 years. Contraindications: Hypersensitivity 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 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 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 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 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 the Pitié-Salpétrière Hospital, University Paris, and porphyrin build up and increased risk of local toxicity upon illumination, and false fluorescence. If a widespread 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 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 into the European Guidelines for the use of blue light undergone surgical procedures of the bladder. Interactions: No specific interaction studies have been performed with hexaminolevulinate. Pregnancy and Lactation: There are no or limited data on the use of hexaminolevulinate cystoscopy should result in an increased level of in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to the reproductive urological care for the management of patients with toxicity. As a precautionary measure, it is preferable to avoid the use of Hexvix during pregnancy. It is unknown bladder cancer in France.” 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. information.uk@ipsen.com Hexvix® is the property of Photocure. EUT Congress News

Adreno-cortical carcinoma Surgery and medical treatments to improve oncological outcomes Prof. Francesco Porpiglia San Luigi Hospital Division of Urology Orbassano (Turin) Dept. of Oncology University of Turin Turin (IT)

Adreno-Cortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million/year. It has two peaks of incidence: the first one in the first decade and the second one between 40 and 50 years. Women are the most frequently affected (55–60%). ACC is associated with poor prognosis, with a 5-year survival rate of approximately 65%, 24% and 0 % for patients in stages I-II, III and IV, respectively. Diagnosis Most patients (40–60%) present steroid hormone excess (glucocorticoids, mineralocorticoids, androgens) or modifications of abdominal mass (30%). Hormone hyper-secretion may lead to Cushing syndrome, virilization (in female patients, up to 10%) or, rarely, to feminization (in male patients) or Conn syndrome (1-2% of ACCs). On the contrary, in up to 20% of cases the diagnosis is incidental. The European Network for the Study of Adrenal Tumors (ENS@T) suggests a pre-operative hormonal workup based (at least) on the assessment of basal cortisol, ACTH, dehydroepiandrostenedione sulfate, 17-hydroxyprogesterone, testosterone, androstenedione, estradiol, dexamethasone suppression test and urinary free cortisol. Contrastenhanced thoraco-abdominal computed tomography is a minimum requirement in the study of ACC.

Proliferation index as Ki-67 immuno-marker mitotic count (Ki-67 index) may help the clinicians to differentiate low-grade (Ki-67 <10%) and high grade ACC (>10%) and to guide clinical decision. Indeed, Ki-67 is a powerful prognostic marker in both localized and metastatic disease.

Need of adjacent organ resection When ACC is diagnosed in advanced stage, surgery is extensive, implying additional procedures beyond adrenalectomy, such as nephrectomy, resection of pancreas tail and/or partial hepatectomy in order to get a R0 resection.

Sequencing methods and genome-wide genomic studies, particularly with high-throughput sequencing (next generation sequencing - NGS) will probably play a role in the future in the field of ACC.

Figure 1: CT scan showing a large left ACC. Controversies exist on the need of nephrectomy even when not macroscopically involved. Many years ago, some authors advocated that nephrectomy would help to decrease the high recurrence rate of ACC, because it would allow wide operative margins and avoid violating the tumor anatomic space, but this opinion has not yet been further validated. In a recent paper, our group demonstrated that adjunctive nephrectomy does not modify the oncologic results of adrenalectomy in the treatment of stage II ACC in terms of recurrence-free and overall survival. Thus, when there are no signs of ACC local invasion, surgeons should make every effort to preserve the kidney. In the previously cited consensus on surgical treatment of ACC, renal-sparing resection of the upper Figure 2: CT scan showing a small, left adrenal incidentalomas pole fatty tissue is suggested when feasible.

Staging Two classification systems have been proposed for ACC: the ENS@T staging system and the Union Internationale Contre le Cancer (UICC). The former (Table 1) proved its superiority over the latter, both in European and in North-American studies; therefore, its use is recommended. Surgery Surgical resection plays a key role in the management of the disease, especially in its early stages, when there might still be a window for cure. Indeed, a complete resection of the ACC (R0 resection) correlates with a better prognosis and represents the only chance of cure. On the contrary, an incomplete microscopic resection (R1), or an incomplete macroscopic resection (R2) are associated with the worst over-all survival. With the aim of providing standards for the perioperative surgical care for patients with ACC, a collaborative working group from ENS@T and ESES (European Society of Endocrine Surgeons) recently proposed the “recommendations on the surgical management of ACC” that will soon be available.

Open versus minimally invasive surgery Traditionally, open surgery has been considered the gold standard surgical approach to ACC. Over the last decade some authors challenged the role of open adrenalectomy (OA) suggesting that laparoscopic 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 [Figure1]. Haemorrhage and necrosis are often based on retrospective studies and most of reported; vascular invasion with a tumor thrombus laparoscopic series published by European and extending within the left renal vein and/or the inferior American centres report small data series and lack of vena cava (IVC) is not uncommon; metastases are long-term oncologic follow-up. In a recent metafrequently found at the baseline staging, most analysis 240 LA and 557 OA for ACC were compared; commonly at regional or paraortic/paracaval lymph no differences were found in time-to-recurrence, as nodes, lung, liver and bone. well as for cancer specific survival, even if tumors that underwent laparoscopic treatment were smaller, with Gadolinium-enhanced Magnetic Resonance Imaging a higher proportion of them being localized (I–II (MRI) and chemical shift MRI may give the same stage) if compared to those who underwent open information as the CT scan but may better define an surgery (80.8 vs 67.7 %, respectively). Interestingly, eventual IVC invasion. Concerning the functional the development of peritoneal carcinomatosis at the imaging, ACC showed a high 18F-fluorodeoxyglucose time of recurrence was higher for LA versus OA (RR: (FDG) uptake but the routine use of FDG-PET still 2.39). The authors concluded that OA should be still needs validation. Recently, the metomidate ([11C]MTO) considered the standard surgical management of ACC proved to be useful in identifying the adrenocortical even if laparoscopy may play a role in this setting, but origin of the tumours because it specifically binds to in carefully selected cases. Tumor size is a major issue adrenocortical CYP11B enzymes, which has a key role as the risk of spillage or capsule rupture is more likely in the synthesis of steroids. This new tracer seems to if the tumor diameter is over 8-10 cm; moreover, be promising but is still under evaluation. imaging should exclude local invasion when an LA is planned. Anyway, when an LA is performed, the Pathology principles of oncologic surgery have to be respected Macroscopy revealed a usually large, heterogeneous and the threshold for conversion to an open surgery lesion with a colour surface that ranges from brown should be low. to yellow depending on the lipid content of the cells; gross necrosis is virtually always present. LND Microscopically, invasion of tumor capsule, Lymph node dissection (LND) as a routine step of the extra-adrenal tissue, lymphatic or blood vessels are surgery for ACC has not been extensively studied. Up the typical features of ACC. The Weiss score is to this day it has not been proven to definitively affect commonly used: it is composed of nine items (three the outcome. In general, retrospective data suggest concerning the architecture, three the nucleus and that regional lymph-node involvement in ACC has a three the presence of any type of invasion). The sum negative impact on over-all survival and is often the of the positive items (each one scores 1 if positive) cause of local recurrences. In terms of oncological defines the final score and a Weiss score > 3 defines outcome, the most important data comes from the an ACC. German ACC registry and suggest a reduced risk of local recurrence and disease-related mortality, when more than five lymph-nodes are removed. In a recent Table 1: ENS@T stage classification. paper, location of lymph-node involvement during surveillance was reported: on the the left side, the ENS@T stage involvement was perirenal-cranial (48.3 %), para-aortic (44.9 %), inter-aortocaval (24.1 %), and I T1, N0, M0 perirenal ventro-caudal (13.8 %) whilst on the right II T2, N0, M0 side, lymph-node involvement was detected in the III T3-4, N1 perirenal-cranial (55 %), paracaval (10 %), interIV T1-4, N0-1, M1 aortocaval (30 %), and para-aortic (10 %) nodes. T1,tumor _ 5 cm; T2,tumor > 5 cm; T3, histologically proven tumor invasion of surrounding tissue; T4, tumor invasion of adjacent organs or venous tumor thrombus in vena cava or renal vein. Venous tumor thrombus is only a criterion in the ENSAT classification. N0,negative lymph nodes; N1, positive lymph nodes. M0, absence of distant metastases; M1, presence of distant metastases

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Based on this information, a routine loco-regional lymph-nodes dissection should be done at the time of adrenalectomy for highly suspicious or proven ACC. It should include (as a minimum) the peri-adrenal and renal hilum nodes. Enlarged lymph-nodes on preoperative imaging should be removed.

Recurrent or metastatic cancer A few studies investigated the role on survival of the exeresis of metastasis in patients with recurrences. The German Group studied 100 patients who underwent surgery for recurrence. Multivariate analysis showed that time to first recurrence > 12 months and resection of all the clinically apparent disease had impact on progression-free survival and overall survival. Similar results came from the Mayo Clinic Group. Moreover, repeated resection can be offered to patients with local recurrence after initial resection of local recurrence if R0 resection is possible [Figure 3]. Obviously, this kind of surgery is not for all patients: the time-to-first recurrence appears to be basic in predicting the course of the disease, and the risk of morbidity and mortality associated with reintervention should be carefully considered. Finally, some authors suggested a role of the heated intra-operative peritoneal extracorporeal chemotherapy (HIPEC) in the treatment of peritoneal spread of ACC. To date, one clinical trial investigating progression-free survival after the use of HIPEC with cisplatin is ongoing. The initial experience appears to be promising, although selection criteria will need to be developed and risk/benefit ratio should be carefully considered. Other than surgery Besides surgery, over the last years a significant effort has been made to improve the outcome of ACC disease, mainly with the use of protocols of chemotherapy. Adjuvant therapy for local disease As recurrence rate is high in patients undergoing radical resection (up to 50%, in R0 patients) and even higher in patients with incomplete resection (up to 80%), adjuvant treatment is of crucial importance. Mitotane remains the mainstay in this setting (mainly on the basis of the results of German and Italian groups), being recommended for patients with potential residual disease (R1 or RX resection) and in patients with R0 resection with a high-risk disease. In the setting of the adjuvant treatment, radiotherapy should be at least mentioned. Despite the good results of this approach in the local control of the disease, unfortunately none of the authors could demonstrate improvement of recurrence-free and over-all survival in patients who underwent radiotherapy. Neoadjuvant therapy for borderline resectable ACC (BRACC) In a single retrospective study, some authors suggested the role of neoadjuvant chemotherapy (mitotane alone or mitotane + etoposide/cisplatin or etoposide/cisplatin alone) in patients with BRACC, defined as imaging suggesting a need for multiorgan/vascular resection; imaging suggesting potentially resectable oligometastases; and patients having marginal performance status/co-morbidities precluding immediate surgery. These authors concluded that the favorable outcome of these patients, despite more advanced stage of disease compared to those treated with surgery as first step, suggests a benefit of neoadjuvant treatment (followed by surgery) in patients with BRACC. Nevertheless, in view of the overall low response rate of available chemotherapy, upfront surgery remains

with inhomogeneous central appearence. Patient underwent laparoscopic adrenalectomy. Final pathology revealed a small ACC, Weiss score 4, Ki-67 index <10%.

