EUT Congress News Sunday 22 March 2015 by European Association of Urology (EAU)

European Urology Today

EUT Congress News

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30th Anniversary Congress of the European Association of Urology

Sunday, 22 March 2015

Madrid, 20-24 March 2015

Chapple is new Robotic cystectomy: not the new standard “Surgeon makes the difference, not the instrument,” says Studer Sec. General By Joel Vega By Loek Keizer Barely two hours after the second day of the Congress opened with the EAU General Assembly, the association welcomed a new Secretary General and a new Executive Member responsible for Science. Professors Chris Chapple (GB) and Francesco Montorsi (IT) succeeded Profs. Per-Anders Abrahamsson (SE) and Walter Artibani (IT), respectively. Chapple had been Secretary GeneralElect for the past year and will formally assume the role as Secretary General after the congress, while Montorsi led as Editor-in-Chief of European Urology.

Abrahamsson (r) congratulates Chapple at the General Assembly

Both Abrahamsson and Artibani are proud of the achievements of the association and its affiliated offices during their tenure. Abrahamsson: “When I took this position in 2007, it was my ambition to see the association better off when I leave. Looking at all of our achievements set out during this General Assembly, we can conclude that this is the case.” Abrahamsson also stressed the increasing global reach of the EAU while at the same time emphasizing that the EAU’s core goals and strategy will stay focused within European borders. He and the other executives, in their annual reports, often refer to the expanding influence of the EAU which is seen by many regional and national urology associations as a crucial link to other professional medical associations. Artibani also laid out some milestones from his term as Executive Member for Science. He mentioned the establishment of the Search and Nomination Committee to make succession a transparent process; the establishment of Section Bylaws; having the previously independent ERUS join the EAU as a Section; and establishing a committee and regulations for live surgery as among the notable achievements. New developments in Communications Treasurer and Executive Member (Communications) Prof .Manfred Wirth (DE) gave an update on several new developments in the EAU’s communications strategy. European Urology will be launching during the congress the EU FOCUS, a new sister publication of European Urology. Wirth also reported on the EAU’s web presence which has been boosted with the recent launch of the new Uroweb and UROsource platforms. Uroweb.org is the EAU’s new home portal, featuring news, information on upcoming meetings, and offering a personalised experience for users through MyEAU. UROsource.com, the new platform for the EAU’s scientific content offers the visitor access to abstracts, webcasts and presentations from every major Section Meeting or Congress of the past five years. Members have free access to content like the EAU Guidelines, or their previous attendance at meetings. Subscriptions for complete access are available at different price levels. Sunday, 22 March 2015

Robot-assisted radical cystectomy fails to clinch the title “new standard” as bladder cancer experts yesterday looked into recent data- or the lack thereof- that could support a crucial advantage over the traditional or open surgery approach. “Robot-assisted radical cystectomy (RARC) is feasible… but RARC cannot yet be considered as a standard treatment for invasive bladder cancer,” said Prof. Urs Studer (CH) who chaired the debate on robotic cystectomy versus open surgery. “Regarding RARC, our initial expectations are not yet met. Why not? Because the surgeon makes the difference, not the instrument,” added Studer. The audience later gave him a standing ovation when session chairmen Profs. Hein van Poppel and Jean Palou announced it would be Studer’s last plenary participation in the annual congress. Following the discussion and presentations by Bernard Bochner (USA) and N. Peter Wiklund (SE) who both provided insights and new data on the topic, Studer, however, noted that comparisons with open RC series may be misleading, and added this is also true for randomised trials for RARC versus open RC. “Surgeon experience and institutional volume strongly predict favorable outcome after open RC or

Studer (left) during Plenary Session 1 where Prof. Van Poppel (R) and Jean Palou (middle) acknowledge his “farewell” participation

RARC. In general, results of large patient series are reported, but these masks negative results from the early learning curve,” Studer said. Bochner, meanwhile, pointed out that doctor’s comfort with a particular technique can prove important. “Patients should also be asking the doctor what procedure he is comfortable with. In the end, it’s the doctors comfort which is key- and that could be my take-home message,” he said. The experts were one in saying that oncological outcomes, one of the crucial factors, remain the same or are equal for both procedures. The clear advantages for RARC are less blood loss and

transfusion rates, but which are counter-balanced by long operative time and high costs. The session also presented two lectures which discussed molecular and genetic research in bladder and kidney cancers. Seth Lerner (USA) provided an update on the work of The Cancer Genome Atlas Project (TCGA), whilst Marco Gerlinger (GB) discussed the role of evolution and mutation in renal cell carcinoma. Noting that kidney cancer cells are highly prone to mutation which makes them unpredictable, the challenge for doctors is to closely track their patients and keep regular re-assessments of disease progression, according to Gerlinger.

Pathology and research in PCa The Joint Meeting of the EAU Section of Uropathology (ESUP) and the EAU Section of Urological Research (ESUR) stressed the importance of combining pathology with morphology in modern medical practice and research. The lectures underscored the need for continued research on high-risk and castration-resistant prostate cancer. Prof. Dr. Sven Perner (DE) opened the session by describing the important role pathologists have in prostate cancer therapy. Prostate cancer is the most diagnosed cancer in men and although in most cases the disease develops slowly and patients die of comorbidities before the cancer is fatal, in a small group of patients the disease is very aggressive and deadly.

resistance have been studied but the molecular mechanisms are complex and, so far, there is no consensus on the definition of docetaxel resistance. It is possible to bypass docetaxel resistance by using other therapies such as enzalutamide, abiraterone, radium223, or sipuleucel-T. None of these treatments are intended to overcome resistance. Another option is to start treatment with the third-generation taxane cabazitaxel. Initial studies show that there is faster drug uptake.

Dr. Anne Chauchereau

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The question that keeps those involved in prostate cancer treatment and research on their toes is: “When cure is possible is it actually necessary and when cure is necessary is it still possible? Therefore, risk stratification of patients is essential and the role of the pathologist is important,” Perner said. Despite the research that has been done to identify prognostic biomarkers, so far none are in use in the current clinical setting. Consequently, the Gleason score remains the key predictor for outcome and therapeutic choices and the pathological analysis of biopsies is crucial. Dr. Anne Chauchereau (FR) discussed the issue of docetaxel resistance in patients with metastatic castration-resistant prostate cancer, which happens in about 50% of cases. Various elements of

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Maximising minimally invasive surgery

Today’s Industry Sessions

Joint ERUS/ESTU meeting

Starting at 14:00 hrs Live surgery: 1st da Vinci Xi Live Surgery in European Urology INTUITIVE SURGICAL - Room Milan Industry sessions, all starting at 17:45 hrs OAB: Who is in control? A patient-centric approach ASTELLAS - eURO Auditorium Navigating the mCRPC landscape: Exploring key clinical decision points BAYER HEALTHCARE PHARMACEUTICALS Room N105-106 The good, the bad and the ugly of testosterone? The relevance of proper treatment of hypogonadism BAYER PHARMA AG - Room Stockholm Pharmacological treatment of BPH symptoms BERLIN-CHEMIE AG - Room Retiro Heart and ADT: Managing benefit/risk ratio FERRING - Room N101-102 More treatments and new challenges in the management of castration-resistant prostate cancer JANSSEN PHARMACEUTICA NV - Room Milan Workshop: Making sense of endoscopic enucleation for BPH: A paradigm shift LUMENIS - Room N107-108

By Alba Leon The Joint Meeting of the EAU Robotic Urology Section (ERUS) and the EAU Section of Uro-Technology (ESUT) highlighted the need for multidisciplinary teams in the treatment of urological cancers, and presented the case for robotic surgery. “This is about our duty of care, to constantly strive to innovate and explore new technologies so that we can offer better treatments to our patients. This is about working together,” said Mark Emberton (GB). The themes of technological advance and multidisciplinarity recurred throughout the session, and all present agreed they were needed in all uro-oncological specialties. “Robotic surgery will take over most indications for nephron-sparing surgery,” said Alexandre Mottrie (BE) in his lecture on kidney outcomes. He noted the quick rise in the number of robotic partial nephrectomies being carried out. In his view, robotic surgery is feasible, even in complex cases, as it has a good oncological outcome and an acceptable learning curve for the surgeon. Peter Wiklund presented bladder cancer outcomes, and concluded that while OR time favours open radical cystectomy, complications, blood loss and rate

of hospital stay tip the balance towards the use of robots. And while hospital costs could favour an open approach, he stressed that “calculating the cost effectiveness overall remains complex,” adding that social costs are not always taken into account. Regarding prostate cancer, Francesco Montorsi (IT) advocated the use of robotic surgery, and patient selection that makes use of technologies like MRI. “I know this is provocative but RARP is the real focal therapy for very young men who want surgery,” said Francesco Montorsi, which triggered a debate. “This is about turning our attention away from the prostate, and actually trying to understand the tumour,” countered Emberton. In his view, innovation can only happen if there is a multidisciplinary setting. He talked about the advances in focal therapy and the evolution of the research to understand the biology of the disease.

Prof. Montorsi at the joint ERUS-ESUT meeting

His team set up a threshold. “It is like active surveillance,” he said about the approach, “but there we surveil the man, and here we surveil the tumour.” He presented the newest protocol that his team is currently working on, which is at the point of becoming a randomised study, for the best evidencebased treatment possible. Finally, he stressed once

The rest of the meeting was dedicated to the evolution robotic surgery, as well as recent innovations and novel approaches. Interesting questions arose, such as the comparison between prostatic laser enucleation versus robotic and laparoscopy¸ and novel approaches to PCNL, among several other promising research areas.

more the importance of imaging techniques for prostate cancer treatment. “The future is almost impossible to predict, but I think it will be almost totally non-invasive,” he concluded.

Inflammation and prostatic diseases: From bench to bedside PIERRE FABRE MÉDICAMENT - Room N103

Value and limitations of PET/CT in PCa

Rationale for more targeted management of BPH patients RECORDATI - Room N104

Technique useful in high-risk prostate cancer patients By Monique van Hout

European Urology Today Editor-in-Chief Prof. M. Wirth, Dresden (DE)

The value and limitations of PET/CT scans in prostate cancer were discussed in the Meeting of the European Section of Urological Imaging (ESUI). Dr. Stefano Fanti (IT) pointed out the limitations of PET/CT in the diagnosis and initial staging of prostate cancer while Dr. Alberto Briganti (IT) focused on the use of the imaging technique in disease recurrence.

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. Patruno, Rome (IT) Dr. G. Ploussard, Paris (FR) Prof. J. Rassweiler, Heilbronn (DE) Prof. O. Reich, Munich (DE) Dr. F. Sanguedolce, London (GB)

“The question in the title of my presentation – Is PET/ CT helpful in diagnosis and initial staging of PCa? – made me consider if I should set the record for the shortest presentation at the EAU Congress by simply saying ‘no’ and leaving it at that,” Fanti jokingly said at the start of his presentation. He went on to present evidence that demonstrates the limited use of Choline-PET in prostate cancer.

Several studies have shown that PET/CT has no use in prostate cancer diagnosis, and is actually not recommended in this setting. In staging N+ and M+ disease, Fanti showed PET/CT’s specificity is not bad but its sensitivity is below 50% which is unacceptable. Moreover, lesions that are smaller than 5 mm are invisible on the scans.

“We can’t make any predictions for the future,” Fanti concluded, “…but today PET/CT has no use in diagnosis and staging of prostate cancer.” The only setting in which the technique currently proves its value is in biochemical recurrence. Briganti agreed and stressed the importance of PET/ CT in prostate cancer recurrence. He showed that the imaging technique is particularly useful in patients with a high PSA level and a low PSA doubling time. Nonetheless, PET/CT has limitations in lesion-based analyses. “PET/CT definitely has a place in diagnosing and monitoring prostate cancer recurrence, but we need to be smart enough to recognise the setting in which to use it. Make sure you use it in high-risk patients,” Briganti said.

Dr. Stefano Fanti

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

Future of targeted prostate cancer treatment

Coordination and Editing J. Vega

Joint meetings look into advances in PCa treatment

Onsite Reporting and Editing Team M. van Hout L. Keizer A. Leon J. Vega

By Loek Keizer As treatment options become more refined and comprehensive, the tools available to the urologist or clinical oncologist to effectively target this treatment become more important. Systems that give precision on a molecular level are becoming a reality.

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A substantial part of the second day of the Annual EAU Congress was devoted to the Section Meeting of the EAU Section of Oncological Urology, which cooperated with EORTC-GUCG, the EUOG, ESSO and ESTRO. Profs. Freddie Hamdy (GB) and Morten Høyer (DK) gave back-to-back State-of-the-art lectures that together painted a poignant picture of the (very near) future for precisely-targeted treatment: surgical and radiotherapeutic, respectively. Key to both talks was the need for better targeting. Hamdy showed the novel techniques of a prototype optical system that was developed in Oxford, which combined white-light with infrared in real time. Combined with the use of molecular mini-bodies, very precise surgical procedures can be achieved. He showed the size and scope of the team, which included engineers and radiologists. Hamdy: “We worked with a broad team to realize this project, but it’s the urologist who knows the unmet needs of patients” (See related story next page).

Speaking as a clinical oncologist on behalf of ESTRO, Høyer discussed the inclusion of pelvic lymph nodes in radiotherapy for prostate and bladder cancer. “The efficacy of elective radiation therapy to pelvic lymph nodes in therapy for PCa has not been proven in randomized clinical trials, and results from retrospective cohort studies are diverging. However, this poor efficacy could be explained by insufficient imaging, radiation techniques and dose.” Speaking after the session, Høyer agreed that the optical system of Hamdy’s team would be very useful, combined with radiation oncology. “Combined, this could be the future of radio oncology and surgical oncology. What we need is better targeting of our treatments, defining volumes that we are treating with surgery or radiation oncology.” “Although I’m well aware that I’m at a congress for urologists, it’s not a competition, there’s a mission for both of us. For instance, it would be obvious to treat patients with lymphnode metastasis with radiation oncology. That’s because we can treat electively, relatively large margins, which is not possible with surgery. We can boost up, give more intensive treatment of high-risk volumes, or volumes where we know there is metastasis.” Asked about the multidisciplinary approach that is often mentioned in the treatment of urological

Prof. Morten Høyer

cancers, Høyer quipped: “You shouldn’t just talk about it, but live together in the same house! Our new hospital in Aarhus, which opens in 2018, will be a single PCa clinic with every discipline under the same roof. I hope to see clinics like this across Europe in the near future!” Sunday, 22 March 2015

Joint EAU-SIU session tackles Molecularly onco-urology issues targeted precision surgery

By Alba Leon

sequence of systemic therapy. In his view, there have been advances on this issue, but the most important Diagnostic and prognostic tools, as well as the consideration is that doctors should not switch therapies and new strategies for the future of medication too fast when the growth of the tumour is metastatic renal cell carcinoma (mRCC), and metastatic slow. He said the first-line choice “…should always be castration-resistant prostate cancer (mCRPC) took based on initial prognosis assessment, and toxicity centre stage in the second Joint Session of the should be taken into account as well.” European Association of Urology (EAU) and the Société Internationale d’Urologie (SIU). Tobias Klatte (DE) discussed the proper use of prognostic tools in metastatic RCC. Due to the heterogeneous nature of the patient population, Klatte said it is important to establish prognostic models that assign or divide patients into specific groups, so that personalised treatment is achieved. On the same line, Guillaume Ploussard (FR) looked into the question whether there is an optimal

Joint EAU and SIU session

International Consultation on Minimally Invasive Surgery in Urology Over 400 pages on the latest in minimallyinvasive urological surgery, edited by W. Artibani, J. Rassweiler, J. Kaouk and M. Menon EAU Members: pick up your USB-card of this latest publication by the ICUD at the EAU Booth! EAU Members can also find the interactive PDF on:

By Joel Vega Molecularly targeted precision surgery for prostate cancer is expected to enable surgeons to refine their techniques in reducing positive surgical margins (PSM), and thereby contribute to lowering rates of biochemical recurrence. Prof. Freddie Hamdy (GB) gave an overview of the work done by a multidisciplinary group of physicians and engineers in the United Kingdom to develop fluorescence image-guided surgery (FIGS) in the hopes to better identify extra-capsular and nodal involvement in prostate cancer during surgery. “I urge urologists not to work in isolation as this type of work can only be possible with the involvement of various specialists and engineers,” said Hamdy during the session of the European Uro-Oncology Group (EUOG) moderated by Prof. Susanne Osanto (NL).

Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1 Congress highlights . . . . . . . . . . . . . . . . . . 2/3 Why does anti-androgen therapy fail? . . . . 4/5 Surgery or radiotherapy: Treatment decision for high-risk PCa . . . . . . . 6 Understanding the role of the urothelium . . . 7 Prostate cancer: Impact of surgeon’s volume on outcome? . . . . . . . . . . . . . . . . . . . 8 Markers of PCa aggressiveness in the tumor stroma. . . . . . . . . . . . . . . . . . . . . . . . . 9 Do we need to continue androgen deprivation therapy?. . . . . . . . . . . . . . . . . . . . 11 Sniffing cancer- Volatile urinary compounds. . . . . . . . . . . . . . . . . . . . . . . . . . 12 Risk stratification for early detection of prostate cancer. . . . . . . . . . . . . . . . . . . . . 13 Robot-assisted radical prostatectomy. . . . . . 15

Hamdy said outcomes of radical prostatectomy are far from satisfactory since 20 to 50% of patients have positive surgical margins, and that margin rates and operative results can be improved by better preoperative, operative staging and precision surgery.

Are there useable molecular markers for prostate cancer?. . . . . . . . . . . . . . . . . . . 18 Insulin resistance, obesity and LUTD. . . . . . . 19

Fluorescence imaging works on the principle where a molecular system absorbs then emits light. During the absorption process lymph nodes and tissue structures are clearly seen by the surgeon enabling them to excise diseased tissue.

Immunotherapy in renal cell cancer. . . . . . . 20

“Our aims are to optimize the techniques for routine clinical application and use molecularly targeted imaging to investigate the genetics of prostate specific membrane antigen (PSMA) expression and genomic diversity of prostate cancer,” Hamdy said.

Guidelines in the jungle of new media. . . . . 25

Best Abstracts. . . . . . . . . . . . . . . . . . . . . 22/23 Large prostates: Knife or laser?. . . . . . . . . . . 24

EAUN: ERAS care pathway aids patient’s rehab. . . . . . . . . . . . . . . . . . . . . . . 27

Day 2 Award Gallery

Best Paper in 2013 on Fundamental Research: P. Uvin (Leuven, Belgium)

Best Paper in 2014 on Clinical Research: R. Karlsson (Stockholm, Sweden)

First Prize Best Abstract (Oncology): C.G.A. Ruf (Koblenz, Germany)

Third Prize Best Abstract (Oncology): J.F.P.L Lestingi (Sao Paulo, Brazil)

First Prize Best Abstract (Non-Oncology): T. Cai (Trento, Italy)

Second Prize Best Abstract (Non-Oncology): E. Weyne (Leuven, Belgium)

Third Prize Best Abstract (Non-Oncology): C. Gratzke on behalf of Y. Wang (Munich, Germany)

Best Scientific Paper Fundamental Research: E. Castro on behalf of E. Bancroft (London, GB)

Best Scientific Paper Clinical Research: H. Van Poppel on behalf of E. Scosyrev (Rochester, United States)

Best Scientific Paper in European Urology: C. Rentsch and F. Birkhäuser (Switzerland)

Campell Team Challenge Quiz winner: M.L. Vrang (Frederiksberg, Denmark)

ESUI Vision Award 2015: V. Pasoglou (Brussels, Belgium)

Sunday, 22 March 2015

EUT Congress News

Why does anti-androgen therapy fail? Drug resistance poses challenge to develop individualised PCa treatment Norman Maitland Professor of Molecular Biology University of York York (UK)

â&#x20AC;?Why does anti-androgen therapy fail?â&#x20AC;? This is probably one of the most common questions asked by prostate cancer patients, especially those for whom anti-androgen therapy has reduced serum PSA and other indicators of tumour growth and bulk to (below) zero. The obvious follow up questions are â&#x20AC;&#x2DC;Why me?â&#x20AC;&#x2122; â&#x20AC;&#x201C; when the therapy fails rapidly, and â&#x20AC;&#x2DC;Whatâ&#x20AC;&#x2122;s next?â&#x20AC;&#x2122; â&#x20AC;&#x201C; or how will you treat my relapsing tumour? There is of course a simple answer to the original question: Anti-androgen therapy fails as a result of the treatment and the biology of the cancers. No treatment, no resistance! Perhaps a better question would be to ask â&#x20AC;&#x2DC;HOW anti-androgen therapy fails?â&#x20AC;&#x2122; This is a harder question, and one which is difficult to explain to patients, beyond â&#x20AC;&#x2DC;Itâ&#x20AC;&#x2122;s complicated!â&#x20AC;&#x2122; Androgens are not just active in the prostate To try to answer these questions we need to understand both the biology and the biochemistry of cellsâ&#x20AC;&#x2122; responses to male sex hormones. Of course prostate epithelial cells (and the malignant carcinoma form) are not the only cells in the body, or indeed the prostate which can respond to male sex hormones. I have illustrated this in Figure 1. This may explain some or all of the observed side effects of anti-androgen therapy: they are not off-target effects, but are the effect of potent inhibitors on the correct target, but in the wrong cell types! Based on more modern targeted drugs, itâ&#x20AC;&#x2122;s unlikely that an anti-androgen (receptor) therapy would be acceptable if discovered today. There is more to the prostate androgen response than PSA In normal prostate, and indeed prostate adenocarcinoma cells, it is the luminal cells which express the receptor for androgens (AR) and respond to the hormone. This results in the potent upregulation of a variety of â&#x20AC;&#x2DC;prostate-specificâ&#x20AC;&#x2122; proteins such as prostate-specific antigen (PSA), a variety of other proteolytic enzymes and polyamines, which fulfil the primary role of prostatic secretions, the maintenance of human sperm, in the hostile acidic environment of the female reproductive tract.

However, as we have seen, AR is expressed in a variety of other human tissues, but perhaps more strikingly in a proportion of the mesenchymal/stromal cells in the prostate itself. In prostate stroma, when treated with androgens, multiple proteins are secreted (andromedins) which can influence the behaviour of the epithelial component of both normal and malignant prostate.

After combination of two AR-DHT molecules to form a dimer, the structure then translocates into the nucleus of the cell, where it binds to multiple recognition sites (the structure of which is sufficiently loose for them to be known as â&#x20AC;&#x2DC;consensus binding sitesâ&#x20AC;&#x2122;). Other steroid hormone receptors can also bind to these sites on DNA. What defines specificity is often the presence in the complex on DNA of co-activator (or co-repressor) proteins (shown in orange in Figure 2). The immediate effect of complex formation (within a few hours) is an increase in the expression of ARregulated genes, which affect cell survival, secretions (such as PAP and PSA) and (in cancers) of cell replication proteins. Some androgen regulated genes take more than 16 hours to be activated. It is likely that these are indirect effects of the AR-regulated genes, but nevertheless have important consequences for cancer treatment. Castration: a miracle cure for AR-positive tumours After treatment with anti-androgens, whose point of action is illustrated in Figure 3 (a simplified version of Figure 2) and listed in Table 1, there is an almost instant cessation in the expression of AR-regulated

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Androgen signalling is complex but vital to our understanding of resistance Within a prostate cancer, the response to circulating androgens in the luminal-like cancer cells is similar to that in normal luminal cells, with the added effects on androgen-stimulated cell replication in the tumours. Whereas the luminal cell in normal prostate is terminally differentiated and programmed to die, the same cell in a cancer is long-lived and is capable of multiple cell divisions. The signalling process from adrenally synthesized androgens within normal and indeed cancer cells is now better understood, and is summarized in Figure 2. In essence, information flows from the outside of the cell and the supply of testosterone, through the cell cytoplasm, where the androgen is modified by 5Îą reductase to a more potent form (dihydrotestosterone or DHT), followed by binding to the androgen receptor (AR) protein (which releases chaperone proteins from the AR such as heat shock proteins).

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genes â&#x20AC;&#x201C; normally monitored in patientsâ&#x20AC;&#x2122; serum by measuring PSA levels, accompanied (in hormonenaĂŻve patients) by the loss of both luminal cancer and normal prostate cells by natural cell death (apoptosis) mechanisms. Such drug treatments, an aesthetic improvement on the surgical castration practised by Charles Huggins, for which he won the Nobel Prize in 1966, are normally only applied when there is evidence of escape of cancer cells from within the prostate, where surgery and/or radiotherapy is least effective. There is however new evidence (from the CHAARTED Trial) to show that a combination of anti-androgens plus radiotherapy provides longer survival times in these patients, although neoadjuvant anti-androgens to shrink tumours before surgery may reduce survival (more of which later). A small proportion of the primary prostate cancers, treated by anti-androgen therapy do fail to respond from day one.

â&#x20AC;&#x153;All patients have different solutions to the resistance problem. The next generation of prostate cancer treatments should be decided on a truly individual, patient-speciďŹ c basis.â&#x20AC;? Castration-resistant tumours remain dependent on androgens However, it is important to realise that even the resistant tumours to a first-line androgen therapy are still dependent on androgens for the expansion of secondary tumours. How do they achieve this? Molecular studies of resistant tumours have indicated multiple mechanisms, which can retain androgen responsiveness, even in castration-resistant cancer patients.

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Is this unexpected? Probably not, as we use a strongly androgen-regulated prostate protein (i.e. PSA) to monitor tumour growth. However, far from overexpressing tumour markers such as PSA, the cancer cells express lower levels, and it is access to the bloodstream from metastases and â&#x20AC;&#x2DC;leakyâ&#x20AC;&#x2122; vascularisation of the tumour mass which results in increased serum PSA concentrations. This is despite the higher levels and hyperactive nature of the AR in the tumour cells. There are many routes to castration resistance The number of biochemical mechanisms which the cancer cells can exploit to achieve resistance to anti-androgens is also surprising. These are summarised in Table 1 for convenience, but include endogenous synthesis of androgens within the tumour to replace adrenal androgens blocked by Zoladex, for example, mutation of the androgen receptor to enable it to utilise other steroid hormones such as oestrogen and progestogen, and even amplification of the androgen receptor gene on the X chromosome, resulting in more receptors which can bind the reduced amount of androgens from the bloodstream. Combination blockade of the androgen signalling axis The sequential use of different anti-androgens after failure on first-line castration therapy, results in significant life extensions: for example abiraterone or enzalutamide treatment in patients whose cancers have relapsed after successful Zoladex/Casodex treatments. Despite the molecular information on androgen signalling and resistance, we are still not able to judge either (i) the longevity of the secondary androgen control or (ii) to identify the 40% of patients for whom it will work. The central role of the androgen signalling axis is not in dispute here, since the various antiandrogens of increasing potency result in tumour shrinkage and relief of symptoms such as bone pain from metastases.

Mechanisms of Therapy Resistance to Prostate Cancer Drug Treatments

EUT Congress News

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Table 1: Mechanisms of Therapy Resistance to Prostate Cancer Drug Treatments

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Figure 2: Schematic outline of the androgen response in prostate epithelial cells. The diagram illustrates the ďŹ&#x201A;ow of signals from serum androgen (pink circles) outside the cells via dihydrotestosterone (red diamonds) into the cell nucleus, where hormone induced changes are stimulated.

Figure 1: Androgens do not only act in the male reproductive system. A number of different tissues, notably the brain and the spleen/bone marrow, express high levels of nuclear androgen receptor. The level of expression and its significance is reďŹ&#x201A;ected in the font size and intensity. Data principally from Dart et al (2013) PLOS One.