Figure 3: CT scan showing a local recurrence in a patient who previously underwent adrenalectomy and nephrectomy for a large pT3 left ACC, Weiss score 8, Ki-67 index >10%.

recommended if the lesion is amenable to a R0 resection. Medical therapies for advanced ACC Patients with locally advanced disease (stage III) or metastatic disease (stage IV) represent up to 45% of cases at diagnosis. When feasible, surgery should be considered in addition to mitotane as systemic treatment. In patients who failed mitotane as adjuvant therapy or patients with large tumor burden and rapidly progressive disease, treatment with systemic chemotherapy should be considered. Based on the results of the FIRM-ACT trial, which compared cisplatin, etoposide plus mitotane (EDP-M) versus streptozotocin plus mitotane (Sz +M), the former became the first-line regimen for patients with progressive metastatic disease. In case of progression with EDP-M, gemcitabine may be used even the evidence is very low. Targeted therapies The lack of an effective medical therapy for the treatment of recurrent, advanced or metastatic ACC compelled the researchers to identify new potential drugs. Several studies were performed to investigate the role of molecular target therapies in this setting, with poor results. Actually, inhibition of epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF-1R) and vascular endothelial growth factor (VEGF) had no impact on clinical outcomes of the disease. On the contrary, the combination of cixutumumab and temsirolimus that was investigated in a phase I study, seems to be promising even if further studies are required. In an ongoing phase I study, the researchers are investigating the role of ATR-101, a selective inhibitor of esterification of intracellular free cholesterol. This inhibition may activate the apoptotic pathway and promote ACC cell death. Editorial Note: Due to space constraints the reference list has been omitted. Interested readers can email at EUT@uroweb.org for a complete listing. Sunday 26 March 10.30.10.50: Thematic Session 5, Adrenal Disorders, State-of-the-art Lecture, Adrenal cortical carcinoma

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EAU-RF PRECISION study recruits ahead of schedule Comparing MRI-targeted biopsy to standard trans-rectal biopsy in PCa patients [HEAD, BOLD] EAU-RF PRECISION ahead of schedule Dr Veeru study: Recruits Background classical pathway for the biopsy diagnosis prostate Kasivisvanathan [SUBHEAD, ITALS] Comparing MRI-targeted biopsyThe to standard trans-rectal in of PCa patients cancer is TRUS biopsy of the prostate following a raised PSA. TRUS guidance is performed primarily for anatomic guidance and the ultrasound discriminates poorly between cancerous and non-cancerous tissue. Biopsies are concentrated in areas of the peripheral zone, which harbors the majority of cancer.

PRECISION Study Dr Veeru KasivisvanathanCoordinator NIHR Doctoral Fellow PRECISION Study Coordinator in Urology NIHR Doctoral Fellow in Urology University College University College LondonLondon Hospitals Hospitals London (GB) London (GB)

An alternative pathway for the diagnosis of prostate cancer in men with raised PSA is to perform a multi-parametric magnetic resonance imaging (MPMRI) to localize cancer and to use this information to influence conduct of a subsequent biopsy, known as an MPMRI-targeted biopsy. This pathway may offer advantages over the classical pathway.

The EAU Research Foundation (EAU-RF) PRECISION Trial (NCT02380027) began recruiting in February 2016. This is an international multi-centre randomised controlled study that compares magnetic resonance [BOLD] The EAUbiopsy Research Foundation (EAU-RF) PRECISION Trial (NCT02380027) began recruiting imaging-targeted to standard trans-rectal inultrasound Februaryguided 2016.biopsy This isforan multi-centre controlled study that theinternational diagnosis of prostate Study randomised design compares magnetic toisstandard trans-rectal ultrasound cancer in men without resonance prior biopsy.imaging-targeted biopsy The study an international multi-centre randomised trial, with prior 470 men randomised 1:1 ratio to guided biopsy for the diagnosis of prostate cancercontrolled in men without biopsy. Study status one of two arms. Men will either undergo TRUS The study is recruiting ahead of schedule with 267 biopsy, or will undergo a MPMRI and targeted biopsy [SUBHEAD, BOLD] Study status men recruited in 11 months at 18 sites (Data correct as suspicious areas. The study is recruiting ahead of schedule with 267ofmen recruited in 11 months at 18 sites (Data of 12 January 2017). Anticipated recruitment end date correct as of 12 January 2017). Anticipated recruitment end date is October 2017. is October 2017.

Primary Outcome: 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 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) Key patient exclusion criteria 1. Prior prostate biopsy 2. Prior treatment for prostate cancer 3. Contraindication to MRI or prostate biopsy

The potential implications of this trial: • Introduction of an alternative prostate cancer diagnostic pathway • A reduction in the number of patients undergoing prostate biopsy • A reduction in the number of biopsy cores taken per patient Olivier Rouviere, Alain Ruffion, Michiel Sedelaar, Paras Singh, Panu Tonttila, Markku Vaarala, Geert • A reduction in biopsy-related sepsis, pain and Villeirs, Arnauld Villers, Jaspal Virdi. other side effects Predicted recruitment • A reduction in the over-diagnosis of clinically Trial Management Group Actual recruitment insignificant prostate cancer UCL Clinical Trials Group: Chris Brew-Graves, Norman Williams, Samim Patel, Fatima Jichi, Susan

PRECISION recruitment

Number of Patients

Recruited to 12th Jan 2017: 267 patients

450 400 350 300 250 200 150 100 50 0

Tebbs

Research Fellowship (DRF-2014-07-146) and UK sites are funded by the NIHR Clinical Research Network. Participating centres Argentina • Centro de Urologia Belgium • Ghent University Hospital Canada • Jewish General Hospital Finland • Helsinki University Central Hospital • Oulu University Hospital France • Bordeaux University Hospital • CHU Lille, University Lille Nord de France • Lyon HEH and Lyon Sud • Paris Pitie Italy • Sapienza University of Rome, Italy • San Raffaele Hospital, Milan Germany • University Hospital Heidelberg Netherlands • Erasmus University Medical Centre • Radboud University, Nijmegen Medical Centre Sweden • University of Gothenburg United Kingdom • Basingstoke and North Hampshire Hospital • Northwick Park Hospital • Princess Alexandra Hospital • Royal Free Hospital NHS Foundation Trust • University College London Hospitals • Whittington Health Trust USA • Chicago University Hospital • Mayo Clinic Rochester • Weil Cornell Medical Centre • USC Institute of Urology

Funding The EAU Research Foundation provides their 0 1 web-based database management system for collection of patient data and provides all sites per Note: For details on the project, visit https://uroweb. Month Background patient recruited funding. The study coordinator, Veeru org/research/projects/ or contact the author at The classical pathway for the diagnosis of prostate cancer is TRUS biopsy of the prostate following veeru.kasi@ucl.ac.uk a raised PSA. TRUS guidance is performed primarily for anatomic guidance and the ultrasound Kasivisvanathan, is funded by a UK NIHR Doctoral discriminates poorly between cancerous and non-cancerous tissue. Biopsies are concentrated in Chief Investigators Hypothesis [BOLD] Chief Investigators areas of the peripheral zone, which the majority cancer. Caroline Moore, Emberton Theharbors proportion of menofwith clinically significant cancer Caroline Moore,Mark Mark Emberton 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 than that detected by to standard 12-core TRUS biopsy. multi-parametric magnetic resonance imaging (MPMRI) localize cancer and to use this [BOLD] Investigators Manit Arya, Chris Bangma, Franck Bladou, Alberto conduct of a subsequent biopsy, known as an MPMRI-targeted biopsy. information to influence LLITE Manit Arya, ChrisBorghi, Bangma, Franck Briganti, Borghi, Silvan Boxler, Marc T E S I UM This pathway may offerAlberto advantages over the Marcelo classical pathway. Briganti, Marcelo Silvan Boxler,Bladou, Marc Methods O Colombel, Sebastien Crouzet, Pieter De Visschere, Scottreferred Eggener, Futterer, Colombel, Sebastien Crouzet, Pieter De Visschere, Scott Men withNicola clinicalFossati, suspicionJurgen of prostate cancer [BOLD] Study design Maneesh Ghei,Fossati, Inderbir Gill, Boris Hadaschik, Gileswho Hellawell, Jim Hu, Jonasto Eggener, Nicola Jurgen Futterer, Maneesh have hadRichard no priorHindley, biopsy are randomised The study is an international multi-centre randomised controlled trial, with 470 men randomised Hugosson, Veeru Kasivisvanathan, Laurence Klotz, either Drew Moghanaki, Caroline Moore, Ghei, Inderbir Gill, Boris Hadaschik, Giles standard 12-core toLance a MPMRI 1:1 ratio to oneHellawell, of two arms. Men will either undergo TRUSTRUS biopsy,biopsy or willor undergo a MPMRI and Richard Hindley, JimMozer, Hu, Jonas Hugosson, Veeru arm. In the MPMRI arm, areas ofMonique the prostate are Mynderse, Pierre Valeria Panebianco, Antti Ranniko, Gregoire Robert, Roobol, targeted biopsy of suspicious areas. Kasivisvanathan, Laurence Klotz, Drew Moghanaki, scored on a five-point scale of suspicion for clinically [BOLD]Pierre Hypothesis Caroline Moore, Lance Mynderse, Mozer, Valeria significant cancer: Chaired by The proportion of men with clinically significant cancer detected by MPMRI-targeted biopsy will be Panebianco, Antti Ranniko, Gregoire Robert, Monique Professor Nicholas D. James no less than that detected by standard 12-core TRUS biopsy 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 Geert Villeirs, Arnauld Villers, Jaspal Virdi. 3 =of prostate The presence clinically cancer Men referred with clinical suspicion cancer of who have hadsignificant no prior biopsy areis randomised to either standard 12-core biopsy or to a MPMRI arm. In the MPMRI arm, areas TRUS equivocal Professor Thomas H. Lynch (Ireland) scaleto ofbe suspicion for significant clinically significant 4 = Likely clinically cancer cancer: Trial Management Group of the prostate are scored on a five-point UCL Clinical Trials Group: Chris Brew-Graves, Norman 5 = Highly likely to be clinically significant cancer How far have we improved on prostate cancer management? 1 = Highly unlikely to be clinically significant cancer Williams, Samim Patel, Fatima Tebbsto be clinically significant cancer Professor Lynch provided an overview of the advances in the diagnosis and 2 Jichi, = Susan Unlikely Areas scoring 3, 4cancer or 5 will undergo targeted biopsy 3 = The presence of clinically significant is equivocal treatment of prostate cancer over the past century, with a focus on the evolving EAU Research Foundation 4 only. Up to three MRI-suspicious areas will be = Likely to be clinically significant cancer role of hormone manipulation in therapeutic strategies for this disease. = Egmond Highly likely to betargeted clinically significant cancer of 4 cores per target with a maximum Wim Witjes, Christien Caris, 5Joke Van 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 and genetic profiling were also critically examined by Professor Lynch. targeted with a maximum of 4 cores per target leading to a maximum of up to 12 cores per may be used. registration Pathologic may findings from all biopsies patient. Visual registration or software-assisted be used. Pathologic findings from be recorded compared between arms. all biopsies will be recorded and will compared betweenand arms. Professor Susanne Osanto (The Netherlands) S S YMP A

EAU Research Foundation 3 Wim 4 Witjes, 7 Christien 9 12 Caris, 15 Joke18 21 24 26 Van Egmond

Treating Urological Cancers

New Twists and Turns In The Road

Systemic therapy in RCC – current landscape and future directions

[BOLD] Study scheme

Study scheme

Man with no prior biopsy referred with clinical suspicion of prostate cancer

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 expanding second-line options on clinical practice guidelines was also discussed.

Registration (n=470) 1:1 Randomisation

Multi-parametric MRI

MpMRI score 1,2 No biopsy

MRI-targeted biopsy of the prostate

EUT Congress NewsPrimary Outcome:

Results given Treatment Decision Questionnaire

Proportion of men with clinically significant cancer detected

Secondary Outcomes include:

Professor Shariat presented the latest developments aimed at improving the management of non muscle-invasive bladder cancer (NMIBC) for patients. Key topics in this field, covered by Professor Shariat, included preventive strategies, earlier and improved detection and resection of NMIBC, more accurate risk stratification, and less invasive risk-stratified follow-up.

10-12 core trans-rectal biopsy of the prostate

MpMRI score 3,4,5

Results given Treatment Decision Questionnaire

The future of non-muscle-invasive bladder cancer management

Arm 2 (n=235)

Results given Treatment Decision Questionnaire

UK/DEC09547c February 2017

Arm 1 (n=235)

Professor Shahrokh F. Shariat (Austria)

TOPIC OF THE YEAR 2017

* The Innovators in Bladder Cancer “Bladder Cancer Topic of the Year” was voted on and the winner announced during the symposium. If you would like further details on the selected Topic of the Year, please visit the Ipsen booth.

This meeting was initiated and funded by Ipsen and included reference to Ipsen medicines relevant to the agenda topics.

Please visit the Ipsen booth E16

Exib. Halls S7-S10 Level 1

Sunday, 26 March 2017

Urothelial cancer How will immunotherapy change the treatment paradigm? Prof. Robert J. Jones University of Glasgow Beatson West of Scotland Cancer Centre Glasgow (GB)

Urothelial cancer, though common, is a very diverse disease. Advanced urothelial cancer spent many years as a poor relation amongst drug developers and the pharmaceutical industry with only minimal progress being made in improving outcomes for patients in the last two decades. But this is changing. Checkpoint inhibitors have shown clear evidence of activity in this disease and are already impacting on outcomes for some patients. The advent of these new technologies brings the opportunity to drive even better outcomes, but also brings the threat of new toxicities and the risk that other active treatments become inappropriately sidelined. Current paradigm Advanced urothelial cancer is generally regarded as an inevitably fatal condition where the aim of treatment is palliation and disease control with little or no chance of cure. This is despite the observation that, even before the advent of immunotherapy, there was a small percentage of patients who were long-term survivors following chemotherapy (von der Maase et al. 2005; Bellmunt et al. 2012). It is widely acknowledged that a significant proportion of patients will never be suitable for palliative chemotherapy due to comorbidities and performance status and that many of those who do receive chemotherapy suffer significant toxicity with little benefit. Despite relatively high response rates to first-line chemotherapy, the duration of benefit, for most, is distressingly short, and prognosis after failure of chemotherapy is exceedingly poor. Whilst the broad concept of sequential ‘lines’ of palliative chemotherapy is applied as much to urothelial cancer as other more common solid tumours, in reality, very few patients receive more than one line, and the evidence to support the use of second-line chemotherapy is relatively weak. Patient stratification with regards to palliative chemotherapy is relatively simple with three groups defined: those who are suitable for cisplatin chemotherapy, those who are suitable for chemotherapy but not cisplatin, and those who are unsuitable for any type of chemotherapy. By and large, there is no significant group of patients who would be considered for ‘deferred’ chemotherapy as there is, for example, in advanced renal or prostate cancer. The chemotherapy drugs that are used are all broad-spectrum cytotoxics and all, with the exception of vinflunine, have broad application across a range of different solid tumours. As a result, most clinics with capabilities to use chemotherapy will be capable of administering chemotherapy to patients with advanced urothelial cancer and many patients are treated in centres with low volumes of patients with advanced urothelial cancer. What can we learn from other diseases? (melanoma and lung) Immunotherapy, in particular the checkpoint inhibitors, is changing the way patients with a variety of advanced solid tumours are managed. They have made their biggest impacts in melanoma skin cancer, where combination anti-PD-1 and anti-CTLA4 therapy has become the mainstay of treatment for those fit enough to receive it (Larkin et al. 2015) and, increasingly, non-small cell lung cancer where anti-PD-1 therapy is now used as a salvage treatment after failure of first-line chemotherapy (Borghaei et al. 2015) and in front-line treatment of selected patients (Reck et al. 2016). In renal cancer, anti-PD-1 therapy is widely used to treat patients who have failed at least one prior tyrosine kinase inhibitor (Motzer et al. 2015). Whilst the treatment paradigms in these diseases are also still evolving, it is likely that the uro-oncology community will learn and adapt from experiences in these other disease areas. Sunday, 26 March 2017

Combination therapy and patient stratification Current data regarding the efficacy of mono-agent anti-PD-1/ PDL-1 therapy strongly suggest that there are substantial benefits which are, nonetheless, afforded to only a minority of patients. This is evidenced by the prolonged duration of response seen in only around 20 –25% of patients regardless of line of therapy (Balar et al. 2016(a); Balar et al. 2016(b); Bellmunt et al. 2016; Galsky et al. 2016; Rosenberg et al. 2016). This contrasts with first-line response rates to chemotherapy of 46 – 49% in first-line (von der Maase et al. 2005).

experience major immunerelated toxicities which require a degree of clinical acumen and a high level of awareness if they are to be identified at a point where effective intervention can be made. When managed in the context of broader oncology services, the advent of immunotherapy in urothelial cancer will present no additional challenge (as the issues are no different than for other cancers).

However, where these patients are to be managed in isolation from other diseases, then the clinical challenges associated with diagnosis and management of immune toxicity may be considerable. For many patients, there is still a high unmet need for better It is likely that some centres will opt to develop Efforts, so far, to define predictive markers which systemic therapies specific ‘immuno-oncology’ services (encompassing might allow the selection of patients for primary the necessary skills and specialisms to deal with the immunotherapy, or, moreover, those for whom toxicities of these drugs, for example gastrochemotherapy may be a preferable alternative, have enterology, respiratory medicine, endocrinology and Beyond advanced disease failed to deliver a marker which could be used in the critical care) to support the expected tidal wave of use The focus of this discussion has been on the immediate clinic. Therefore, current knowledge would suggest applications of immune checkpoint inhibitors in of these drugs across multiple tumour types. that there are risks in the wholescale replacement of advanced urothelial cancer. However, trials are already primary chemotherapy with mono-agent underway to explore their role in settings other than Place alongside stratified medicine immunotherapy. Indeed, even in the second-line advanced disease. These include trials in the postAs we get swept up by this important new class of setting, where, in unselected populations, cystectomy adjuvant setting, the neo-adjuvant setting, drugs in urothelial cancer, it is important to consider immunotherapy clearly performs better on average and in combination with radical radiotherapy in muscle that, for many, there is still high unmet need for than chemotherapy (Bellmunt et al. 2016), it is invasive bladder cancer and also in high risk nonpossible that some patients would in fact derive more better systemic therapies, and we must not allow muscle invasive bladder cancer (NMIBC). momentum to be lost in the search for new targets benefit from chemotherapy. and new drugs in urothelial cancer. Whilst it is premature to speculate how these trials Thus, the inability to stratify patients who should will change treatment in the future, it is likely that receive immunotherapy and those who should receive The current focus of drug discovery and drug immunotherapy will, in the future, be seen as an development is to combine targeted therapy with chemotherapy is a pressing concern. One solution to additional modality of care (rather than simply as a this concern could be offer patients combined therapy predictive biomarkers to deliver precision medicine. substitute for chemotherapy) in the multi-modality Whilst it is possible that some patients needs will be with both chemotherapy and immunotherapy treatment of urothelial cancer. completely met by immunotherapy, it is certain that delivered either in combination or in a sequential regimen. In urothelial cancer, there are now ongoing for many they will not. Editorial Note: Due to space constraints the reference phase III trials of anti-PD-1 and platinum-based list has been omitted. Interested readers can email at combination chemotherapy which may drive a change Trials are continuing to develop precision medicines EUT@uroweb.org for a complete listing. in urothelial cancers (for example the ongoing in practice whereby the initial treatment of advanced urothelial cancer remains much as at present but with development of the fibroblast growth factor receptor Sunday 26 March inhibitors, or the UK ‘ATLANTIS’ trial (www. the addition of mono-agent checkpoint inhibitor for 11.38-11.53: Thematic Session 6, Changing clinicaltrials.gov)) but also to explore the role of all patients where it is safe to do so (in combination treatment landscape of renal and urothelial targeted therapies in combination with with cisplatin or non-cisplatin based regimens and, cancer: The impact of immunotherapy immunotherapy (for example in the ‘BISCAY’ trial conceivably, alone for those unsuitable for (www.clinicaltrials.gov)). chemotherapy). The Immuno-oncology (IO) tail and urothelial cancer The checkpoint inhibitors have, to date, had more impact in advanced melanoma than in any other disease. The excitement here is largely generated by a substantial minority of recipients who appear to experience long-term, durable disease control. With mono-agent anti-CTLA4 therapy, it appears that around 20% of patients assume a risk of all-cause death which is little different from that of the age-matched, cancer-free population (Hodi et al. 2010). When treated with combination anti-CTLA4 and anti-PD-1, the proportion of long-term beneficiaries is even greater (Larkin et al. 2015). Whether this effect holds true in patients with urothelial cancer remains to be seen in long-term follow-up of recent and ongoing trials, but there is already a suggestion that this might also be the case in renal cancer patients treated with anti-PD-1, an effect which was previously well-described in patients treated with high dose Interleukin-2 (McDermott et al. 2015). The long duration of responses seen in some patients with urothelial cancer may be an early sign.