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Drug Target Supply of androgens to the PCa cells (1) From Adrenal Gland (e.g. Zoladex) (2) Endogenous synthesis in the tumour via Cyp17 (Abiraterone) Activation of testosterone to dihydrotestosterone via 5Îą reductase (e.g. Finasteride and Dutasteride) Binding of DHT substrate to monomeric androgen receptor (1) Steroidal (estrogen/cyproterone acetate) and (2) non-steroidal (Casodex/ Enzalutamide) Dimerisation and modification (phosphorylation) of androgen receptor Nuclear translocation of androgen receptor Binding or nuclear androgen receptor to (1) Recognition sites on DNA (2) Co-activator molecules Downstream effects of AR-stimulated effector molecules Heat Shock Protein inhibition and Androgen receptor degradation

Resistance Mechanism Switch to intratumoral androgen synthesis Amplification of the androgen receptor gene to maximise the use of low androgen concentrations. Not established Switch in 5aR isotype or use of testosterone/adrenal androgens Gain of function mutations in the androgen receptor gene to enable it to use other steroid hormones. Bypassing of the AR by ligand independent activation of androgen responsive genes

Mutation of the AR gene and expression of ligand-independent splice variants Expression of AR splice variants which translocate to the nucleus in the absence of androgen. Changes in balance between AR co-activator and co-repressor molecules and relative affinity of the receptor by mutation of AR. Activation of alternative salvage pathways which stimulate the signalling molecules downstream from AR activation. Redundancy in the Heat-shock Chaperone system, inhibition of AR proteolysis

Sunday, 22 March 2015

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Figure 3: Intervention points for therapy in the androgen response pathway. Potential and actual drug targets are indicated by the numbers in black boxes, described in more detail in Table 1.

However, attempts to achieve total blockade, either of exogenous and endogenous androgen supply, or simultaneous blockade of AR by enzalutamide plus androgen synthesis with abiraterone, do not seem to have achieved a better patient outcome than the single agents.

â&#x20AC;&#x153;It is the treatment which induces the most variability, propelling the cancer mass towards a fatal and heterogeneous mixture of phenotypes, which more readily resist even the most radical of chemotherapies.â&#x20AC;? They achieve this (i) by folding their chromosomes to turn off unwanted genes in a highly reversible manner, (ii) when a gene is not required for a long time period the cytosine bases are heavily modified (by methyl groups) which is also reversible, but less so than (i) and only when there is a strong selective or mutagenic pressure (iii) a gene is lost, transposed or inactivated/changed by an irreversible point mutation. Progression from (i) to (iii) destroys the SCâ&#x20AC;&#x2122;s flexibility.

founder changes, which enable the tumour to prosper (and be clinically detectable and relevant) in the tumour microenvironment, both before, during and after treatment. It is the treatment which induces the most variability, propelling the cancer mass towards a fatal and heterogeneous mixture of phenotypes, which more readily resist even the most radical of chemotherapies. What strategies can we evolve to combat the treatment resistant phenotype? It is clear that our increasingly sophisticated oncology drug cocktails are simply getting better at doing what their predecessors could do 40 years ago: killing dividing cells â&#x20AC;&#x201C; but with more acceptable side effects, and at a much higher cost. Studies with antibiotics provide some of the clues to the way forward: as do some of the very first chemotherapy studies (from the 1980s). (i) For example, to select a resistant cell in the laboratory, one treats a population (a large population) of cells with low levels of the drug under study for a long period of time. This is how drugresistant LNCaP prostate cancer cells were derived. In a patientâ&#x20AC;&#x2122;s tumour, the structure and vascularisation means that the blood levels of a drug are rarely uniform across the cancer mass, and many cells are deprived of a toxic dose: especially within the therapeutic window of docetaxel for example.

As I have illustrated in Figure 4b (a schematic illustration of multiple dynamic changes) it is highly Whilst there remains uncertainty about the merits of likely that there will be at least five different cell intermittent androgen therapy (IAT) as discussed populations to be treated after a patient has failed recently in Lisbon at EUMC 2014, drug resistance first-line castration. Is it therefore possible to ever kinetics argues strongly that cycles of high-dose achieve tumour control in CRPC, especially using treatment should minimise the generation of variants. Within this changing population of cells there is a targeted agents (which will normally be directed Any prolongation of sub-toxic treatment simply adds minor population (about 1% in normal prostate and against the most common tumour target â&#x20AC;&#x201C; but not to the tumour complexities. <0.1% in malignant tumours), which is highly invasive necessarily against the population of cells which but relatively quiescent, even within the dividing mass defines malignancy)? (ii) Combination therapies should be designed with of cells in a tumour. complementary and â&#x20AC;&#x2DC;salvageâ&#x20AC;&#x2122; cell-signalling As quantified with other tumour types, and best pathways in mind, now that we can map their This population, which expresses little or no AR in understood (but not solved) in a number of existence in vitro and in vivo. humans, contains the tumour-inducing or cancer leukaemias, highly targeted agents have only a stem cell population resides. Impervious from the limited potency with profound side effects. It is our (iii) The ordering and timings of such combinations start to anti-androgen therapies, it is capable of therapies which select for and define the resistant has not been well developed: for example, does one regenerating the tumour mass, after further multiclonal cancers - which kill patients. anticipate resistance by blocking the resistance adaptation to the chemotherapy-rich environment strategy, or should the secondary treatment be resulting, by differentiation and expansion in a If we are treating not one but many cancers in one delayed? Just because androgen therapy achieves secondary tumour, sharing the â&#x20AC;&#x2DC;founder mutationsâ&#x20AC;&#x2122; of patient, can we ever achieve cure or even control? control, it is perhaps important to supplement it the original tumour, and the therapy-induced It may seem from the preceding discussion that before resistance occurs. adaptation of the androgen response. cancer cures are impossible or at best unlikely, in a heterogeneous stem cell-based model of cancer. The (iv) Combination therapies should probably include Whether all the AR-modifying mutations (from Table current mean survival time of CRPC patients argues targeting of multiple cell types including the stem-like 1) will be found in the stem cell component remains strongly that this is currently true! It is clear that early cells (if possible or feasible) in addition to pathway to be established. surgery and radiotherapy can be curative, but targeting. nevertheless there are more frequent relapses than Castration resistant prostate cancer: a moving target expected, probably because of early metastasis. (v) As seen by the number of mechanisms in Table 1, As can be seen in Figure 4b, the tumour cell all patients have different solutions to the resistance populations in prostate cancer are constantly evolving. My current model of prostate cancer implies that the problem. The next generation of prostate cancer New populations arise by random mutation - and not founder cells of each cancer (of which there can be treatments should be decided on a truly individual, always in the SCs. This will result in new dominant several in a single patient) are defined in their patient-specific basis. cell populations (if the mutation is advantageous) or a malignant potential when the cancer emerges from series of â&#x20AC;&#x2DC;failed cancersâ&#x20AC;&#x2122; of limited size and survival â&#x20AC;&#x2DC;pre-tumour progression.â&#x20AC;&#x2122; characteristics (as seen on sectioning of whole mount Sunday, 22 March prostates from cancer patients and indeed healthy All subsequent mutations and the gene 07.30-10.55: Plenary Session 2 individuals over 50). rearrangements (found more commonly in prostate Prostate Cancer, State-of-the-art lecture cancers) are an enhancement of the original suite of In addition, the presence of a mutation in a single copy of the two genes (apart from androgen receptor which is present in one copy on the X chromosome), can frequently be silenced or is subject to an allelic switch if the tumour microenvironment (and treatment) demands the normal gene allele for cell

5 6 *' ! %%"%& *% ! -# !& "!

! 3"% 5 6 & ("! . '* "% Thus, many â&#x20AC;&#x2DC;prostate cancer-specificâ&#x20AC;&#x2122; genes are actually those which represent the absence of the basal cells and luminal cells which can now actively divide. This is illustrated in Figure 4a.

Androgen biochemistry in a multicellular context To explain the latter results, in a more scientific manner than simply restating the fact that prostate cancers show considerable heterogeneity between patients, we should perhaps consider the cellular content of the tumours: another form of heterogeneity. Firstly, as discussed previously, the key AR target is widely expressed in a number of relevant cell types, apart from the luminal-like prostate cancer cells. â&#x20AC;&#x2DC;Off-targetâ&#x20AC;&#x2122; effects on the bone marrow, spleen and perhaps most importantly the tumour-associated stromal cells can also account for the spectrum of patient responses observed. Do cancer stem cells exist in prostate cancer: and how do they influence the outcome of anti-androgen therapies? There is another potential confounding element, which my own research has highlighted over the last 10 years, since my laboratory first identified a tumour-initiating cell population from hormone-naĂŻve prostate cancers. Within each tumour there are two important cellular hierarchies. The first is a differentiation hierarchy. In a prostate acinus there is a balance between basal and luminal cells, limited by strict cell adhesion criteria, and bounded by a basement membrane. As elegantly described by Gleason, almost 50 years ago, the basement membrane progressively disappears with increasing tumour grade, and most prostate cancers are virtually devoid of basal cells: reduced from a 40-50% content in normal prostate acini.

Normal

survival. In fact, stem cells, whose aim is to survive in an unaltered form throughout the life of the patient, appear to have evolved a hierarchy of gene inactivation, which allows them to be flexible in their responses to changing environments.

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Figure 4a: Cell type heterogeneity and changes in cell proportions between normal and malignant prostate Italic symbols in brackets indicate molecular markers of individual cell types

Sunday, 22 March 2015

Figure 4b: Fluctuations in clonal cell populations during the development of prostate cancer, and after anti-androgen treatments. The triangles indicate a bulk of proliferating cancer cells, including the multiple cell types in the lower part of figure 4a. Stem and tumour initiating cells are shown by coloured circles: there are multiple stem-like cells in a single tumour (0.1% of total cell number)

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Surgery or radiotherapy: Treatment decision for high-risk PCa Is radiotherapy less toxic than surgery? Dr. Alberto Bossi Dept. of Radiation Oncology Gustave Roussy Villejuif (FR)

Due to the absence of randomized data clearly showing a superiority of one treatment option over the others in terms of classical survival endpoints, patients diagnosed with High-Risk Prostate Cancer (HRPCa) are currently basing their choice mostly on individual reasons and personal motivations. Also the fear for side effects and for quality of life (QoL) deterioration after treatment, have been consistently shown to affect treatment choice. A significant number of papers have been published comparing toxicities and QoL impact of the different management options available for PCa: some of them, but not all, have carefully compared the incidence of side effects during and after treatment also took into account the base-line patient profile in an attempt to derive the actual and net impact of surgery or radiotherapy (RT).

needed following international Guidelines based on randomized evidence (as it is the case for RT) or adopted for the majority of patients due to the post-op findings or the late evolution of the disease (as it is the case for upfront surgery). Patients and their families, but also professionals responsible for treatment counselling for patients diagnosed with HRPCa are thus left in a real absence of contemporary, validated, comparative data on toxicities and their impact on QoL for this particular subset of patients. The side effects profiles for the available options in the management of the PCa localized disease are well defined and compared in several non-randomized studies. Generally speaking the long term impact of RP, EBRT and brachytherapy (BT) on QoL is, in all series, negligible while erectile dysfunction appears more frequently after surgery as compared to EBRT or BT (especially in the first two to three years after treatment) and gastro-intestinal side effects are more common after EBRT. Radiotherapy plus ADT The knowledge that for patients having HRPCa the adjunction of (long-term) ADT to RT yields better survival results as compared to RT alone comes basically from old randomized clinical trial (RCT) launched in the late 1980s by the EORTC (22861) and the RTOG (92-02). At that time, only treatment-related, physician-reported toxicity were described without detailed information about their impact on patientperceived QoL; furthermore only the most classical toxicity (genito-urinary, GU, and gastro-intestinal, GI) were reported with little, if any, consideration for the persistence of erectile dysfunction once ADT was stopped.

alone at least in terms of GU and GI toxicity. On the other hand, it is out of question that adding ADT to RT will translate in a long-lasting erectile dysfunction. Furthermore, it is noteworthy that any evidence exists about an increase likelihood of any toxicity when RT is employed for patients with HRPCa as compared to patients having low-risk PCa while mono-institutional surgical series clearly suggest that an increased risk of urinary incontinence and erectile dysfunction is associated with RP for HRPCa patients versus surgery for low-risk ones (Suardi, 2012). Radiotherapy after radical prostatectomy When RP is adopted as initial treatment option for HRPCa, mature series emanating from centres of surgical excellence, clearly indicates that at least 75 to 80 % of patients will need some form of (early) adjuvant treatment (RT and/or ADT) or of (late) salvage ones. This means the added toxicity of both treatments (RP plus RT and eventually ADT) should be considered when counselling HRPCa patients for a surgical approach. In this respect, RCT of post-op immediate RT versus observation have not shown an increase risk of developing GU nor GI toxicity but mono-institutional series are less reassuring and seem to suggest that adding RT to RP may impact on the time- to-continence recovery both after nerve-sparing and non-nervesparing surgery (Suardi, 2014).

Radiotherapy- less toxic than radical prostatectomy for HRPCa? The global picture of the toxicity profile for the different treatment options available for HRPCa is difficult to derive from the published literature and it is thus impossible to give a clear answer to this question. Most of the existing comparative data apply to the low-risk Even more recent RCT, confirming the merit of the scenario where the vast majority of patients are combination of RT with ADT versus ADT alone for managed with a single treatment modality. This is HRPCa patients (SPCG-7, INT-94.0110), only concentrated rarely the case for the HRPCa group of patients for the toxicity report on GU and GI toxicity, with virtually whom RT is invariably supplemented with (long-term) no data on sexual QoL. All together the bottom line of ADT with a clear detrimental impact on the sexual In the HRPCa setting, on the contrary, this is rarely the these randomized evidences is straightforward: RT+ADT domain, but no clear evidence of a worst GU and GI AZ_TUR_133.4x194.3_EAU_2015_Layout 1 17.02.15 13:06 Seite 1 case and multimodality approaches are quite often is not more toxic as compared to RT alone or to ADT toxicity profile as compared to RT alone. Interestingly, almost all of these papers are devoted to localized disease where the comparison is largely among “single therapies” arms as virtually all patients are treated with a single modality and where association of modalities (RT + Androgen Deprivation Therapy, ADT, or radical prostatectomy, RP, followed by RT or brachytherapy, BT, + RT…) are extremely unusual because generally never recommended for the optimal management of these stages of the disease. Radical prostatectomy alone is thus compared to brachytherapy alone and/or external beam radiotherapy (EBRT) alone.

On the contrary, for 75 to 80 % of patients undergoing RP as first treatment for HRPCa, the need for subsequent adjuvant/salvage RT/ADT will exacerbate both GU toxicity (= incontinence) and erectile dysfunction. When discussing the different treatment options for their HRPCa, patients should be fully informed about the toxicity profiles associated with their choice, taking into account the whole “package” of potential treatments needed to maximise the chance of controlling the disease. The future HRPCa patients represent a highly heterogeneous group. For the vast majority of these patients, the association of irradiation and (long-term) ADT will remain mandatory. In the spectrum of HRPCa we cannot exclude that a selected subgroup of patients (those with local low burden of disease, cT3a or initial cT3b, Gleason score 7 and PSA < 20 ng/ml for ex) may benefit from a dose escalation into the prostate with short-term (six months) of ADT thus reducing the likelihood of combined RT-ADT side effects. Furthermore, data are accumulating on the possible toxic effect of ADT in terms of cardiac deaths especially for patients with an initial greater burden of comorbidities. These considerations need to be addressed in the everyday clinical practice by radiotherapists treating HRPCa suggesting that clinicians will need to personalize decision to use ADT as adjunct to RT balancing the proven benefits against the known side effects of ADT but also the potential cardiovascular harms. One of the challenges for the radiotherapy community in the near future when managing HRPCa patients will certainly be to better stratify patients to better adapt the duration of ADT based on the characteristics of the disease, but also on the comorbidities profile of every single patient. Sunday, 22 March 07.30-10.55: Plenary Session 2, Prostate Cancer

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Sunday, 22 March 2015

The exciting urothelium Understanding the role of the urothelium can lead to better treatment strategies Dr. Lori Birder University of Pittsburgh School of Medicine Departments of Medicine and Pharmacology Pittsburgh (USA)

A focus of current lower urinary tract (LUT) research has been afferent mechanisms, and the processes of how afferent information is generated and conveyed to the central nervous system (CNS) in the control of micturition. One of the pathways defined involves the bladder mucosa, but attention has been given mainly to the urothelium. The urothelium, which lines the inner surface of the renal pelvis, the ureters, and the urinary bladder, not only forms a high-resistance barrier to ion, solute and water flux, and pathogens, but also functions as an integral part of a sensory web which receives, amplifies, and transmits information about its external milieu. Urothelial cells have the ability to sense changes in their extracellular environment, and respond to chemical, mechanical and thermal stimuli by releasing various factors such as adenosine triphosphate (ATP), nitric oxide, and acetylcholine. They express a variety of receptors and ion channels, including P2X3 purinergic receptors, nicotinic and muscarinic receptors and TRP channels. All of these have been implicated in urothelialneuronal interactions, and involved in signals that via components in the underlying lamina propria (LP), such as interstitial cells, can be amplified and conveyed to nerves, detrusor muscle cells, and ultimately the CNS. Alterations in urothelial-cell signaling in various bladder pathologies (including the aging bladder) can lead to symptoms such as urgency, urinary incontinence, nocturia and even impaired bladder emptying.

“Activation of the urothelial cells by chemical, thermal or mechanical stimuli can evoke the release of various mediators or neurotransmitters...” Barrier function The urothelium plays a critical role as a permeability barrier to urine, and an intact barrier is a prerequisite for normal afferent signaling from the bladder. The ability of the bladder to maintain a barrier, despite large alterations in urine volume and increases in pressure during bladder filling and emptying is dependent on several features of the outer umbrella cell layer. These features include tight-junction complexes that reduce the movement of ions and solutes between cells and specialized lipid molecules and proteins in the apical membrane, which reduce the permeability of the cells to small molecules. During bladder filling, the umbrella cells become flat and squamous and this shape change is accompanied by vesicular traffic (i.e. exocytosis/endocytosis), adding membrane to the apical surface, thereby increasing overall urinary bladder surface area. These processes allow the bladder to accommodate increasing volumes of urine during filling without compromising barrier function. The processes underlying urothelial repair following inflammation or damage are complex, involving several structural elements, signaling pathways, trophic factors and the cellular environment. Furthermore, the interaction between these biochemical signals and mechanical forces in the bladder during the course of urothelial repair is not well understood. Though the urothelium maintains a tight barrier to ion and solute flux, a number of local factors or stressors, such as tissue pH, mechanical or chemical trauma, hormonal changes or bacterial infection can modulate its barrier function. Sunday, 22 March 2015

Other conditions, such as bladder pain syndrome/ interstitial cystitis (BPS/IC), senescence or spinal cord injury are also associated with changes in the urothelial barrier. Both physiological and psychological stress can result in a failure of urothelial and suburothelial ‘defensive’ systems and thereby promote changes in both urothelial barrier and signaling function. Modification of the urothelium and/or loss of epithelial integrity in a number of pathological conditions can result in passage of toxic/irritating urinary constituents through the urothelium or release of neuroactive substances from the urothelium. This may lead to changes in the properties of sensory nerves and in turn sensory symptoms such as urinary frequency and urgency. Thus, chemical communication between the nervous system and the urothelial cells may play an important role in the generation of urinary bladder dysfunction. “The Sensory Web” It is likely that a cascade of urothelial inhibitory and stimulatory transmitter/mediators is involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. The mucosal activation pathway (the sensory web) includes the urothelium, the afferent (and efferent) nerves, the LP interstitial cells, and possibly the muscularis mucosae. It is clear that communication between these different structures ensures normal function of the organ, and may explain how the effect of various neurotransmitters/mediators when given intravesically can modify bladder function by changing neurotransmission, the spontaneous activity of the detrusor smooth muscle, and thereby bladder function. While urothelial cells are often viewed as bystanders in the process of visceral sensation, recent evidence has supported the view that these cells function as primary transducers of some physical and chemical stimuli and are able to communicate with underlying cells, including nerves, smooth muscle and inflammatory cells. The urothelium is able to respond to a wide variety of mechanical stresses during bladder filling and emptying by activating a number of possible transducer proteins. Possibilities of mechanical signals include bladder pressure, tension in the urothelium or bladder wall, torsion, geometrical tension and movement of visceral organs. Recent studies have demonstrated that urothelial cells release transmitters (such as ATP) during changes in hydrostatic pressure (in ranges that normally trigger micturition). Urothelial cells express numerous receptors/ion channels similar to what is found in both nociceptors and mechanoreceptors elsewhere in the body, and these cells secrete a number of transmitters or mediators capable of modulating, activating or inhibiting sensory neurons.

Transitional epithelium of the urinary bladder Photo: Wikipedia/Polarlys

turnover time of urothelial cells of approximately 200 days. In terms of barrier ‘repair,’ instillation of liposomes composed of phospholipids has been shown to support repair of the urothelial barrier in animals following bladder irritation.

dense in the bladder neck and the trigone. It is likely that a cascade of inhibitory and stimulatory transmitters/ mediators is involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling.

Though the mechanism is not well defined, by forming a protective coating on the urothelium, liposomes may act as a mucosal protective agent and thereby decreasing irritation of underlying afferent nerves. In this regard use of intravesical liposomes on a single subject with ulcerative BPS/IC has shown promise to repair and enhance the barrier function of a dysfunctional urothelium though further trials are needed to fully assess this type of treatment.

For example, the urothelium seems to be a site with abundant expression of both NGF and its receptors, and NGF has been found to be elevated in the bladders and urine of patients with various types of storage LUTS, including neurogenic and idiopathic detrusor overactivity, BPS/IC, and also in models of bladder inflammation in animals.

As mentioned previously, the urothelium is likely to play an important role by actively communicating with bladder nerves, smooth muscle cells, or even cells belonging to the immune and inflammatory systems. Altered expression or sensitivity of molecular targets such as TRPV1, acid-sensing channels and muscarinic receptors, have been reported in BPS/IC patients, as well as in animal models for the syndrome.

Bladder NGF lowers the threshold for bladder TRPV1 signalling, and TRPV1 is essential for NGF-driven bladder dysfunction. It is obvious that mechanisms that can influence the generation and release of factors from the urothelium can affect afferent nerve activity, and also may be interesting targets for drugs aiming at controlling sensory and motor activity of the bladder.

Bladder mucosa- a treatment target The bladder mucosa, consisting of the urothelium, basement membrane, and underlying lamina propria Involvement of the sensory web in bladder In addition, augmented release of transmitters, most (the sensory web) works in concert with other disorders notably ATP, from the urothelium can lead to painful components in the bladder wall. The urothelium not sensations by excitation of purinergic receptors on only forms as a highly efficient barrier to potentially Bladder Pain Syndrome sensory fibers both peripherally and centrally. harmful urine components, but also exhibits A hallmark of chronic visceral pain syndromes, properties similar to those of nociceptive and including bladder pain syndrome / interstitial cystitis Thus, inhibition of purinergic P2X3 receptors has been mechanoceptive afferent neurons. (BPS/IC), is pain in the absence of readily shown to be effective in suppressing afferent demonstrable pathology of the viscera or associated excitation in various animal models and may be Activation of the urothelial cells by chemical, thermal nerves. These disorders are currently defined by effective in clinical conditions associated with pain or mechanical stimuli can evoke the release of various symptom criteria in the absence of organic disease. such as BPS/IC. Onabotulinum toxin A (BoNT-A) has mediators or neurotransmitters that through the There is no general agreement upon etiology or been used in the treatment of lower urinary tract sensory web can influence nerve activity, detrusor cell pathophysiology for these syndromes, and no disorders including BPS/IC and appears to have a contraction and ultimately bladder function. The effective treatments able to eradicate the symptoms in positive therapeutic effect. By inhibiting SNARElamina propria with its several types of interstitial humans. This condition is characterized by suprapubic dependent exocytotic processes, BoNT-A can prevent cells and afferent nerves, may act as a coordination pain, associated with bladder filling and can also be the release of transmitters (such as ATP) as well as center for bladder activity both during bladder filling accompanied by a persistent strong desire to void, normalizing the expression of various receptors, (spontaneous activity) and for initiation of the increased frequency of urination and nocturia. channels and trophic factors. micturition reflex, thus having an important integrative role in e.g., signal transduction to the BPS/IC has often been described as a disease of the Preliminary studies using immunoblotting indicate central nervous system (nociception, urothelium. Ultrastructurally, an altered vascular expression of the SNARE proteins SNAP23 and mechanosensation). supply is observed in its ulcerative form with locations SNAP25, as well as the high affinity binding site, SV2, of moderate-to-severe redness, interspersed among a in both rodent and human mucosa. These and other The mucosa undergoes important changes in many whitish discoloration. There is also evidence that the studies suggest that the urothelium may be a target bladder diseases, e.g., bladder pain syndrome, urothelium in BPS/IC is associated with altered for this treatment and that urothelial-released neurological injuries, and bladder overactivity, and is synthesis of a number of proteins including those mediators may contribute to sensory urgency/pain. an important target for treatment. We have begun to involved in cellular differentiation, barrier function understand the fundamental properties of the bladder and bacterial defense mechanisms. Bladder Overactivity mucosa, which is a rapidly expanding research field Studies suggest that changes in urothelial receptor with exciting translational possibilities, and Thus, removal of diseased urothelium during the function and neurotransmitter release, as well as considerable progress in this area can be anticipated. treatment of the ulcerative form of BPS/IC by laser changes in the sensitivity and coupling of the treatment can be beneficial to symptoms of bladder suburothelial ICs, may lead to enhancement of Monday, 23 March or pelvic pain. The formation of a fresh urothelial involuntary bladder contractions. 7.30-11.00: Plenary Session 3 lining immediately after treatment is associated with Functional urology: Hot topics below the belt; non-recurrence of pain for as long as six to 12 months The suburothelial afferent nerve plexus that lies State-of-the-art lecture after therapy, and may be related to the very long immediately beneath the urothelium is particularly EUT Congress News

Prostate cancer: Impact of surgeon’s volume on outcome? An ethical need to create transparent, standardized outcome measurements Prof. Hartwig Huland Martini-Klinik Prostate Cancer Center University of Hamburg Hamburg (DE)

Significant variations in outcome of many treatments of different diseases have been clearly shown in almost every health care system in the last years. To mention only three examples from three different countries: There is a four-fold variation in bypass surgery mortality in UK, 18 times variation in reoperation rates after hip surgery in Germany, and a 20x variation in mortality after colon surgery in Sweden. Similar data exist from all over the world. Another serious problem is the fact that information about the differences in treatment outcome of specific hospitals is not available to patients. Even worse, most hospitals and their medical staff themselves do not have information about their own treatment results, because patients are usually followed up in offices or clinics outside the hospital after discharge.

clearly a selection bias. 3. Low volume institutional series are unlikely to be published, thus there is definitely a publication bias. 4. It is too simple to exclusively relate surgical volume to outcome quality without including any process measures and quality management such as regular, well documented mortality and morbidity conferences, presence or absence of a pathology department, available intensive care or intermediate care unit, use of thrombosis prophylaxis or antibiotic wound prophylaxis and so on. 5. Some parameters have a low event rate –such as perioperative mortality- resulting in a low statistical power. One completely different promising perspective to improve outcome quality and especially such variations in outcome is a risk-adapted, systematic outcome measurement for each disease – using an identical minimal standard data set for each treatment, which is designed and accepted internationally.