Call for Abstracts Submit your abstract by 28 April 2017 at www.WCE2017.com

This so-called ‘IO tail’ will impact on the way in which we regard systemic treatment for urothelial cancer: for some patients, at least, the primary objective of treatment will no longer be symptom control, but long-term disease control with the expectation that these patients may die of unrelated causes. The fact that this benefit is only afforded to a minority further reinforces the need for predictive markers, if only to establish the treatment objective for the individual patient. Long-term treatment One significant unknown is whether those that respond to checkpoint inhibitors need to continue treatment indefinitely. What is clear is that many patients will be spending longer on treatment than has been the case in the ‘cytotoxic era’. This has significant implications for patients – for some of whom the morbidity associated with long-term treatment will become more significant than that associated with the disease – but also for clinical services which will need to increase capacity to provide treatment.

Toxicity management and service organisation Immuno-therapy toxicity is dominated by autoimmune events, many of which are tolerable and manageable. However, a small percentage of patients EUT Congress News

BCG-unresponsive bladder cancer Recommendations from the International Bladder Cancer Group (IBCG) Dr. Ashish M. Kamat MD Anderson Cancer Center Dept. of Urology MD Anderson Cancer Center Houston (US)

induction course of BCG, a second induction course may be associated with a 50% response rate16. However, for patients with persistent disease after two or more than two BCG courses – or with progression of disease – there is minimal response expected and the risk of invasive and even metastatic disease outweighs the minimal potential benefit. Thus, if a patient is truly BCG-unresponsive and their high-grade bladder cancer persists after one or two courses of BCG, additional BCG is not recommended.

Current Options Of course, patients are always seeking alternatives to radical cystectomy, so it behoves us to objectively consider and offer them such options. Prior to offering bladder-sparing therapies, thorough evaluation of sanctuary sites is paramount, including It is an inescapable fact that some patients treated with evaluation of the prostatic urethra and upper urinary intravesical immunotherapy using Bacillus Calmettetract. Enhanced optical imaging of the urothelium Guerin (BCG) will have recurrence of their disease. with blue light and/or narrow band imaging (NBI) However, not all such recurrences are cause for should ideally be used to provide for a more complete concern and the definition of what truly defines failure tumor resection. of BCG therapy is critical when evaluating patients. Intravesical chemotherapy after BCG failure has been For example, the prognosis of patients with a attempted with several agents. Valrubicin remains low-grade recurrence is markedly better than those the only FDA-approved, intravesical agent for use in who develop a high—grade tumor1, to the extent that BCG-refractory CIS when cystectomy is not an option, this is considered a ‘non-event’ by regulatory bodies. but has dismal response rates17. Other intravesical chemotherapies such as gemcitabine, mitomycin, What are the factors that we must remember when taxanes have each demonstrated a hint of efficacy considering patient management? First, it is essential after BCG; however overall response rates are not to verify that the patient has indeed received optimal durable and so less than optimal. Based on BCG therapy – i.e. BCG induction with a six-week mechanisms of action, chemotherapeutics have been induction course followed by three-weekly combined; of these combinations the most studied is maintenance given at 3, 6, 12, 18, 24, 30, and 36 sequential intravesical gemcitabine with either months (SWOG maintenance)2,3,4.1 While other intravesical docetaxel or MMC. Reports from maintenance regimens (monthly or quarterly single-centre studies have demonstrated activity; instillation) have been studied; these have been longer follow-up will be crucial to determine the role shown to be no better than induction alone and in our armamentarium. hence do not constitute optimal therapy5,6,7. Electromotive drug administration (EMDA) enables Next it should be determined as to which category of optimization and deep penetration of BCG failure applies to the particular patient. “BCG chemotherapeutics. EMDA with mitomycin has been refractory” indicates persistent high-grade cancer six extensively studied including in the pre-TURBT 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 9,10 BCG . 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 uncommon situation today11. non-failures24. Thus, results are encouraging. On behalf of the IBCG (Andreas Boehle, Maurizio Brausi, Roger Buckley, Marc Colombel, Ashish M. Kamat, Donald Lamm, Raj Persad, Joan Palou, Mark Soloway and J. Alfred Witjes)

When we consider this subgroup of patients - the BCG unresponsive category - radical cystectomy is the only standard salvage therapy that is currently available. While there have been numerous clinical trials in the BCG failure setting (summarized in our review12, in press) it has been difficult to interpret these studies due to non-uniform definitions and end-points used. Since placebo comparators are considered unethical and reported single-arm trials have had widely varying results, experts have proposed threshold response rates to differentiate positive from negative trials. We have previously published our consensus that disease-free response rates of 30% and 25% at 12 months and 18 months, respectively, for papillary tumours (or complete response rates for carcinoma in situ (CIS)), can be considered as clinically meaningful9.

A large multicentre phase II trial initially suggested that BCG plus IFNα might be effective in patients with prior BCG exposure. Long term follow-up and detailed analysis eventually demonstrated that among truly BCG-unresponsive patients, the response rate to BCG + IFNα at 24 months is around 20%25, similar to many other agents. Along the IFN paradigm, gene therapy with an adenovirus that expresses an IFNα transgene has demonstrated a 35% 12 month response rate at 12 months in the BCG unresponsive setting26 and is currently being evaluated in a single-arm phase III trial (NCT02773849).

Other strategies Fortunately for our patients, there are several ongoing clinical trials, and more in development, to address the problem of BCG unresponsive disease. These are summarized in our recent review12 and include studies Current recommendations with immune checkpoint blockade (anti-PD1 agents), So what are the current recommendations for patients growth factor receptor agonists, photodynamic 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 chemotherapypatients 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 intravesical chemotherapy for intermediate-risk will be the subject of the randomized PRIME trial (low-grade) tumours14. Similarly, the American (NCT02326168). Urological Association (AUA) guidelines state that 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 welldefined and clinically meaningful endpoints. 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

regulatory approval but especially with regards to benefit for our patients. References 1. Mmeje CO, Guo CC, Shah JB, et al. Papillary Recurrence of Bladder Cancer at First Evaluation after Induction Bacillus Calmette-Guerin Therapy: Implication for Clinical Trial Design. Eur Urol. 2016;In press. 2. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance Bacillus Calmette-Guerin Immunotherapy for Recurrent Ta, T1, and Carcinoma in situ Transitional Cell Carcinoma of the Bladder: a Randomized Southwest Oncology Group Study. J Urol. 2000;163(April):1124-1129. 3. Oddens J, Brausi M, Sylvester R, et al. Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guerin rin in Intermediate- and High- risk Ta , T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Mainte. Eur Urol. 2013;63(3):462-472. doi:10.1016/j.eururo.2012.10.039. 4. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-Term Efficacy Results of EORTC Genito-Urinary Group Randomized Phase 3 Study 30911 Comparing Intravesical Instillations of Epirubicin, Bacillus Calmette-Guerin, and Bacillus Calmette-Guerin plus Isoniazid in Patients with Intermediate- and High-Risk . Eur Urol. 2010;57(5):766773. doi:10.1016/j.eururo.2009.12.024. 5. Palou J, Laguna P, Millan-Rodriguez F, Hall R, SalvadorBayarri J, Vicente-Rodriguez J. Control group and maintenance treatment with Bacillus Calmette-Guerin for carcinoma in siute and/or high grrade bladder tumors. J Urol. 2001;165(May):1488-1491. 6. Kamat AM, Porten S. Myths and Mysteries Surrounding Bacillus Calmette-Gue Therapy for Bladder Cancer. Eur Urol. 2014;65(2):267-269. doi:10.1016/j.eururo.2013.10.016. 7. Kamat AM, Flaig TW, Grossman HB, et al. Consensus statement on best practice management regarding the use of intravesical immunotherapy with BCG for bladder cancer. Nat Publ Gr. 2015;In press:1-11. doi:10.1038/ nrurol.2015.58. 8. Kamat AM, Cookson M, Witjes JA, Stenzl A, Grossman HB. The Impact of Blue Light Cystoscopy with Hexaminolevulinate (HAL) on Progression of Bladder Cancer – A New Analysis. Bl Cancer. 2016;2:273-278.

Prior to offering bladder-sparing therapies, thorough evaluation of the prostatic urethra and upper urinary tract is of utmost importance

doi:10.3233/BLC-160048. 9. Kamat AM, Sylvester RJ, Andreas B, et al. Definitions, End Points, and Clinical Trial Designs for Non–MuscleInvasive Bladder Cancer: Recommendations From the International Bladder Cancer Group. J Clin Oncol. 2016;34(16):1935-1944. doi:10.1200/JCO.2015.64.4070. 10. Lerner S, Dinney C, Kamat A, et al. Clarification of Bladder Cancer Disease States Following Treatment of Patients with Intravesical BCG. Bl Cancer. 2015;1:29-30. doi:10.3233/BLC-159002. 11. Shah JB, Kamat AM. Strategies for Optimizing Bacillus Calmette-Guerin. Urol Clin North Am. 2013;40:211-218.

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. Sunday 26 March 8.30-8.45: Plenary Session 3, Redefining and optimising contemporary bladder cancer care

EAU Patient Information New Topics Available! •

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Visit us at the EAU Booth G50

New Navigation Tool in Kidney Stones and OAB Treatment

patients.uroweb.org Sunday, 26 March 2017

Personalised approach to antagonising ERG in PCa New findings define a therapeutically actionable pathway

Cancer of the prostate is a leading cause of cancer death in men worldwide. While localized prostate cancer is highly curable, nearly all patients with metastatic disease progress to castration-resistant prostate cancers for which there are presently limited treatment options. There is a high need to develop selective, contextdependent therapeutic strategies to manage metastatic prostate cancer. The identification of the pathways that, in a specific tumor context, lead to disease progression and metastasis is an important step in developing more effective treatments based on the tumor molecular and biological characteristics. E26 transformation-specific (ETS) transcription factors constitute a family of signal-dependent transcription regulators with important roles in cell differentiation and carcinogenesis1,2. The ETS gene family includes 28 members in the human genome. ETS factors share the highly conserved DNA binding domain and recognize similar ETS binding motifs in the promoter of target genes1,2. Nevertheless, individual ETS factors activate or repress transcription of largely distinct subsets of genes. Furthermore, ETS factors interact with distinct protein partners inducing different transcriptional and biological responses. These differences among ETS factors contribute to their specific properties and regulatory functions and are reflected in their diverse roles in tumorigenesis1,2. In normal development the ETS transcription factor ERG has a critical role in the formation of the vascular system, urogenital tract and bone development. ERG is also expressed at high levels in embryonic neural crest cells during migratory phase. ERG expression regulates the pluripotency of hematopoietic stem cells, endothelial cell homeostasis and angiogenesis. In the adult mouse ERG is expressed in endothelial tissue including adrenal, cartilage, heart, spleen, lymphatic endothelial and eosinophil cells. ERG has been shown to have a major role in cell response to vascular inflammation and cell adhesion, normal hematopoietic stem cell function and the maintenance of normal peripheral blood platelet numbers. Gene rearrangements involving ERG are very frequent in prostate cancers. These events link the ERG gene to the promoter of the androgen-regulated gene TMPRSS2 providing a mechanism for over-expression of ERG in androgen-stimulated prostate epithelial cells. Aberrant overexpression of ERG due to the TMPRSS2 translocation in prostate epithelial cells, a cell context inappropriate for ERG, results in significant alterations and broad transcriptional reprogramming. However, more than 10 years since the discovery of the TMPRSS2-ERG gene rearrangement in prostate cancer, its clinical impact is still unclear. Uncertainty persists regarding the molecular determinants of ERG-induced oncogenesis and its role in tumor progression. While aberrant expression of ERG does not lead to invasive carcinomas in mouse models, aggressive castrationresistant human prostate tumors are ERG- positive, supporting a role for ERG in disease progression.