One such initiative was started by Harvard Business Case load or surgical volume of hospitals and/or surgeons in surgically treated diseases lead to variations in treatment outcomes School, Boston Consulting and the Karolinska Institute which founded a non-profit institution called ICHOM organ-confined cancer is largely related to (International Consortium of Health Outcome sich nicht mit allgemeinen Bemerkungen über inadequate surgical technique. Vickers AJ, Bianco FJ, Measurement) in 2012.The goal is to establish diese und jene Erfolge zufrieden geben, sondern Gonen M, Cronin AM, Eastham JA, Schrag D, Klein standard sets, which focus on the results that matter jeden Arzt für einen Scharlatan halten, der nicht EA, Reuther AM, Kattan MW, Pontes JE, Scardino PT. One intensively discussed possible reason to explain most to patients and provide an internationally – im Stande ist, seine Leistungen in Zahlen Eur Urol. 53(5):960-6, 2008. doi: 10.1016/j. variations in treatment outcome is the case load or agreed upon method of measuring each of these auszudrücken. eururo.2008.01.005. surgical volume of hospitals and/or surgeons in outcome. In cooperation with ICHOM such a minimal (in: Kern E. Theodor Billroth (1829-1894) 2. A systematic review of the volume-outcome relationship surgically treated diseases. An example, Vickers et al.1 data set for localized treated prostate carcinoma was Biographie anhand von Selbstzeugnissen, 1996) for radical prostatectomy. Trinh QD, Bjartell A, Freedland reported a 10-fold difference in biochemical established from a group of 28 international experts Translation: “Time will come soon when our SJ, Hollenbeck BK, Hu JC, Shariat SF, Sun M, Vickers AJ. (urologists, radio oncologists, oncologists, experts of recurrence rate after radical prostatectomy (RP) students and colleagues will not be satisfied by Eur Urol. 64(5):786-98, 2013. doi: 10.1016/j. between more or less experienced surgeons. It is also national registries, patient representatives) in 2014 giving only general comments about their results, eururo.2013.04.012. under the leadership of the Martini-Klinik (H.Huland, well-documented for RP, that a large number of but when they will regard a medical doctor as a surgeons perform a small number of RPs. Example: In M.Graefen). charlatan, if he is not able to give exact data about Germany 50% of all RP are done in hospitals doing the results of his performances.” Sunday, 22 March less than 50 cases per year, distributed among two or It was the fourth standard set after cataracts, low back pain and coronary artery disease. By 2017 the 10.30-12.00: Thematic Session 4: Localised more surgeons in each center. In the US, 80% of References 1. Effects of pathologic stage on the learning curve for aim of ICHOM is to have published 50 standard sets prostate cancer- Hot topics surgeons perform < 10 RP`s per year and only 5% radical prostatectomy: evidence that recurrence in covering more than 50 % of global disease burden. performed more than 50 cases per year. The aim is to make the treatment results of all There is an increasing literature relating outcome to institutions and hospitals transdisciplinary hospital and surgeon’s volume for many operations comparable and - most important - transparent for patients, insurance companies and all other and also with respect to RP. The latter has recently been summarized by Trinh et al. in an excellent review stakeholders of health care systems. article2. It is well-documented in many studies, that hospital, as well as surgical volume, correlates with Transparent outcome measurements To overcome the outcome variations, regulations and different outcome parameters, such as: Perioperative mortality, perioperative complications, transfusion rate, audits to control process measures are also needed length of hospital stay, RP costs, readmission rate, and an additional important instrument, as we have long-term functional outcomes such as urinary learned from certification processes for qualified complications including continence, bladder neck prostate cancer centers in Germany. But, in addition, obstruction, strictures, fistulas, erectile function, short risk-adapted outcome data should be included and long-term oncologic outcome such as rate of identifying the variations in treatment outcome. If positive surgical margin, biochemical-recurrence-free then a center –independent of its case load, low or or metastatis-free survival, the need for salvage high-volume- can be identified as an institution with therapy, the rate of lymphadenectomy in intermediate bad results and if these results are transparent and and high-risk tumors and lower or higher nodal yields. comparable, this will obviously create a great pressure to improve the specific therapy in that center All this information has initiated national and or there will be a risk to lose certifications and most international discussions about treatment quality and likely patients in the future. how to control and improve it. In respect to the above-mentioned correlation of treatment outcome to In addition, it is discussed in some countries like caseload, regulations such as enacting a minimal Sweden and Germany, if outcome results should have case load and regionalization of certain treatments is an impact on the reimbursement. Pay for performance discussed in different health care systems. is a hot topic.

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Impact of regulations However, from my point of view I see critical points with regards to such regulations. First of all, currently there is no commonly accepted cut-off for surgical or hospital volume with respect to good or bad outcome quality. In addition, a strict cut off regulation for e.g. “no less than 30 RP per year” could result in a wrong and increasing indication to do this operation, if the minimum number is far from being reached by a certain hospital at the end of a year, especially in face of the strong economic pressure many hospitals have today.

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I believe a combination of primarily transparent, standardized outcome measurements, followed by analysis of process measures and caseloads in cases of low outcome quality would be a meaningful way to overcome the problem of significant variations in therapy results. Such an approach would improve quality in health care without increasing the costs. It has - most importantly- the perspective to increase efficiency and, thus, even reduce the costs of health care, leading to a higher value in the whole system as well as for the single patient.

Therefore I believe, that without any question, there is Finally, there are caveats in some of the studies about also an ethical obligation to establish systematic the correlation of surgical volume and outcome quality transparent, standardized outcome measurement. as mentioned in detail in the review of Trinh et al.2: Finally I want to quote two statements: 1. Many studies are retrospective, population based, 1. Michael E. Porter from Harvard Business School which rely e.g. on the SEER – Medicare data base –the initiator from ICHOM: “The universal in the US, which are restricted to patients > than development and reporting of outcome at the 65 years of age. Such data cannot be necessarily medical condition level is the single highest priority transformed to men in other countries. to improve the performance of health care system 2. Not all studies analyze their data with risk (in: M.E Porter, O.Teisberg in: Redefining Health stratification with respect to the patient selection Care, 2006) as well as to the tumor risk groups. Since almost 2. Theodor Billroth 1860: “Bald wird die Zeit all studies are retrospective, there might be kommen, wo auch unsere Schüler und Kollegen 8

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Sunday, 22 March 2015

Markers of PCa aggressiveness in the tumor stroma PCa growth depends on multidirectional exchanges of neoplastic cells and their environments Prof. Anders Bergh Department of Medical Biosciences, Pathology Umeå University Umeå (SE)

such as vimentin and smooth muscle actin. Prostate CAFs, sharing some characteristics with fetal stroma cells, secrete high levels of tumor promoting factors, for example TGFβ, CXCL12, CXCL14, CTGF, FAP, ASPN, HIF1α, ERα, Hes1, VEGF-D, IGF-1, tenascin-C, periostin, collagen-1, EGF, FGF2, FGF7, HGF, Wnt-3a and PDGF-receptor beta. In contrast, prostate CAFs display reduced levels of caveolin-1, S100A6, NKTR, stanniocalcin-1 and AR, and loss of TGFβRII in a subset of CAFs.

c. Angiogenesis. Prostate cancer development is Prostate cancer is a common and highly associated with increased formation of blood and unpredictable form of malignancy. Current diagnostic lymph vessels in and around tumors. procedures do not safely discriminate indolent tumors from the life threatening forms of the disease. d. Accumulation and functional reprograming of inﬂammatory cells. Prostate cancer formation is Novel markers for disease aggressiveness are needed. associated with an influx of macrophages, Traditionally, such markers have been searched for in lymphocytes and mast cells to tumor-bearing organ the epithelial compartment of primary tumors. and into the tumor stroma. Factors in the Studies during the last two decades have shown that microenvironment reprogram these inflammatory the non-epithelial components of cancers, referred to cells into tumor promoting phenotypes. The as the “tumor stroma” or the “microenvironment,” inflammatory cells affect adjacent CAFs, blood vessels have a major impact on tumor development, growth, and tumor epithelial cells. Androgen ablation results metastasis and metastases growth. in an additional influx of inflammatory cells that may influence tumor behavior. Neoplastic cells and their environments The emerging concept that the environment is of For example, accumulating B-lymphocytes secrete major importance in tumor biology is not a surprise to lymphotoxin B promoting castration-resistant growth. researchers and clinicians working with the prostate, as in this organ it is firmly established that its function, e. Altered extracellular matrix. Prostate cancer from fetal to adult life, is dependent on an androgen development is associated with tumor promoting regulated crosstalk between epithelial and stromal changes in the extracellular matrix. Collagen-1, Prostate cancer cell cell-types. In order to grow and spread, neoplastic hyaluronan, versican, periostin and matrix cells needs to instruct closely adjacent cells (normal metalloproteinase 9 are, for example, all increased. prostate stroma cells inhibit neoplastic cells) and more remote tissues and organs to cooperate and assist. f. Increased nerve density. Nerves play a central role in have named this “tumor instructed (or indicating) normal tissue = TINT.” In patients the magnitude of the regulation of prostate function. During cancer It is therefore reasonable to expect that future progression nerve density is increased in and around TINT changes is related to tumor aggressiveness and biomarkers, and therapy targets, can be identified in outcome. Many of the changes observed in TINT are tumors, and genes involved in neurogenesis are similar to those seen in the tumor stroma (Table I), the stroma of primary tumors, in the tumor-bearing markedly upregulated in the tumor stroma. suggesting that the signals shaping the tumor stroma organ, in pre-metastatic niches and in the metastasis may reach into the surrounding normal prostate. stroma. The signals forming a prostate cancer stroma also affect the tumor-bearing organ – markers of disease The stroma regulates organ development, function The stroma may determine the response to aggressiveness can therefore be found outside the treatment and androgen-dependency, and is affected by age tumor. and disease. In other tumor types stroma-targeted therapies During fetal life androgens exclusively stimulate the The formation of a tumor stroma, like the similar enhance the effect of common epithelial cell directed prostate stroma. This leads to differentiation of the formation of a wound healing stroma, is started by therapies. The standard treatment for advanced glandular epithelium. The development of the stroma is factors like TGFβ secreted by the neoplastic cells. prostate cancer (castration) is, in addition to the direct in turn dependent on signals from the epithelium. In Stroma morphology is different in fusion-gene positive inhibitory effects of androgen shortage in tumor the adult prostate, androgen receptor (AR) positive cells and negative tumors suggesting that epithelial tumor epithelial cells, also a stroma-targeted therapy. in the stroma regulate epithelial cell growth, death and cell phenotype affects adjacent stroma. Patients with low AR levels in the stroma have a differentiation via stroma-produced “andromedins.” limited response to castration. One reason for this By implanting cancer cells into the normal rat prostate, could be that stroma-produced factors like IGF-1 are For example, members of the FGF, insulin-like growth we showed that the presence of a tumor-induced not, in contrast to the situation in normal prostate IGF, EGF, Wnt and HGF families apparently function as adaptive changes also in the tumor-bearing organ. We tissue, downregulated by castration in cancers. andromedins. ARs in luminal epithelial cells maintain cell survival whereas ARs in basal/intermediate epithelial cells suppresses proliferation. CastrationTable 1: Factors associated with poor prognosis or high tumor grade in the stroma of the prostate tumor or induced normal prostate shrinkage is dependent on in the surrounding tumor-bearing organ (TINT) actions in AR and transforming growth factor receptor Factor Alteration in tumor stroma Alteration in TINT stroma beta receptor-bearing cells in the prostate stroma. a Local differences in stroma composition and function General morphology Reactive stroma grade Increase along individual prostate ducts determine epithelial Increase Gleason scoreb androgen dependency. Cellular composition Macrophages Increase Increase The prostate stroma is affected by ageing. Mast cells Decrease Increase Inflammatory cells and myofibroblasts become more T-cells Increase abundant. Aged stroma myofibroblasts stimulate prostate cancer cells in vitro. Common non-malignant CAFs Increase diseases in the prostate, like BPH and prostatitis, are Vascular density Increase Increase associated with alterations in cellular composition Smooth muscle cells Decrease and functions of the stroma. Neurons Increase Increase Changes in the tumor stroma are related to tumor ECM proteins HA Increase Increase behavior and patient outcome COL1A1 Increase During cancer development altered epithelial cells VCAN Increase induces changes among the different cell types present POSTN Increase in the stroma. These stroma alterations, similar to the stroma in healing wounds, in turn, affect the neoplastic MMP9 Increase [ epithelium. The nature and magnitude of stroma Growth factor receptors AR Decrease Decrease changes (summarized below and in Table I) are related to tumor aggressiveness and patient outcome. PDGFRβ Increase Increase a. Altered stroma gene and protein expression pattern. b. Changes among smooth muscle cells and fibroblasts.