New data New data from our group provide further evidence of the cross-talk between ERG and EZH2 and support a novel mechanism leading to aberrant ERG activation and prostate cancer progression. We have recently examined more in depth the relationship between ERG and EZH2 and have found that EZH2 fulfils a very important role in mediating ERG oncogenic activity. Protein lysine methyltransferases, such as EZH2, regulate the methylation of histone and non-histone proteins. Lysine methylation has recently emerged as an important post-translation modification that can profoundly affect the function of diverse non-histone proteins18,19. Indeed, there are few examples of transcription factors and epigenetic regulators methylated by histone-modifying enzymes18,19.

References

Figure 1: ERG and EZH2 cooperate and activate a protumorigenic and pro-metastatic program in ERG fusion positive prostate cancers. This pathway is enhanced by PTEN loss.

and differentiation program13,22. More recent work highlighted the important role of ERG ability to interact with other epigenetic and transcriptional regulatory proteins, such as the epigenetic effector BRD4 and the RNA binding protein EWS23,24. Notably, the discovery of this complex ERG interactome, along with our novel finding of the ERG/EZH2 crosstalk, We found that EZH2 induces lysine methylation of ERG opens new opportunities for understating the molecular mechanisms of ERG induced oncogenesis in cells and human tumors and that the physical and for development of targeted therapeutic interaction between the two proteins is instrumental strategies to reverse prostate cancer progression. in this process20. EZH2, by interacting with ERG, significantly enhances its activity and contributes to Collectively, our data provide advance on defining the ERG-induced transcriptional reprogramming in epigenetic network connected with TMPRSS2-ERG prostate epithelial cells. As supporting evidence, we found that ERG-induced transcriptional activation and gene fusion and the role of ERG and EZH2 in prostate repression are both reduced upon depletion of EZH2, cancer progression. Importantly, these findings define underlying the functional relevance of the interaction. Furthermore, these events were enhanced by PTEN deficiency providing for the first time a direct mechanistic explanation of the synergistic effects of PTEN loss and ERG gene fusion on progression of ERG positive tumors.

1. Seth, A. & Watson, D.K. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer 41, 2462-2478 (2005). 2. Hollenhorst, P.C., McIntosh, L.P. & Graves, B.J. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu Rev Biochem 80, 437-471 (2011). 3. Chen, Y., et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med 19, 1023-1029 (2013). 4. Robinson, D., et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215-1228 (2015). 5. Beltran, H. & Rubin, M.A. New strategies in prostate cancer: translating genomics into the clinic. Clin Cancer Res 19, 517-523 (2013). 6. Taylor, B.S., et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11-22 (2010). 7. Cancer Genome Atlas Research Network. Electronic address, s.c.m.o. & Cancer Genome Atlas Research, N. The Molecular Taxonomy of Primary Prostate Cancer. Cell 163, 1011-1025 (2015). 8. Beltran, H., et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 1, 487-495 (2011). 9. Beltran, H., et al. Divergent clonal evolution of castrationresistant neuroendocrine prostate cancer. Nat Med 22, 298-305 (2016). 10. Jeronimo, C., et al. Epigenetics in prostate cancer: biologic and clinical relevance. Eur Urol 60, 753-766 (2011).

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. 10.50-11.10: Thematic Session 1: Personalised medicine in urological oncology, Personalised approach to antagonising ERG in prostate cancer

Come and meet with Peyronie’s experts

We have observed that ERG and EZH2 form a complex that is detected by immuno-precipitation in VCaP cells, an ERG fusion positive prostate cancer cell line, and in samples from ERG fusion positive human tumors, confirming the clinical relevance of our findings (Figure1). Moreover, analysis of CHIP-seq data in VCaP cells revealed the localization of ERG and EZH2 complexes at a number of genomic sites, including promoters and enhancers. Interestingly, many of the ERG-EZH2 co-occupied genes are over-expressed in ERG fusion positive cells and their expression depends on both ERG and EZH2 and is significantly reduced after knockdown of either ERG or EZH2. Furthermore, ERG/EZH2 co-occupied genes are deregulated more prominently in prostate tumors with concomitant ERG fusion and PTEN loss compared to the others, consistent with cooperation between the two events in driving clinical progression of prostate cancer. From one hand, these results confirm that EZH2 is an ERG co-factor in gene silencing by mediating histone methylation at the promoters of repressed genes. On the other hand, our data show that EZH2 together with ERG forms also activating complexes on a distinct set of gene promoters, which is consistent with the recently identified activating function of EZH215. Thus, these data provide novel insights about non-canonical functions of EZH2, showing that this function in ERG-positive cancer cells involves direct cooperation with ERG. Drugs directed to EZH2 and other epigenetic targets are undergoing clinical testing in various tumor types21.

The emerging view is that ERG requires additional cooperating factors to fully exert its oncogenic effects and drive tumor progression. In human cancers ERG gene fusions are often concomitant with other genetic events. Co-occurrence of ERG gene fusion and PTEN loss are associated with more aggressive disease3. Furthermore, both pre-clinical and clinical evidence suggest that cross-talks and cooperation between multiple signaling pathways are involved in the progression of ERG-positive tumors. However, the molecular details of these interactions are not defined yet. Understanding these mechanisms could greatly impact on development of new therapeutic approaches for prostate cancer.

The efficacy of EZH2 inhibitors is generally attributed to the inhibition of histone H3K27 methylation and reversal of epigenetic gene silencing21. We found that inhibition of EZH2 has also a direct impact on ERG functions inhibiting ERG/EZH2 promoter occupancy and transcription of co-regulated genes. Consistently, EZH2 inhibition reversed in vitro and in vivo the malignant phenotype of ERG fusion positive cancer cells.

While numerous genetic alterations have emerged in prostate cancer, epigenetic events clearly cooperate in determining malignant transformation and tumor

The ERG co-regulatory network has been matter of investigation in the recent years. ERG can form complex with AR and is able to disrupt AR signaling

Sunday, 26 March 2017

a therapeutically actionable pathway, modulation of which could have a broad impact on the treatment of ERG-positive prostate cancer.

progression4-9. Prostate cancer can be considered a model of a disease driven by transcriptional and epigenetic events whereby changes in transcription and epigenetic regulators play a critical role occurring at early stages and further throughout disease progression10,11. We and others have shown the presence of cross-talks between ETS factors and epigenetic effectors12,13. Over-expression of ERG leads to the induction of Enhancer of Zest Homolog 2 (EZH2), which in turn mediates silencing of several genes12,13. EZH2 is the catalytic subunit of the Polycomb repressive complex 2 (PRC2) that catalyzes histone H3 lysine 27 tri-methylation (H3K27me3)14. Interestingly, EZH2 has been recently shown also to exert PRC2-independent functions, including interaction with and methylation of various transcriptional regulators15-17.

TAKE THE CHANCE – TALK TO EXPERIENCED COLLAGENASE USERS Booth # H02 March 25, Saturday 10.00-10.30 15.30-16.00

Mr Amr Raheem Mr David Ralph

March 26, Sunday 13.00-13.30

Mr David Ralph

March 27, Monday 10.00-10.30

Mr Amr Raheem

XIAPEX® Abbreviated Prescribing Information (Peyronie’s Disease): (See XIAPEX Summary of Product Characteristics for full Prescribing Information). 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 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 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 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 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 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 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; 0.9%), a combination of penile ecchymoses or haematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in 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 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. Special penile conditions/diseases not studied in clinical trials – Xiapex treatment in patients having a calcified plaque that could have interfered with the 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 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 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 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 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 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 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 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 is available on request from: medical.info@sobi.com, Tel: +46 8 697 20 00. Date of Preparation: February 2017. Adverse events should be reported to your local regulatory authority and to Sobi at DrugSafety@sobi.com SE-112 76 Stockholm Phone: +46 8 697 20 00 www.sobi.com

PP-2089

Dr. Giuseppina Carbone IOR Institute of Oncology Research Tumor Biology and Experimental Therapeutic Bellinzona (CH)

EUT Congress News

New Endoscopic Stone Treatment EST-s1: A “Made in the EAU” novel basic training curriculum for endoscopic stone therapy Dr. Domenico Veneziano Member, YAU Working Group Endourology & Urolithiasis Ospedali Riuniti, Dept. of Urology & Kidney Transplant Reggio Calabria (IT)

Dr. Bhaskar Somani Member, YAU Working Group University Hospital Southampton NHS FT Dept. of Urology Southampton (GB)

endourological techniques was essential. As opposed to E-BLUS, the EST s1 (Endoscopic Stone Treatment, step 1) protocol has been completely developed in the European Association of Urology, under the coordination of the European School of Urology (ESU)/ EAU Section of Uro-Technology (ESUT) training research group, and thanks to the close collaboration of these groups with the EAU Section of Urolithiasis (EULIS). The team involved experts in simulation and stone treatment: Domenico Veneziano, Bhaskar Somani, Kamran Ahmed, Alberto Breda and many others. The “full life cycle curriculum development” template, as described by Richard Satava was followed along the process, which started in 2014 with a Cognitive Task Analysis of the RIRS (Retrograde Intra-Renal Surgery) procedure, operated by the YAUWP (Young Academic Urologist Working Party) Endourology & Stone Treatment group. This initial research, based on a broad literature review, was the solid base behind the development process.

place in Athens, during the ESUT16 congress. Data collection for validation took place during EUREP16 in Prague and involved 134 participants with different expertise. All trials have been DVD-recorded for re-evaluation and quality feedback sheets have been used to score several aspects of the procedure.

The training curriculum is composed of four tasks Olivier Traxer (middle) gives comments during the EST s1 validation in Prague and requires mastering of four different instruments to ability with the flexible ureteroscope. The original successfully complete the test. The first two tasks focus on flexible and rigid cystoscopy. In these, the K-Box was slightly modified to correctly meet the assessment requirements. During the task the scope EST-s1, as suggested by its name, is the first of a participant needs to touch (with the guidewire) a 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 following the instructions of the tutor. This is to points in the simulator, mimicking rotation, deflexion of endoscopic stone treatment: navigation and basic and in-out movements, in a standardised fashion. use of the operative channels. After several consensus demonstrate an understanding of the proper The last few years have seen a fast growth in the meetings and test sessions, the preliminary trials took taxonomy, to move the guidewire in and out when field of urological education and simulation, Assessment has been designed to rely not only on needed and to correctly particularly with the aid of hands-on-training. In time taken, but also on a questionnaire on the quality manoeuver the 2013, the E-BLUS exam was delivered for the first cystoscope. of trainee performance, to be filled out by the proctor. time during the European Urology Residents Based on the literature research made upfront, the Education Program (EUREP). This year, we are finally After Task 2, the safety examination sheet contains a list of critical aspects ready to deliver the novel EST-s1. guidewire is left in one of related to basic endoscopic skills, such as positioning and use of the scope, handling the access sheath, and the ureters. Task 3 E-BLUS, the renowned basic laparoscopy exam, was consists of simulating a correct navigation based on technical needs. All tasks born from an analysis and integration of the American will be available for hands-on training sessions semi-rigid ureteroscopy, FLS (Fundamentals of Laparoscopic Surgery) project. with a working guidewire during this congress, while the first official exam In time, the curriculum was slightly modified to meet placement. This task ends session is planned for September this year, during the the specific needs of urology. Over the last few years, EUREP17 course. with a successful E-BLUS has spread the European teaching standards placement of an access to even outside European borders, reaching as far as sheath. Task 4 takes place With step 2 already in the works, we are sure that the Indonesia and beyond. EST-s1 curriculum will allow once again the sharing on the K-Box, a low-fidelity simulator of surgical standards, contributing to an improved With a recent surge in endourology and stone designed by Olivier educational system for residents and better treatment, a development of dedicated protocolTraxer, and tests trainees’ healthcare. based training and assessment relating to Author Veneziano explains the modifications applied to the K-Box

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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 enhancing the technology of shock waves. With the new compact MODULITH® SLK »intelect« a lithotripter has been developed which can be perfectly adapted to different imaging modalities. The device features a fully motorized positioning of the therapy source making it easy to set up the lithotripter or to target stones in the urinary tract. The Companion for Urological Workstations Urological X-ray workstations are an important part of equipment in urological departments. They can be used for diagnosis and interventional procedures. But they are often lacking in the possibility of performing instantly an SWL when a stone is detected in the KUB of a patient.

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an urological workstation, C-arc or ultrasound device. The set-up of the lithotripter in combination with an X-ray system and the focus adjustment during the therapy are assisted by this navigation system. Once the stone is visualised, it only has to be marked in the ultrasound image and the automatic positioning system LITHOPOS® moves the shock wave focus on the stone for the treatment. The same smart function works with X-ray systems as well. The Lithotripsy Module for C-arcs The MODULITH® SLK »intelect« in its basic version can be combined with various surgical C-arcs and OR-tables with lateral cut-out. The motorised movements of the therapy source facilitate the focus alignment for a fixed therapy head position. In-line ultrasound can be used for targeting radiolucent stones. The MODULITH® SLK »intelect« can optionally be linked to C-arc and ultrasound device via the optical navigation system LITHOTRACK®. This version allows maximum flexibility in set-up and use. No dedicated table is needed to perform a SWL, normal surgical OR-tables are sufficient.

In this combination the superior image quality of the workstation’s X-ray can be used for localising the stone and in-line X-ray control of the therapy success during the treatment.

Smart Features The lithotripter can be folded easily to a space saving transport position for storage or transport. Safe and simple handling is ensured through the integrated After the therapy the lithotripter can easily be moved brake which fixes the device securely for operations. away from the urological workstation and be stored The integrated focal gauge allows re-aligning the without using much space. system or checking the focus alignment within seconds. It’s appealing design was already awarded 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. LITHOTRACK® Navigation System LITHOTRACK® is an optical navigation system comfortably linking the MODULITH® SLK »intelect« to 24

EUT Congress News

Economic Solution The long service life of the proven shock wave components makes the investment economic and

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Olaf Gleibe Product Manager Urology

Sunday, 26 March 2017

Male contraception: Where are we going? Future genomics can lead to new and innovative fertility products Dr. Ferdinando Fusco Azienda Ospedaliera Universitaria Federico II Center of Preclinical & Clinical Research In Sexual Medicine Naples (IT)

Co-Authors: Massimiliano Creta (IT), Nikolaos Sofikitis (GR) Fertility control represents a global health issue as overpopulation and unintended pregnancy have both major social and personal consequences1. To date, a large percentage of births remain undesirable with about 80-90 million unintended pregnancies occurring annually2,3. Many men wish to take active responsibility for family planning2-7. According to some authors, the ideal male contraceptive should have the following characteristics2: 1. At least as effective as the corresponding female methods; 2. Be acceptable by both partners; 3. Have quick results; 4. Have not significant adverse effects, especially in relation to virility, libido and erectile function; 5. Not affect the offspring; 6. Be reversible with regards fertility; and 7. Be readily available and affordable. Based on their target of action, male contraceptive methods are classified into three main categories2: 1. Methods that hinder the transport of sperm in the female reproductive system; 2. Methods that suppress spermatogenesis; and 3. Methods that disrupt the maturation or fertilizing ability of spermatozoa. Currently, in the clinical practice, three options for male-based contraception exist: coitus interruptus, condoms and vasectomy. However, these methods are acknowledged as inadequate1. The main disadvantage of condoms is the high failure rates, which in “real life” conditions concern up to 19% of couples during the first year of use2. On the other hand, usage of condoms in sexual activities offers a protection against sexually transmitted diseases. It should be mentioned that vasectomy is poorly reversible and male reproductive potential postvasectomy reversal depends on the technique/ equipment used for this procedure. The loupeassisted group had a 72% patency and a 28% pregnancy rates, whereas the microsurgical group had a 96% patency and a 40% pregnancy rates8. Moreover, vasectomy is associated with considerable short and long-term complications2. Finally, concerns have been raised regarding a potential association between vasectomy and a modestly increased incidence of high-grade prostate cancer2. It should be emphasized that there is no association between vasectomy and risk of developing aggressive prostate cancer. Men who had undergone a vasectomy were at an increased risk for nonaggressive prostate cancer9. Consequently, male contraception remains an important area of research and introduction of new forms of male contraception based on both hormonal and non-hormonal paradigms are wanted and needed1. This need is becoming recognized by both the public and private sectors1. Male hormonal contraception (MHC): Role of androgens Normal sperm production is maintained by high intratesticular testosterone concentrations. Very low intratesticular testosterone levels result in few or no detectable sperm, irrespective of circulating testosterone levels. MHC clinical trials began in the 1970s. The mechanisms of action of MHCphrmaceutical agents is based on the suppression of the secretion and production of the gonadotropins, both luteinizing and follicle stimulating hormone, from the pituitary by exogenous sex steroids (androgens with or without progestins) or gonadotropin-releasing hormone analogues6. The ultimate goal of MHC is to reduce the number of sperm in the ejaculation so drastically that it is impossible to achieve fertilization2. Studies using Sunday, 26 March 2017

testosterone alone showed that it is very effective with few adverse effects. Addition of a progestin acting synergistically increases the rate and extent of suppression of spermatogenesis. However, the fact that supernormal testosterone levels are necessary to achieve the desirable suppression of spermatogenesis has raised concern over the long-term effects of contraceptive treatment on men’s health, especially as concerns the cardiovascular system and prostate associated morbidity2. The focus of MHC development in recent years has been the development of novel androgens that may be more potent than testosterone in the suppression of gonadotropins and with fewer potential side effects6.

Gossypol Gossypol is a compound found in cotton seed oil. Effectively suppresses spermatogenesis. In a clinical study carried out in China, gossypol rendered 98.5% of volunteers infertile at an oral dose of 20 mgr per day for 75 days as the initial dose, followed by a maintenance dose of 40-50 mgr per week, but its effects are not consistently reversible, and it causes hypokaliemia and myoparesis15.

could act on male fertility both effectively and reversibly because inhibition of PPP3CC/PPP3R2 targets spermatozoa in the epididymis. Manipulation of cellular junctions in the seminiferous epithelium The testis is a unique organ with complex junction arrangements in the seminiferous epithelium7. Cell junction dysfunction in the seminiferous epithelium is one of the many causes of male infertility7. Recent findings in different animal models support the hypothesis that cell junction may be one of the prime targets for male fertility regulation7. Adjudin, for example, a compound able to perturb germ cell adhesion in the seminiferous epithelium7.

Immunization GnRh vaccination involves the injection of GnRH conjugated to a foreign protein such as ovalbumin, and combined with an adjuvant, to induce anti-GnRH antibody formation. The antibodies bind to endogenous GnRH within the hypothalamic-pituitary The ideal steroid for therapeutic androgen portal vessels and prevent it from binding to receptors The epididymis as a contraceptive target replacement would be a potent testosterone agonist 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 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 decrease steroid hormone secretion and reduced androgen 7a-methyl-19-nortestosterone (MENT) has vivo. Their full maturation, including potential to 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 Spermatogenic germ cell-specific proteins stimulating effects on the prostate gland6. Initial pharmacological inhibitors to target epididymal Several agents that inhibit the sperm-specific or proteins necessary for the sperm maturation process studies using MENT as an implant in men showed testis-specific targets have been identified and studies represent an attractive choice for non-hormonal male very effective suppression of spermatogenesis with in animals have shown promising results. To date, contraception. Despite the existence of multiple four MENT implants6. however, most methods are still in experimental potential epididymal targets, the major difficulty in stages, since both toxicity and reversibility data are delivering the drugs to epididymis is represented by Another androgen, dimethandrolone undecanoate discouraging2. Bromodomain, testis-specific (BRDT) is the blood–epididymis barrier. (DMAU), is being developed as an oral preparation as well as an intramuscular injection. In the body, DMAU is a tissue-restricted, chromatin-associated protein converted to dimethandrolone (DMA) which is the active expressed in spermatocytes and round spermatids. The New and innovative products will come from our knowledge of the unique physiology and genetics of entity6. In in vitro studies, DMA showed dose-dependent feasibility of targeting human BRDT with acetyl-lysine competitive small molecules (JQ1), which blocks the androgenic and progestational activities6. The dual reproduction, as well as by exploiting existing and interactions of bromo and extra terminal (BET) proteins future genomics, proteomics and protein network activities on the androgen and progesterone receptors (BRD2, BRD3, BRD4 and BRDT) with histones has been platforms. may create a single agent capable of suppressing spermatogenesis while maintaining androgenic activity tested16. Sperm-specific calcineurin represent a further Editorial Note: Due to space constraints the reference in men1. A single-dose escalation study in healthy male potential target. Genetic disruption of either the catalytic subunit (PPP3CC) or the regulatory subunit volunteers has shown that DMAU appears to be a safe list has been omitted. Interested readers can email at (PPP3R2) of sperm-specific calcineurin or short-term in EUT@uroweb.org for a complete listing. and well-tolerated contraceptive agent6. vivo pharmacological inhibition with calcineurin inhibitors (cyclosporine A or FK506) leads to complete Role of anti-androgens Saturday 25 March male infertility, with reduced sperm motility owing to Cyproterone acetate (CPA), is an antiandrogen with 09.45-10.00: Plenary Session 2, Hot topics in an inflexible midpiece during sperm maturation in the progestational action. In men, CPA has been widely Andrology Inhibitors of sperm-specific calcineurin used for the treatment of hypersexuality and prostatic epididymis. vprobeQuarterAdEUTFinal_Layout 1 2/14/17 10:14 PM Page 1 cancer. Moderate dose cyproterone aceteta (CPA), induces progestational/anti-gonadotropin effects at the hypothalamo-pituitary level in addition to its antiandrogenic action at the testicular level10,11. Addition of cyproterone acetate to testosterone is considered effective to suppress spermatogenesis and is based on the hypothesis that the synergistic action of these compounds can induce a more profound suppression of gonadotropins than either compound administered alone and that cyproterone acetate can act directly at the gonadal level to block the stimulation effect of androgens on spermatogenesis12.