Others

In the normal stroma smooth muscle cells are common. During carcinogenesis they are gradually replaced by myofibroblasts, often termed cancerassociated fibroblasts (CAFs). Consequently, the cancer stoma is characterized by decreased expression of smooth muscle cell markers such as desmin, and increased myofibroblast markers Sunday, 22 March 2015

a b

TGFβRII

Decrease

TRAIL

Increase

PAR-1

Increase

CAV-1

Decrease

EpCAM

Increased

CDH11

Increased

[

Stroma grade according to Rowley and coworkers Gleason score is defined as a grading of glandular pattern but could equally well be seen as a grading of stroma morhology

Is the stroma similar in primary prostate cancer and in metastases? When prostate cancer cells arrive on the bone marrow they encounter an environment different from that in the primary tumor. The neoplastic cells need to instruct the new environment to form a stroma supporting colonization and growth. It is however also likely the microenvironment selects the cancer cells that are allowed to grow. It is thus not unlikely that a metastasis stroma shares characteristics with that in the primary tumor, but also that it in some aspects can be fundamentally different. Very few studies have compared the stroma in paired primary tumors and metastatic lesions in prostate cancer. As metastasis occurs early and most micrometastases remain dormant whereas some become clinical significant, the nature, role and usefulness of the metastasis stroma as therapy target needs to be explored in more detail. Multidirectional interactions The formation, growth and spread of prostate cancers are largely dependent on multidirectional interactions between neoplastic cells and their environments. Aggressive cancers need to reshape their environments in ways quantitatively and/or qualitatively different than indolent tumors. Increased knowledge of this can probably be used to develop new markers of disease aggressiveness and new therapeutic targets. References Barron DA, Rowley DR. The reactive stroma microenvironment and prostate cancer progression. Endocr Relat Cancer. 2012;19: R187-204. Franco OE, Hayward SW. Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. Adv Pharmacol. 2012; 65:267-313. Halin S, Hammarsten P, Adamo H, Wikström P, Bergh A. Tumor indicating normal tissue (TINT) could be a novel source of diagnostic and prognostic markers for prostate cancer. Expert Opinion on Medical Diagnostics, 2011;5:37–47. Hanahan D, Coussens LM. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21:309-322 Hägglöf C, Bergh A. The stroma - a key regulator of prostate function and malignancy. Cancers. 2012; 4:531-548. McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014; 16:717-27 Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423-37

Monday, 23 March 10.30-12.00: Thematic Session 11 Markers in urologic oncology, State-of-the-art lecture

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XOFIGO® IS INDICATED for the treatment of adults with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastases.1

At the onset of symptoms from bone metastases in prostate cancer,

Intervene early with Xofigo

30% REDUCED

RISK OF DEATH (HR: 0.70; 95% CI: 0.55-0.88)2a

Extend life while preserving its quality2 In the phase III pivotal trial • Symptomatic was defined as regular analgesic use, including OTC, or use of EBRT to treat bone pain2 • In the Xofigo arm, 42% of patients were on non-opiate pain medications, 57% were on opiate pain medications, and 2% were not taking any pain medications2 • The effect of Xofigo on overall survival was consistent across patients with opioid use and without opioid use. The addition of Xofigo to best standard of care reduced the risk of death by 30% in the non-opioid subgroup, and by 32% in the opioid subgroup2 • 3.6-month increase in median overall survivalb (14.9 months in the Xofigo armc [n=614] vs 11.3 months in the placebo armc [n=307]; HR=0.695; 95% CI: 0.581-0.832)1

ADT=androgen-deprivation therapy; EBRT=external beam radiation therapy; OTC=over the counter. vs placebo plus best standard of care.1

Updated analysis.1

Plus best standard of care. In ALSYMPCA, best standard of care was defined as local EBRT or treatment with glucocorticoids, antiandrogens, ketoconazole, or estrogens such as diethylstilbestrol or estramustine.1

Essential Information Xofigo 1000 kBq/mL solution for injection (Refer to full Summary of Product Characteristics before prescribing). • Composition1: Active ingredient: radium Ra 223 dichloride (radium-223 dichloride, 1000 kBq/mL, corresponding to 0.53 ng radium-223 at the reference date). Each vial contains 6 mL of solution (6.0 MBq radium-223 dichloride at the reference date). Excipients1: Water for injections, sodium citrate, sodium chloride, hydrochloric acid, dilute. • Indication: Treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. Xofigo should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings. • Contraindications: There are no known contraindications. • Warnings and Precautions: Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, has been reported. Haematological evaluation of patients must be performed at baseline and prior to every dose. In case there is no recovery in values for absolute neutrophil count (ANC) and haemoglobin within 6 weeks after the last administration of Xofigo despite receiving standard of care, further treatment with Xofigo should only be continued after careful benefit/risk evaluation. Patients with evidence of compromised bone marrow reserve e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT) or patients with advanced diffuse infiltration of the bone (EOD4; “superscan”), should be treated with caution as an increased incidence of haematological adverse reactions such as neutropenia and thrombocytopenia has been observed. Limited available data indicate that patients receiving chemotherapy after Xofigo had a similar haematological profile compared to patients receiving chemotherapy after placebo. Crohn’s disease and ulcerative colitis: due to the faecal excretion of Xofigo, radiation may lead to aggravation of acute inflammatory bowel disease, therefore Xofigo should only be administered to these patients after a careful benefit-risk assessment. In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Xofigo. In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo. In patients treated with bisphosphonates and Xofigo, an increased risk of development of osteonecrosis of the jaw (ONJ) cannot be excluded. In the phase III study, cases of ONJ have been reported in 0.67% patients (4/600) in the Xofigo arm compared to 0.33% patients (1/301) in the placebo arm. However, all patients with ONJ were also exposed to prior or concomitant bisphosphonates and prior chemotherapy. Xofigo contributes to a patient’s overall long-term cumulative radiation exposure and therefore may be associated with

an increased risk of cancer and hereditary defects. No cases of Xofigo-induced cancer have been reported in clinical trials in follow-up of up to three years. Depending on the volume administered, this medicinal product can contain up to 2.35 mmol (54 mg) sodium per dose. • Undesirable effects: Very common: thrombocytopenia, diarrhoea, vomiting, nausea; Common: neutropenia, pancytopenia, leukopenia, injection site reactions; Uncommon: lymphopenia. • Classification for supply: Medicinal product subject to restricted medical prescription. • Marketing Authorisation Holder: Bayer Pharma AG. 13342 Berlin. Germany. • Date of revision of the underlying Prescribing Information: November 2013. References: 1. Xofigo® (radium Ra 223 dichloride) solution for injection Summary of Product Characteristics (SmPC), Bayer Pharma AG, 13342 Berlin, Germany, 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. This medicinal product is subject to additional monitoring. Este medicamento está sujeto a seguimiento adicional, es prioritaria la notificación de sospechas de reacciones adversas asociadas a este medicamento. Xofigo is not currently reimbursed in Spain. Information is correct at time of printing (1 February 2015). En el momento de imprimir este material (1 de Febrero de 2015) Xofigo no está comercializado en España. To learn more, visit www.xofigo.com.

Please see Summary of Product Characteristics available at the Bayer HealthCare booth (FO2) in Hall 9. La ficha técnica del producto está disponible en el stand de Bayer HealthCare (FO2) en el pasillo 9.

List of excipients should only be included when required according to national legislation.

L.ES.SM.02.2015.0344_Global_EAU_Ad_FR.indd 1

2/19/15 5:05 PM

THIS ADVERTISEMENT PREPARED BY AREA23

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Do we need to continue androgen deprivation therapy? Reliable predictive biomarkers are urgently needed to optimise ADT for metastatic CRPC Prof. Dr. Axel Merseburger Vice Chairman Department of Urology and Urologic Oncology Hannover Medical School Hannover (DE)

Fortunately, a growing number of treatment options exist to treat metastatic castrate-resistant prostate cancer (mCRPC); however, with these newer options many questions about optimising treatment remain unanswered. There is an on-going discussion on the value and need of androgen deprivation therapy (ADT) in this highly palliative stage of the disease. Should ADT be continued when abiraterone, enzalutamide, or chemotherapy are initiated? Are there downsides to ADT in this stage? Does it affect the health-related quality of life (HRQoL)? Those questions are worthy of scrutiny. This article is based on today’s presentation which will focus on the evidence for maintaining ADT in CRPC patients, the statements provide basis for a discussion of the evidence and the rationale behind the recommendation if/that ADT should be continued in mCRPC. The European Association of Urology (EAU) guideline clearly states that patients with metastatic castrateresistant prostate cancer (mCRPC) should indefinitely continue androgen deprivation therapy (ADT); this recommendation applies to metastatic CRPC (mCRPC) and non-metastatic CRPC (nmCRPC)1. Other guidelines, such as that from the American Urological Association (AUA)2 and the National Comprehensive Cancer Network (NCCN)3, likewise mention the need to maintain ADT when mCRPC develops.

therefore providing a rationale for combining abiraterone with ADT. Remarkably, experimental evidence suggests that the testosterone suppression achieved by abiraterone monotherapy is not sustained in non-castrated men and is overcome by a subsequent two- to three-fold surge in luteinising hormone (LH) levels20. Although the pharmacokinetic study of O’Donnell et al20 assessed a small number of men, it does suggest a need to maintain castrate levels of testosterone with ADT when initiating abiraterone therapy. This rationale has been used in the pivotal phase III trials of abiraterone. The efficacy of abiraterone in combination with prednisolone was demonstrated in two trials in patients with mCRPC as previously published4,5 (LoE: 1b). Importantly, castration levels of testosterone were maintained in both these studies with the continuation of ADT. Currently, a German multicentre trial (SPARE trial) is investigating the impact of continuing ADT when initiating abiraterone. This study (German Association of Urological Oncology trial number AUO 67/11) is investigating abiraterone monotherapy (plus prednisolone) versus abiraterone plus ADT (plus prednisolone) in 70 men with chemotherapy-naïve mCRPC. Preliminary results of this study should be available in 2016, which will provide the first prospective insight on the potential efficacy advantages of maintaining ADT when abiraterone treatment is initiated in mCRPC. Interestingly, there is no published data assessing abiraterone (with or without ADT) in patients with non-metastatic CRPC (nmCRPC). More data on the use of newer agents for the treatment of nmCRPC are needed.

The rationale for ADT use with enzalutamide Androgen receptor signalling persists during castration, and several mechanisms, even in individual patients (through clonal heterogeneity), may explain this persistence23. Addition of androgen receptor blockers to ADT may therefore help achieve more complete androgen blockade. With the As support, all randomised controlled trials of the development of the novel androgen receptor blocker many newer agents for mCRPC, including abiraterone, enzalutamide, which binds to the androgen receptor enzalutamide, sipuleucel-T, radium 223 and with eight-fold higher affinity than bicalutamide32, it is 4-10 cabazitaxel all had continuation of ADT and important to ask whether there is any clinical need to mainstay of castration levels of testosterone (<50 ng/ combine enzalutamide treatment with ADT. dl) as an inclusion criterion. However, this does not prove the value of ADT in this setting. In metastatic To date, however, there have been no clinical trials disease, while hormonal treatment improves comparing enzalutamide monotherapy with symptoms11, there is no conclusive prospective enzalutamide plus ADT to confirm the need for evidence that lowering testosterone levels improves continued ADT when initiating abiraterone therapy in life expectancy12. With the event of evaluating novel patients with mCRPC. Unlike bicalutamide, substances in the setting of non-metastatic CRPC, the enzalutamide has no known agonist activity, and it is value of combining ADT with tertiary hormonal thought that bicalutamide resistance does not exclude manipulation (e.g. Enzalutamide, Abiraterone, subsequent enzalutamide use32. In addition, a recent ARN-509, etc.) has not been investigated. report has assessed enzalutamide monotherapy in hormone-naive men with prostate cancer33. This initial Sparse evidence report of enzalutamide monotherapy in 67 patients The evidence for continuing ADT in metastatic prostate suggested a lower frequency of gynaecomastia (36%) than previously reported with bicalutamide cancer is based on sparse literature. A single study demonstrated that androgen priming in a small group monotherapy. Furthermore, PSA declines were of a of patients (n=85) using chemotherapy regimens that similar magnitude to those achieved by ADT but are now outdated altered the prognosis13. adverse events were frequent and testosterone levels increased33. However, it is becoming clear that within the prostate and prostate tumour microenvironment androgen Therefore, more data are needed to determine activity continues even when serum testosterone whether the combination of enzalutamide with ADT levels are suppressed by ADT14, and intracrine has a favourable efficacy and safety profile for the androgen synthesis is sufficient to activate androgen treatment of CRPC compared with enzalutamide receptor target genes15. Adaptive alterations include monotherapy. In the meantime, as with abiraterone, alternative androgen synthesis pathways, and pivotal trials of enzalutamide in men with CRPC androgen receptor overexpression, mutation and included the need for castration maintenance with splice variations16. Furthermore, many mechanisms ADT6,7; these studies have shown that this combination that may confer castration-resistance still require, or improved OS when used before chemotherapy and are enhanced by, the presence of androgens or after chemotherapy. androgen receptor ligands. Together these observations suggest that treatment combinations Ongoing clinical studies may provide some clues to the that include ADT and suppress intracrine and systemic need for backbone ADT when initiating enzalutamide androgen contributions are required in CRPC. in patients with CRPC (Table 1). However, there are no

Side effects of androgen deprivation therapy Photo: European Urology Archives

trials with enzalutamide that are equivalent to the SPARE study with abiraterone, which directly compare enzalutamide monotherapy with enzalutamide combined with ADT in men with CRPC. ADT during chemotherapy EAU guidelines state that ADT with GnRH analogues should be continued when giving mCRPC patients chemotherapy1. The theory for continuing ADT when starting chemotherapy in mCRPC is that pausing ADT may lead to renewed release of testosterone and stimulation of the remaining androgen-sensitive elements of the tumour. Conversely, approximately 50% of men receiving ADT in the long-term remain castrated for 2.5 years after stopping ADT34, and stopping ADT might re-induce hormone sensitivity35. These conflicting viewpoints are difficult to prove as there is a lack of well-designed prospective trials exploring this issue, and retrospective data are conflicting36-38. There is no evidence that the combination of ADT with chemotherapy causes harm; however, there is also no strong evidence of benefit in this clinical scenario. Two ongoing studies (ClinicalTrials.gov identifiers: NCT01487902 and NCT01224405) are investigating the possible advantage of maintaining ADT during chemotherapy. One of these studies (NCT01487902) that is comparing docetaxel plus prednisolone with docetaxel plus prednisolone and leuprolide in approximately 90 men with CRPC was due for completion in October 2013, and results may therefore be available soon. Until these results are available ADT should be continued when chemotherapy is initiated in mCRPC in daily practice also according to the current guidelines. Prospective data and biomarkers needed All clinical trials of newer agents (and recent trials of chemotherapy agents) in mCRPC include patients who maintain castrate levels of testosterone, and so clinical practice should adhere to this principle of continuing ADT when initiating abiraterone, enzalutamide or chemotherapy. However, not only are more prospective data needed to assess the importance of backbone ADT in CRPC, but also reliable prognostic and predictive biomarkers are urgently needed to individualise treatment with newer agents, their combination with ADT, and the optimum treatment sequences. References 1. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU Guidelines on Prostate Cancer. Part II: Treatment of Advanced, Relapsing, and CastrationResistant Prostate Cancer. Eur Urol. 2014;65:467-79. 2. Cookson MS, Roth BJ, Dahm P, Engstrom C, Freedland SJ, Hussain M, et al. Castration-resistant prostate cancer:

The presentation will cover the evidence and rationale for continuing ADT in CRPC when other treatments are Table 1: Ongoing studies investigating enzalutamide and hormone deprivation therapy initiated, and aim to provide clear statements on this issue. Trial identifier Overview of design Patients Expected results The rationale for ADT use in combination with abiraterone acetat Abiraterone acetat selectively inhibits the enzyme 17 α-hydroxylase/C17, 20-lyase (CYP17) and thus inhibits androgen biosynthesis18. Abiraterone acetat also has direct activity on reducing the expression of the androgen receptor gene in tumour cells19. This underscores the need to target as many parts of the androgen receptor signalling pathway as possible and Sunday, 22 March 2015

NCRN322 (TERRAIN)

ADT + enzalutamide vs. ADT + bicalutamide

370 men with mCRPC

NCT01547299

Enzalutamide monotherapy vs. enzalutamide + leuprolide + dutasteride

As neoadjuvant treatment in Trial completed in 2013 approximately 50 men with localised prostate cancer who are undergoing RP

ADT + enzalutamide vs. ADT alone

Approximately 1560 men with nmCRPC

NCT02003924 (PROSPER)

Summer 2015

2017

AUA guideline. 2013. 3. NCCN. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. 2014. 4. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983-92. 5. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48. 6. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:118797. 7. Beer TM, Armstrong AJ, Sternberg CN, Higano CS, Iversen P, Loriot Y, et al. Enzalutamide in men with chemotherapy-naïve metastatic prostate cancer (mCRPC): results of phase III PREVAIL Study. J Clin Oncol. 2014;32 (suppl. 4):LBA1^. 8. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22. 9. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-23. 10. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54. 11. Morote J, Orsola A, Planas J, Trilla E, Raventos CX, Cecchini L, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178:1290-5. 12. Merseburger AS, Hammerer P, Rozet F, Roumeguère T, Caffo O, da Silva FC, Alcaraz A. Androgen deprivation therapy in castrate-resistant prostate cancer: how important is GnRH agonist backbone therapy? World J Urol. 2014; Sept 27. 13. Manni A, Bartholomew M, Caplan R, Boucher A, Santen R, Lipton A, et al. Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. J Clin Oncol. 1988;6:1456-66. 14. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al. Intraprostatic androgens and androgenregulated gene expression persist after testosterone suppression: therapeutic implications for castrationresistant prostate cancer. Cancer Res. 2007;67:5033-41. 15. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-54. 16. Egan A, Dong Y, Zhang H, Qi Y, Balk SP, Sartor O. Castration-resistant prostate cancer: Adaptive responses in the androgen axis. Cancer Treat Rev. 2014;40:426-33.

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at EUT@uroweb.org for a complete listing. Sunday, 22 March 11.00-12.00: Thematic Session 1 Managing the early metastatic CRPC patient State-of-the-art lecture

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Sniffing cancer- Volatile urinary compounds UK researchers develop Odoreader device to analyse urine of bladder cancer patients and the US. Particularly people who have undergone prior resection may benefit from the application of surveillance using a biomarker.

Prof. Chris Probert Dept. of Gastroenterology University of Liverpool Liverpool (GB)

Exquisite smell Dogs have an exquisite sense of smell. It has been reported that dogs can be trained to recognise the odour associated with bladder cancer in urine. Researchers in Buckinghamshire, UK, have reported that the best performing dog could identify 73% of cancer samples6, although not all dogs can perform this well.

Dr. Raphael Aggio University of Liverpool Liverpool (GB)

Furthermore, this performance seems to be influenced by the choice of controls. Dogs have been found to be highly effective when detecting drugs and explosives, but it is hard to imagine that they could be deployed in urology clinics. The dogs, however, do provide proof of concept that bladder cancer is associated with a unique odour in urine samples.

Bladder cancer is common and >10,000 new cases are diagnosed in the UK annually, half of whom will die of the disease1. The majority of patients (70%) present with early stage (non-muscle-invasive) disease and are relatively easy to treat by transurethral resection during cystoscopy, which produces an excellent five-year survival (~94%). However, recurrence is common (50-70%) and 30% may progress, meaning that all patients must be followed up by undergoing repeated cystoscopy2. Consequently, bladder cancer is reported to be the most expensive cancer to manage3. Environmental risk factors are well known. Therefore, bladder cancer is an ideal disease to detect by screening or surveillance, for example, using biomarkers. Much effort has been devoted to the identification of suitable biomarkers4,5 and some are close to adoption by screening programmes in Europe

Smell is the detection and interpretation of volatile organic compounds (VOCs): small molecules of high vapour pressure and present at the vapour phase at room temperature. The composition of gaseous mixtures can be determined by gas chromatography / mass spectrometry (GC/MS). We have been interested in the detection of diseases by the use of GC/MS to analyse gases emitted from clinical samples including faeces and urine. This work has shown that VOC profiles have characteristic patterns in health and disease: in particular Clostridium difficile, Campylobacter and Cholera7-9. GC/MS has to be undertaken in sophisticated laboratories with appropriately trained staff. To overcome this issue, other groups have investigated VOC analysis using e-nose technology for the diagnosis of bladder cancer: they reported 70% sensitivity and specificity for the differentiation of bladder cancer from healthy controls, dropping to 60% and 67%, respectively, when testing urine controls from patients with non-malignant urological diseases10.

We aimed to develop a user-friendly low-cost device that would give similar information to the GC/MS, but which could be easily applied in a clinical setting. The result was the Odoreader: a heated GC column linked to a metal oxide sensor. The GC separates VOCs in a mixture by their mass and/or charge, while the level of the electrical resistance of the sensor changes in the presence of VOCs. The resulting sensor output (recording of current or resistance) is, essentially, a chromatogram. The output can then be used to compare the VOC profiles of different sets of samples11. The gases that enter the GC column are derived from clinical samples such faeces or urine. In this way, the ‘odour’ of the samples can be read by the device. We used the Odoreader to compare VOC profiles from patients with bladder cancer (n=24) and controls, investigated by urologists, in whom no bladder cancer (n=74) was detected. The sensor output was divided into short segments (bins) to enable the current at each time point to be compared in patients with bladder cancers and controls. The data were compared using two established statistical approaches based on discriminant analysis (DA). In the first approach, linear DA defined 9 bins and correctly identified 100% of cancer and 95% of controls: after leave -one-out cross-validation the sensitivity and specificity was 96% and 93%, respectively (PlosONe). In the second approach, partial least squares DA found 96% of cancers and 93% of controls (PlosOne). We have recently undertaken a new approach to analyse this data and the results will be presented for the first time in this congress. An in-house pipeline was developed to overcome some of the vagaries of gas chromatography by, for example, incorporating techniques to align chromatograms and correct retention times. This new approach does not take ‘bins’ of data, unlike the previous approach; it searches for patterns and features that are specific to each medical condition. As a result, it produces sensitivity of 97% and specificity of 100%, after a rigorous validation scheme involving double-cross

Bladder cancer can be identified with accuracy through rapid analysis of gas from urine samples

validation. The same approach was used to determine whether the Odoreader could be used to identify prostate cancer and to separate bladder cancer from prostate cancers. Prostate cancer was found with 91% accuracy, while bladder and prostate cancer samples were classified with 93% of accuracy. This new approach indicates that the Odoreader can now be readily used to analyse new sets of data without the need to create new specific statistical scripts. We have shown that cases of bladder cancer can be identified with great accuracy, by the rapid analysis of gas from urine samples utilising a user-friendly device. The device could be used in screening and surveillance programmes, reducing patient discomfort and costs. Editorial Note: Due to space constraints the Reference List has been excluded. Interested readers can email a request for the complete list at EUT@uroweb.org. Sunday, 22 March 10.30-12.00: Thematic Session 6 Non-muscle invasive bladder cancer, Hot topic lecture

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Sunday, 22 March 2015

Risk stratification for early detection of prostate cancer Stratifying screening implies focusing on screening men at highest risk Dr. Sigrid Carlsson Sahlgrenska Academy Gothenburg University Göteborg (SE)

To screen, or not to screen, for prostate cancer? That is the question. Or should the question rather be – how to screen and how not to screen? Large, randomized screening trials show that regular screening reduces prostate cancer mortality, but does so at high cost in terms of risks of overdiagnosis and overtreatment. Hence, there is an urgent need to improve the ratio of benefits to harm of PSA screening. One way to do this is risk stratification. Risk stratification is ubiquitous in modern medicine; triage of patients presenting to the emergency department, tools to help guide treatment decisions for patients with myocardial infarction, or “stratified medicine” in oncology to help decide the right treatment, for the right patient, at the right time. Can we take a risk stratified approach also to populationbased screening of healthy men?

mutation are also suggested to get screened with PSA and DRE starting in their 40-50s. Stratifying screening also implies choosing age to start and stop screening, as well as the length of the re-screening interval. More research is needed on the age to start and stop; in the European screening trials men were screened every two to four years starting at 50-55 and ongoing until 70-75 years. An increasing number of guideline groups, including the EAU guidelines, now recommend screening starting earlier with a baseline PSA at age 40-458, based on the growing body of evidence from several cohorts around the world about the value of a baseline PSA-test and its association with long-term prostate cancer outcomes9. At what age screening should stop is not well understood. Comparing unscreened men in Malmö to screened men in the Göteborg trial, we were able to demonstrate that the ratio of benefits to harm of prostate cancer screening is an average of two very different subgroups based on PSA-levels. Rescreening men with PSA < 2 ng / ml at age 60 was associated with no mortality benefit but considerable risk of overdiagnosis, whereas re-screening men with PSA ≥ 2 ng / ml at 60 was associated with a dramatic reduction in prostate cancer mortality at the cost of little overdiagnosis.10

Let us first look at the two extreme strategies; screen all or screen none. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Göteborg trial have given us level 1 evidence that regular screening with prostate-specific antigen (PSA) decreases risks of metastatic disease (relative risk RR 50% at diagnosis and 30% during 12 years of follow-up) and prostate cancer mortality by 21% at 13 years in the ERSPC and 44% at 14 years in the Göteborg trial.1,2,3

Studies like this show that a baseline PSA measurement can help define groups of men needing closer versus more relaxed re-screening and help build guidelines regarding the re-screening interval. Restricting re-screening in men over 60 to the ~25% of men with a PSA > 2 ng / ml would dramatically shift the ratio of benefits to harm. This implies that for the ~75% of men over 60, either no further screening is needed or re-screening can take place at a longer interval. Modeling studies confirm the finding that screening men with low PSA-levels less frequently may optimize the ratio of benefits to harm.

However, screening all would inevitably open the door to down-stream potentially negative consequences for many men in terms of falsepositives, risks with prostate biopsy such as infectious complications, overdiagnosis and side-effects from treatment that affect quality of life (which can be partly mitigated by considering active surveillance for men with low-risk tumors).4

Comorbidities imply competing risks that may pose a bigger threat to life than prostate cancer. The metabolic syndrome is linked to poor prostate cancer outcomes. Though many guidelines suggest screening and treatment be restricted to men with a 10-year life expectancy, the Melbourne Consensus Statement states that older men in good health should not be denied PSA testing just based on their age.11

The fear that the harms of screening may outweigh the benefits, is why the United States Preventive Services Task Force recommend the other extreme strategy – recommending against PSA-based screening for all men.5 A problem with that approach is that we may risk going back to seeing scenarios such as men presenting with unrelenting bone pain from bone metastases or even spinal cord compression as the first presentation of prostate cancer. It is expected that without screening, the total number of men presenting with metastatic prostate cancer would be approximately three times greater than today6. Since the early 1990’s we have observed a 70% decline in the incidence of advanced stage prostate cancer in the US, together with a 45% decline in prostate cancer mortality, attributable to screening and improvements in primary treatment.7

Though family history and black race are well-known risk factors for prostate cancer outcomes, summarizing estimates from the published literature, Vertosick and colleagues showed that stratifying screening by family history accounted for 14% of prostate cancer deaths by age 75, stratifying by black race accounted for 28% whereas stratifying screening by the 10% of men with the highest PSA-level at age 45 accounted for as many as 44% of deaths.12

A middle ground can be achieved through an individualized approach including weighing the man’s risk factors. Prostate cancer is a heterogeneous disease and we want to maximize the benefits in terms of reduced morbidity and mortality from the disease while minimizing harms in terms of overdiagnosis and overtreatment – on the individual level. Most guidelines today emphasize shared-decision making between the man and his doctor and an informed choice after discussing the pros and cons of screening.

decision-making and obtain consent; has he undergone many previous biopsies, is he particularly reluctant to biopsy or is he anxious about a cancer diagnosis? Second, PSA has a tendency to fluctuate. Therefore, repeat a first elevated PSA in a few weeks before considering biopsy. Third, although early screening studies have shown that PSA outperformed DRE as a screening tool in finding the disease early, good old clinical examination should not be forgotten in stratifying risk before biopsy. Do not automatically consider a biopsy for a modestly elevated PSA without work-up for benign disease, including DRE. Conversely, there is a correlation between smaller prostates < 40 cc and risk of high-grade disease. Fourth, a previous negative biopsy lowers risk compared to men with no previous biopsy, yet the former are still at increased risk. Fifth, the discussion about family history, ethnicity, age, life expectancy, comorbidities and health status is similar before the decision to biopsy as before the decision to screen; all must be considered individually in each case. Certain co-morbidites and/or medications may also act as contraindications to prostate biopsy.