CRYOABLATION OF THE PROSTATE

™

Role of progestins Nestorone is a potent progestin that has minimal androgen or estrogen activity6. Nestorone applied transdermally has been used in combination with testosterone gel for hormonal contraception clinical trials in men. In a six-month study, a combined gel (testosterone 100 mg/day and nestorone 8 mg/day on skin) suppressed sperm output to <1 million/ml in 89 % of men compared to 23 % of those who applied testosterone gel alone. There were minimal adverse effects6. Role of GnRH analogues or GnRH antagonists There are two different approaches to male contraception that are presently based on two distinct types of derivatives of luteinizing hormone releasing hormone (LH-RH), the antagonistic and agonistic analogues. GnRH agonistic analogs were originally developed as longer acting therapeutic agents to treat GnRH deficient patients, and given chronically, they had paradoxical inhibitory actions on LH and FSH secretion13. GnRH antagonists, block the pituitary GnRh receptors, and have been shown to be among the promising additives to testosterone14. The overall effect of the administration of either GnRH agonists or GnRH antagonists on male reproductive tract is the development of azoospermia. However the requirement of daily or weekly injections and the high costs of the currently available preparations have hindered the futher development of GnRH antagonists for hormonal male contraception. Non-hormonal contraception methods Non-hormonal targets of contraception include sperm production at the testicular level, sperm maturation at the level of epididymis and development of sperm motility. Selectivity, specificity and lesser side effects compared to hormonal methods make these approaches attractive so non-hormonal contraception methods represent the most promising field of research2.

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EUT Congress News

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 Department of Urology Herlev and Gentofte University Hospital Herlev (DK)

Testosterone replacement therapy after curativeintended treatment It is intuitive to state that if the patient is cured from his PCa, i.e. the patient does not harbor any cancer cells, then TRT is as safe for the man with a previous 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 male has gained interest as several studies have demonstrated a beneficial effect of testosterone replacement therapy (TRT) especially on sexual health.

Only a few studies have addressed this issue and the available studies have all been small with short followup. One cohort study reported on 103 hypogonadal men undergoing TRT after radical prostatectomy and found no increased risk of PCa recurrence compared with 49 eugonadal men7. Both men with high and low-risk PCa were included in the analyses. A second retrospective study of 57 hypogonadal men with mainly low risk PCa (4 men had gleason ≥ 8) treated with radical prostatectomy and subsequent TRT found no increases in PSA during a median follow-up of 13 months from TRT commencement8. Similarly, no increased risk of disease recurrence has been demonstrated after radiotherapy in the currently available small retrospective cohort studies9. However, TRT seems contra-intuitive after radiotherapy at least in men with locally advanced PCa. In this setting there is substantial evidence demonstrating improved survival when combining androgen deprivation therapy with external beam radiotherapy.

The combination of testosterone deficiency and clinical symptoms in the ageing male are referred to as late onset hypogonadism and the prevalence increases with age1. Among men 40 to 49 years of age the prevalence is estimated to be 0.1% using data from the European male Ageing study (EMAS)1. This is using the definition of late onset hypogonadism: Serum total testosterone < 11.0 nmol/L and having decreased frequency of morning erection, decreased frequency of sexual thoughts, and erectile dysfunction. Among men 70 to 79 years of age the prevalence increases to around 5%. Thus a sizeable proportion of men will, with increasing age, have impaired sexual function associated with low testosterone. At the same time the risk of being diagnosed with prostate cancer (PCa) increases with age. A recent systematic review on autopsy studies estimated the age specific prevalence of PCa for men >79 years of age to be 59% (95% CI 48-71%)2.The timing of being diagnosed with late onset hypogonadism may therefore coincide with a diagnosis of PCa. Previously, an active or previous PCa diagnosis was a contraindication for starting TRT. However, the available evidence challenges this paradigm and current recommendations state that TRT may be a possibility in selected well informed patients with PCa after curative treatment. But what is the rationale for this change of mind? Endogenous and exogenous testosterone and PCa risk Huggins and Hodges discovered the association between androgens and PCa in 1941 by observing changes in serum phosphatases in men with PCa and proven bone metastases when they were androgendeprived (orchiectomy or estrogen injections). Since then, serum testosterone has been investigated extensively as a potential risk factor for PCa without any studies convincingly demonstrating this. An explanation may be found in the proposed saturation model, which states that maximal androgen stimulation of healthy prostate- and PCa tissue already happens at low testosterone levels3. As such, further increases in testosterone do not affect PCa development or progression.

“The long-term safety of TRT is uncertain. Current evidence does not support an association between high levels of endogenous serum testosterone and the risk of developing PCa.” Overall, TRT has mainly been investigated after curative treatment in men believed not to harbor residual disease. Currently, the EAU guidelines propose that TRT is restricted to men who have been treated for low-risk cancers, i.e. gleason grade <8, pathological pT1-2 and preoperative PSA < 10. Furthermore, TRT should not be started earlier than one year after the end of PCa treatment.

Vials of injectable anabolic-androgenic steroids that contain natural androgens like testosterone and synthetic substances, Photo: WIkipedia/US DEA

risk of developing PCa. Similarly, TRT does not appear to increase the risk of developing PCa, but the follow-up time of the currently available trials is too short to convincingly answer this question. Monitoring with digital rectal examination and PSA measurements is therefore still recommended in men commencing TRT. In patients previously treated with curative intend for PCa and thought not to harbor residual disease, TRT may be an option in the well-informed patient under close monitoring. TRT is not recommended in patients with active PCa. Acknowledgement: I would like to thank Prof. Jens Sønksen, Dr. Mikkel Fode and Dr. Christian Fuglesang S. Jensen from the Urological Research Unit, Herlev and Gentofte University Hospital, Denmark, for their contributions and scientific sparring for this article.

References 1. Wu FCW, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. N Engl J Med 2010;363:123–35. 2. Bell KJL, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J Cancer 2015;137:1749–57.

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. Saturday 25 March Plenary Session 2, Hot Topics in Andrology

Testosterone replacement therapy during active disease Reports on TRT in men with active PCa are limited. Men diagnosed with a low-risk PCa have excellent cancer specific survival and not all will require active treatment even after long-term follow-up. Clinical trials therefore require a very large sample size and long-term follow-up to address safety of TRT in men undergoing active surveillance.

Morgentaler et al. reported results from 13 men with PCa undergoing TRT and found no association between 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 26

EUT Congress News

Sunday, 26 March 2017

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Sunday, 26 March 2017

EUT Congress News

Today’s European Urology Events • Introduction by Jim Catto

Social Media Course

• Source for scientific research by Stacy Loeb • 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

Surgery in Motion

To be held in room 13 from 11.45 - 14.15

10:45 - 11:15 Male cystectomy 11:15 - 11:45 Female cystectomy 11:45 - 12:15 Ileal conduit 12:15 - 12:45 Neobladder

March 26th

Peter Wiklund, Stockholm (SE), Jim Catto, Sheffield (GB), Alex Mottrie, Aalst (BE), Joan Palou, Barcelona (ES) To be held in Room Copenhagen, North Hall (Level 1), 10.45 to 12.45

Platinum hour

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. 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 Adverse effects of BCG therapy are also a limiting factor in adhering to treatment and patient selection. BCG systemic toxicity may be life-threatening and local toxicity may cause major loss of urinary function14. It is recommended that BCG therapy should not be used in case of active tuberculosis and immune deficiency. The immune-dependent response in these 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 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. 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 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 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. 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 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. 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-muscletumor 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 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 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 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 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 5 and more recently the rate of instillations and types of chemotherapy (MMC) or BCG intravesical therapy . 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. and high-risk patients. For both groups, randomized the reduction in the number of instillations, keeping immunotherapy by dose reduction. Cooperative Group Saturday 25 March 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. Special Session, EAU Research Foundation 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 maintenance6. The alternative in case of that the suppression of instillations of weeks 3,4,5 Meeting frequently recurrent non-muscle-invasive bladder 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. 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 reasons: a reduction in the number of instillations will Despite recommendations, it is estimated that 30% of improve tolerance and therefore treatment adherence; patients will not be treated8,9. The non-prescription this treatment will be prescribed and followed by a factors of BCG are numerous; they include the greater number of patients. On the other hand, in the 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 in the effectiveness of BCG ; financial issues given the number of patients, and finally, this European study is low valorization of BCG instillations. Another a good opportunity for a new cost efficacy study. non-prescription factor is the refusal of the patient to receive treatment that requires repeated weekly References Dr J.B Roche instillations and exposure to serious adverse events. 1. Antoni, S., et al., Bladder Cancer Incidence and Mortality: Groupe Urologie Saint-Augustin – Bordeaux (Fr) Previous studies have shown that non-prescription or A Global Overview and Recent Trends. Eur Urol, 2017. 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 Prof. Marc Colombel Hôpital Edouard Herriot Dept. of Urology and Transplantation Lyon (FR)

Prostate enucleation using low energy pulsed Thulium laser with preservation of ejaculation

The effectiveness of adjuvant therapy for bladder carcinoma depends on a careful selection of patients and adapted timing to start bladder instillations. At the level of a urological unit, this means that a dedicated nurse will have a central role to informing the patient, organizing and delivering treatments, and detecting adverse events. In our case, a meticulous management has considerably decreased the rate of treatment drop-out and grade III toxicity. Patient selection Apart from patients with allergies or with a contraindication to BCG therapy (persistent hematuria, active tuberculosis, history of complication with BCG therapy) and for whom conservative treatments must be adapted, patients at very high-risk of progression must be rapidly identified and oriented towards radical treatment11. Criteria include the size (> 3cm), the multifocality, diffuse carcinoma in situ, lympho vascular invasion and finally tumors that progress during BCG12.This justifies that all high-risk tumors including those not invading the basal membrane (pTa) have endoscopic and biopsy control before receiving a course of bladder instillations. In a recent retrospective study, 30% of high grade tumors (Ta and T1) had a positive histology at the second TUR increasing the risk of early recurrence and stage progression despite intravesical therapy13. Here again, in daily practice, there is great reluctance to perform a second-look TUR; considering that a visually complete resection is a fair criteria or because of the patient’s refusal of a new surgical procedure. Sunday, 26 March 2017

bladder cancer: an updated review of the published literature. Pharmacoeconomics, 2014. 32(11): p. 1093-104. 4. Heyes, S.M., et al., The relative contributions of function, perceived psychological burden and partner support to cognitive distress in bladder cancer. Psychooncology, 2016. 25(9): p. 1043-9. 5. Babjuk, M., et al., EAU Guidelines on Non-Muscleinvasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol, 2016. 6. Oddens, J., et al., Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol, 2013. 63(3): p. 462-72. 7. Lamm, D.L., et al., Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol, 2000. 163(4): p. 1124-9. 8. Snyder, C., et al., Patterns of care for the treatment of bladder cancer. J Urol, 2003. 169(5): p. 1697-701. 9. Witjes, J.A., et al., Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscleinvasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guerin (BCG): results of an international individual patient data survey (IPDS). BJU Int, 2013. 112(6): p. 742-50. 10. Takeda, T., et al., Discontinuance of bacille CalmetteGuerin instillation therapy for nonmuscle-invasive bladder cancer has negative effect on tumor recurrence. Urology, 2009. 73(6): p. 1318-22. 11. Shahin, O., et al., A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-

Harnessing the latest in laser technology, this low-energy pulsed device provides excellent results in terms of post-operative urinary function, minimizing the risk of incontinence, pelvic discomfort, and storage-related symptoms. When combined with an anatomically precise application, this type of dissection affords the maximum level of protection to the patient’s ejaculatory function, and greatly reduces the risk of recurrence. The presentation gives a clear, accessible, step-by-step insight into laser-based prostate enucleation, showing all phases of the procedure, from dissecting the apex of the prostate through to nal morcellation.

Pre-recorded video Session

March, 25th 16:55 eURO Auditorium (Level 0) Procedure performed with 200W Hemera® Thulium Rocamed Laser

Visit Us Booth I26 EUT Congress News

Overcoming obstacles in patient communication Things patients do not ask or do not dare to ask their doctors Ms. Corrine Tillier Netherlands Cancer Institute Antoni Van Leeuwenhoek Hospital Dept. of Urology Amsterdam (NL)

Communication between patients and health professionals is nowadays one of the most important aspects of the support given to the patients and contributes to the high quality of healthcare. This fact has led to the introduction of courses at medical schools and universities to improve the communication skills of medical students. Future physicians learn techniques in listening, explaining, questioning, counseling, and motivating. Compared to previous decades, patients today are less passive than 50 years ago. They want to be informed, they play an active role in their health process, they use the internet to search medical information about their symptoms, illness, etc. But still there are things that patients do not ask or do not dare to ask their doctors. The question is not only what they do not ask the doctor, but why.

Patients are satisfied when they estimate the length of the visit > 20 minutes7. In the institute where I work, the visit length for new patients is 20 minutes for the urologist and for a follow-up visit, 10 minutes. When patients complain over the fact that the urologist was too busy or had to rush, it concerns usually follow-up and routine visits. They indicate that the time they 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. There are some disturbing factors as a phone call to the urologist during the consultation. It is very annoying for the patient when the conversation with the urologist is interrupted by a phone call. Another disturbing factor could be the attitude of some physicians during the consultation. Some physicians are so busy to type in the digital file that there is no eye contact with the patient. This attitude doesn’t encourage patients to ask questions.

In addition, there are things patients don’t dare to ask the doctor. It concerns psychological needs or the use of complementary and alternative therapies. Patients very often think that doctors are disinterested about psychological matters and only talk about medical matters. Patients talk easily with the nurse about non-medical matters. Nurses play a unique role by monitoring patients and can provide psycho-social support in adult oncology patients8. More and more As a clinical nurse specialist, I am a contact person for hospitals or institutions have understood this unique patients. It happens very often (almost daily) that role of nurses and provide nurse consultations beside patients call me the day after the consultation with the doctor consultations. the urologist to ask things they didn’t ask to the doctor. When I question them about the reason not A bridge asking the doctor, I hear several reasons, such as: Nurses are a privileged interlocutor. Patients often do not dare to say that they use natural products or • After the consultation with the urologist the complementary therapies to their doctor, but dare to patient realized that he/she should have asked tell the nurse. Seventy five percent of cancer patients more details. It could be about the diagnosis, using complementary and alternative medicine (CAM) treatment or about results of the pathology report; do not inform the physician about their CAM use9. It • Patient’s perception of the physician’s being could have some serious consequences, as we know rushed or busy; that that some herbal remedies or vitamins interact • 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. case of minor surgery or prostate biopsies, the procedure and the possible complications were Other factors which can influence the patient not vague to the patient; and asking the doctor are: • The patient didn’t understand/forgot the information given by the urologist about a new • Uncomfortable or intimate subjects in the prescription. presence of a conjoint or accompanying person, and Patients remember about 20% of the verbal medical • The patient didn’t understand what the doctor said and didn’t dare to ask more explanations. information the physician gives1. Different reasons could explain this issue: the physician use medical 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 related to the patient such as low level of education2. the patient during the consultation, can ask questions but another person present can influence the But since patients are more confident and become more active or involved in their own health issues, the communication between the patient and the doctor. Patients then don’t dare to ask the doctor particularly physician gives more and more information. 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 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 encourage the patient to ask questions. At the end of Older adults have more difficulty to encode and remember medical information and their memory the consultation, it is often sufficient to just ask patients if everything was clear, or if they have other also fades more rapidly. We have to consider this 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 nurses have complementary roles with regards the communication with patients, and they can both Consultation hours 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. 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 Visit length can vary by specialist. A new patient visit with an internist takes between 29 and 17 minutes and a follow-up visit between 19 and 16 minutes6. 30

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analogue study. Health Psychol 1992;11: 61-6 4. Groenewegen PP, Hutten JBF. Workload and job satisfaction among general practitioners: a review of the literature. Soc Sci Med. 1991;32:1111–9.

A doctor still has to make efforts to improve tcommunication with the patient by encouraging the patient to ask questions

5. Andersson SO, Mattsson B. Length of consultations in general practice in Sweden: views of doctors and patients. Fam Pract. 1989;6:130–4. 6. Watanabe J, Schulman K, Sulmasy D. The changing times: patient visit duration with internists, 1980-1996 [abstract]. Paper presented at: 1998 National Research Service Award (NRSA) Trainees’ Research Conference July 20, 1998 Washington, DC 7. Chen-Tan Lin, MD; Gail A. Albertson, MD; Lisa M. Schilling, MD; et al. Is Patients’ Perception of Time Spent With the Physician a Determinant of Ambulatory Patient Satisfaction? Arch.Intern.Med/Vol 161, June 11, 2001 8. Melanie Jane Legg. What is psychosocial care and how can nurses better provide it to adult oncology patients? Australian Journal of Advanced Nursing Volume 28 Number 3, 2011

Want to learn more about the

9. Eisenberg DM, Kessler RC, Foster C, et al. Unconventional medicine in the United States: prevalence, costs, and patterns of use. N Engl J Med. 1993;328(4):246–252. 10. Sanders K., Moran Z., Shi Z. , Paul R., Greenlee H. Natural Products for Cancer Prevention: Clinical Update 2016. Seminars in Oncology Nursing, Vol 32, No 3 (August), 2016: pp 215-240 11. Quilliam, Susan (April 2011). “’The Cringe Report’: why patients don’t dare ask questions, and what we can do about that”. J Fam Plann Reprod Health

Friday 24 March Special Session Patient Information, EAU Patient Information Project: Setting standards in cooperation and care

Please join us for a casual Q&A session to Meet the Expert on phi featuring: Dr Massimo Lazzeri

Istituto Clinico Humanitas, Milan, Italy

Saturday, March 25

10:00-11:00 & 15:30-16:30

phi

Dr. Vincent Gnanapragasam

Addenbrookes Hospital, Cambridge, UK

Sunday, March 26

(Prostate Health Index)

10:00-11:00 & 15:30-16:30

test?

Dive into the history of Annual EAU Congresses! www.eaucongresshistory.org

YEARS

AWARDS

PRESIDENTS

HIGHLIGHTS

Sunday, 26 March 2017

Current issues in urological nursing care Changes in urological nursing include diversity in roles and practices benefits as a result. There is also increasing evidence that nurses bring a different dimension to patient care that other clinicians are unable to provide, as nurses are more holistic in their approach to a patient’s problems.

Mrs. Paula Allchorne EAUN Board member Guy’s and St Thomas’ NHS Foundation Trust Dept. of Urology London (GB)

Nursing is evolving at an accelerated pace. In some countries this is happening more quickly than others and the EAUN is making sure that it can encourage and support advanced nursing practitioners at the forefront of change as well as the many urological nurses undertaking more traditional roles. It is now seen in many countries as ‘normal’ for urology nurse specialists to undertake advanced practices in diagnostics such as urodynamics, flexible cystoscopies and transrectal and transperineal biopsy. As well as developing nurse-led follow-up in outpatient clinics, and treating patients using flexible laser cystoscopy, intravesical therapy and port insertion in laparoscopy. This collaborative session at the EAUN conference will describe nursing developments in many areas of urology using presentations from the British Association of Urology Nursing (BAUN) in the UK, Denmark and the Netherlands.

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 place. These holistic needs are assessed by the specialist cancer nurses during various stages of a patient’s treatment pathway and then are addressed in a timely manner, allowing earlier discharge to primary care. National concerns Most of us have our own national concerns with regards to healthcare; economic constraints, workforce shortages and an increasing demand in patient activity. Assigning nurses in advanced roles are cost-efficient, effective, patient-centred and provide much needed continuity of care to patients. But nurses undertaking these roles still need the support of urological colleagues and work in a department that encourages innovation and the attainment of high standards.

Majority of healthcare models endorse collaborative approaches to delivering care to patients such as multi-disciplinary teams

European countries. Encouraging a nurse from each department to join the EAUN would allow the standardisation of urological nursing within the EU Realising the important contribution that nursing and nursing innovation to be shared more easily and makes to urology, the Secretary General of the EAU more quickly through the regions. We welcome you to and the EAUN launched the Plus One campaign to Many years ago, when the fledgling EAU was the collaborative EAUN-BAUN session to get a promote membership of the EAUN; an initiative to The majority of healthcare models endorse evolving, the standards of urology across Europe were glimpse of what are the Current issues in Urological encourage every department across Europe to 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. evidence-based guidance, urological surgery has department to become a member of the EAUN. grown from strength to strength across all countries Sunday 26 March As each different discipline (surgeons, pathologists, of Europe. 16.30 – 17.30: 18th International EAUN Meeting, The main reason behind this was that although the 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 value the access to the published EAUN guidelines and the EAUN conference. At the EAU Square in the Exhibition (EAUN counter) more information is available as well as instant membership registration.

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Sunday, 26 March 2017

EUT Congress News

Sunday, 26 March 2017