Sixth, consider reflex tests before biopsy such as the free-to-total PSA ratio. There are three additional A baseline PSA level can accurately separate men into commercially available tests: Prostate health index high and low-risk of prostate cancer outcomes years, (PHI), 4Kscore and the urine test Prostate Cancer Gene and decades, before diagnosis. The Swedish Malmö 3 (PCA3). These tests all outperform PSA alone and all studies demonstrate a strong relationship with have potential to reduce the number of biopsies. They PSA-levels in midlife and risk of metastasis and have fairly similar performance characteristics for prostate cancer death 15-25 years down the road, with high-grade (Gleason score ≥7) in studies, and 4Kscore very low risks of these outcomes for men with below is specifically designed to calculate a man’s individual median PSA-levels in midlife.9,13 Thus, a PSA-level risk of high-grade disease, integrated with clinical above average for the man’s age justifies repeat information, whereas the PHI and PCA3 gives you a screening, and biopsy should be considered at a PSA score that puts the man in a risk group for any grade level ≥ 3 ng/mL. prostate cancer.

Stratifying biopsy The decision to biopsy should preferably also be based on risk assessment; some men with elevated PSA need a biopsy, others do not. The EAU guidelines states that “PSA testing should not be considered on its own, but rather as part of a multivariable approach to early detection”. Stratifying biopsy could Now we are getting to the nitty gritty of how to stratify involve additional laboratory testing with either blood men’s risk. Here we need to make a distinction and/or urine tests, clinical examination including between 1. Stratifying screening, and 2. Stratifying digital rectal examination (DRE), as well as transrectal biopsy. ultrasound and/or magnetic resonance imaging (MRI). Stratifying screening The key questions here are: if I apply a certain test to After engaging in shared decision-making and obtaining consent from the man to get screened, my clinical practice will it change my decision to stratifying screening implies selecting men at highest perform prostate biopsy or not? Will the outcome of risk, on which we should focus screening. Ethnicity and biopsy be better in those I biopsy? How many biopsies family history are risk factors for overall, high-grade will I avoid? What is the risk of missing high-grade disease and prostate cancer mortality. Therefore earlier prostate cancer?14 and more intense screening of men of AfricanAmerican descent and men with strong family history, There are many factors that could be considered including two or more first-line relatives with prostate before prostate biopsy15,16. First, as with the decision cancer is indicated. Similarly, men with the rare BRCA2 of getting screened or not, engage the man in shared Sunday, 22 March 2015

Re-screening guidelines for men from age 60

Seventh, in this context, do not worry about PSA velocity, that is, the rate of change in PSA levels over time. Though it has a prognostic role in patients with treated prostate cancer, it has limited utility in the screening and diagnostic setting, compared to PSA alone. Eight, there are other markers in the pipeline, but none yet proven for clinical use. For instance, the field of genomics is rapidly evolving; some 100 SNPs have been identified associated with both familial prostate cancer risk and increased PSA-levels. The TMPRSS2ERG gene fusion, the HOXB13 G84E variant, GSTP1 methylation and hypermethylation of the APC gene show promise; however none are yet introduced in routine clinical practice. Ninth, two-sequence screening with PSA and magnetic resonance imaging (MRI) and targeted biopsies is being studied at the moment. The hope is that MRI can overcome the shortcomings with current screening; the low specificity of PSA in combination with systematic biopsies that may both over- and

under detect prostate cancer and lead to incorrect risk stratification as evidenced by upgrading at radical prostatectomy. MRI appears to fill a gap in the previous negative biopsy setting, where it can improve sensitivity over transrectal ultrasound (TRUS) guided biopsy. However, skeptics fear that MRI may miss a significant proportion of high-grade tumors, if restricting biopsy only to men with PIRADS scores 3-5. Tenth, risk calculators have been developed to ease the integration of information to stratify risk; the ERSPC 1-6 risk calculators, ProstataClass or the PCPT risk calculators, to mention some. Their performance characteristics depend on the cohort in which they were developed and the PSA-cut off chosen for biopsy. Some of these can also incorporate information from markers other than PSA. Shared decision-making In summary, stratifying screening implies focusing on screening men at highest risk and stratifying biopsy implies deciding to biopsy based on risk assessment. First, engage in shared-decision making and get consent. Don’t screen men who won’t benefit; avoid screening elderly men over in poor health. For men who wish to be screened, consider a baseline PSA assessment starting at age 45 and individualize re-screening intervals according to the PSA-level for the man’s age; consider stopping screening for men with a PSA < 1 ng/mL at age 60. Consider family history, ethnicity and health status. Do not biopsy unless you have a compelling reason. Repeat PSA, evaluate the PSA-level for the man’s age, perform urological work-up for benign disease and consider reflex tests and/or risk calculators – the outcomes of which will tell you whether cancer suspicion still remain. Unnecessary biopsies should be avoided, but biopsy should not be delayed for men at high risk of significant prostate cancer. References 1. Schröder FH, Hugosson J, Carlsson S et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2012;62:745-52. 2. Schröder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384(9959):2027-35. 3. Hugosson J, Carlsson S, Aus G et al. Mortality results from the Göteborg randomised population-based prostatecancer screening trial. Lancet Oncol. 2010;11:725-32. 4. Heijnsdijk EA, Wever EM, Auvinen A et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367(7):595-605.

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at EUT@uroweb.org for a complete listing. Monday, 23 March 10.30-12.00: Thematic Session 14 Prostate cancer epidemiology State-of-the-art-lecture

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Length of catheterization and hospital stay values shown in median. 1. Bachmann A, Tubaro A, Barber N, et al. 180-W XPS GreenLight laser vaporization versus transurethral resection of the prostate for the treatment of benign prostatic obstruction: 6 month safety and efficacy results of a European multi-centre randomized trial: The GOLIATH study. Eur Urol. 2014;65:931-42. 2. Bachmann A, Tubaro A, Barber N, et al. A European multicenter randomized noninferiority trial comparing 180 W GreenLight-XPS laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the GOLIATH study. J Urol. 2015 Feb;193(2):570-8. The GreenLight™ laser system is intended for incision/excision, vaporization, ablation, hemostasis and coagulation of soft tissue, including photoselective vaporization of the prostate for benign prostatic hyperplasia (BPH). The laser system is contraindicated for patients who: are contraindicated for surgery, contraindicated where appropriate anesthesia is contraindicated by patient history, have calcified tissue, require hemostasis in >2mm vessels, have uncontrolled bleeding disorders, have prostate cancer, have acute urinary tract infection (UTI) or severe urethral stricture. Possible risks and complications include, but are not limited to, irritative symptoms (dysuria, urgency, frequency), retrograde ejaculation, urinary incontinence, erectile dysfunction, hematuria – gross, UTI, bladder neck contracture/outlet obstruct, urinary retention, perforation – prostate, urethral stricture. Prior to using these devices, please review the Operator’s Manual and any accompanying instructions for use for a complete listing of indications, contraindications, warnings, precautions and potential adverse events. Rx Only

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Agostino Mattei Assoc. Professor and Chairman Department of Urology Director, Robot Surgery Program Luzerner Kantonsspital Lucerne (CH)

In recent years, robot-assisted surgery has become very popular in urology. This technique is mainly used for oncological purposes in prostate and kidney surgery as well as for reconstructive purposes such as pyeloplasty. At the beginning of the “robotic era,” this technology was mostly exclusively offered in reference centres with large caseloads. During the last years, robotassisted surgery has been introduced even in smaller urological institutions with a limited caseload. This evolution is still strongly supported by the fact that a hospital offering robotic surgery has an important marketing advantage. While outcomes of the different operations using the robot-assisted laparoscopic approach are largely documented for renal, prostate and even bladder cancer surgery by most large reference centres worldwide, there is still a lack of detailed data concerning the outcomes of the same kind of surgery for centres with a small case load. Of further interest would also be the comparison of intra- and postoperative complications in large versus small centres.

“We strongly believe that today the acquisition of know-how for performing RARP is at least as important as the acquisition of a robot itself!” Case load How can we explain this lack of data? Smaller institutions often have less manpower to conduct prospective long-term collection of their own clinical data. This can mislead some robotic surgeons in smaller institutions, to cite published results concerning outcome and potential complications from large and better documented series instead of their own data. Before starting the discussion concerning the oncological and functional outcomes and complication profile for RARP of such “small case load centres” the question to be answered is how to define a “Small Case Load Centre.” We are obliged to consider from, the one point of view, the case load of RARP performed in an institution and, from another point of view, the experience and the number of cases per surgeon. According to the German Cancer Society (DKG), to be certified as a prostate cancer centre a

minimum of 25 radical prostatectomies (RP) per year must be performed per surgeon and a minimum of two surgeons have to be present in the centre. In 2008 at the Lucerne Hospital (County Hospital in the central part of the Swiss Alps performing an average of 60 to 70 RP per year), we started a robotic program by purchasing a four-arm refurbished Da Vinci standard System. The appointed robotic surgeon had at this time 10 years of experience in urology, including three years of experience in laparoscopic and robot-assisted surgery, trained at the University of Berne by U.E. Studer and at the Clinic Saint Augustin in Bordeaux, France, by R. Gaston. The surgical technique was strongly standardized using a monoblock technique for (extended) pelvic lymph node dissection and tension and energy-free technique for radical prostatectomy.1,2

Study results Median follow-up was 32 months (IQR: 16-50). Overall positive surgical margins were found in 13.2% of all patients and in 9.6% of patients with a stage pT2. Median number of lymph nodes removed was 17 (IQR: 13-22) and 88% of patients were free from nodal Robot-assisted radical prostatectomy Photo: European Urology metastases. One or more complications were reported in 31.2% of patients. Minor complications (Clavien grades 1-2) represented the most frequent events and were observed in 24.6% of patients. There is a 20% incidence of Biochemical Relapse (BCR) after a median time of 12.0 months (IQR: 3-12). In the patients who recurred, 85% of BCR occurred within two years and 97% within four years. No patient died of prostate cancer and 2% of patients died from other causes. Complete follow-up for functional outcomes is available for 78% of our patients. 94% patients reported complete continence (no pads or safety-pads only). Median time to continence recovery was seven days (IQR: 0-30). Among 55% of patients preoperatively potent who did undergo at least unilateral nerve-sparing RARP, a recovery of erectile function was observed in 59%, with a median recovery time of three months (IQR: 3-12).

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Tips for introducing a robot-assisted surgery programme

Because in prostate cancer oncological long term outcome has to be considered, we analysed our results after more than five years of experience and after performing more than 360 procedures.

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1) Do not start a Robot Assisted Radical Prostatectomy (RARP) program if your institution does not have a case load of minimum 50 cases per year. 2) Concentrate the learning process only on one surgeon for at least 50 to 100 procedures. 3) Start the teaching procedure in House with a coaching program over the first 10 to 20 RARP. 4) Standardize as much as possible each operation step and give a time limit in which it has to be accomplished. 5) Start a strict and standardized control of the intra and postoperative complications and the functional as well as the oncological outcomes using validated questionnaires beginning from the first procedure.

The first assessment of the quality of our centre was performed already one year after introduction of the robotic technique, comparing the perioperative, oncologic and functional outcomes from the last 75 patients treated by retropubic RP (RRP) and the first group of 75 patients treated by the newly established RARP. Despite an initial limited case load and including the learning curve, RARP offered slightly better short-term results than RRP in terms of PSM, major complications, urinary continence and erectile function.3

ChM in Urology

LC.

Five tips for a safe introduction to the Robot Assisted Radical Prostatectomy (RARP) Program in a "Low Volume Centre"

According to literature, our results over a five-year period are comparable with the results of highvolume centres. RARP offers good results in terms of safety as well as oncological and functional outcomes also in a low-volume centre, provided the surgeon has enough experience.

“Start the teaching procedure in your own institution not only organizing two or three mentored procedures, a coaching process over 10 to 20 RARP should be warranted.” Recommendations Which particular aspects must be considered introducing RARP in a “Low-Volume Centre”? 1) Even in small volume centres, a critical case load per surgeon and institution is mandatory to permit to achieve a learning curve, not only for the console surgeon but also for the surgical assistance and the nurse team. It is our opinion that the criteria of certification as “Prostate Cancer Center” recommended by the German Cancer Society has to be achieved with minimal 50 RARP per year for the institution, and a surgeon case load of minimum 25 RARP per year. Institutions with a smaller case load should seriously reconsider if an introduction of Robotic Surgery makes sense at all. 2) Start the RARP program with the most experienced surgeon and concentrate the learning process only with him. The introduction of the second surgeon should begin after consolidated experience of the first one (after about 50-100 procedures) 3) Start the teaching procedure in your own institution not only organizing two or three mentored procedures, a coaching process over 10 to 20 RARP should be warranted. With this manoeuvre you can neutralize the learning curve concerning oncological and functional outcomes4 4) To facilitate the learning process, standardize as much as possible each operation step, and

give a time limit in which it has to be accomplished. This will avoid unnecessary, and for the patient, potentially dangerous extreme long procedures. 5) Be courageous and accomplish from the beginning a strong standardized control of the intra and postoperative complications and functional as well as oncological follow-up using validated questionnaires. This will help you improve, as fast as possible, your critical steps. These five points have been strongly applied during the RARP introduction in our institution. Because of the solidity of the results and safety of the learning process, our surgeon team was asked to introduce the robotic surgery program in two other large Swiss hospitals (one large county hospital and one university hospital). We strongly believe that today the acquisition of know-how for performing RARP is at least as important as the acquisition of a robot itself! References 1. Mattei A, Di Pierro G. B., Grande P., Beutler J., Danuser H. Standardized and simplified extended pelvic lymph node dissection during robot-assisted radical prostatectomy: The monoblock technique. Urology 2013;81:446-50. 2. Mattei A, Naspro R, Annino F, Burke D, Guida R Jr, Gaston R. Tension and energy-free robotic-assisted laparoscopic radical prostatectomy with interfascial dissection of the neurovascular bundles. Eur Urol. 2007;52:687-94 3. Di Pierro GB, Baumeister P, Stucki P, Beatrice J, Danuser H, Mattei A. Prospective trial comparing consecutive series of open retropubic and robotic-assisted laparoscopic radical prostatectomy in a center with a limited case load. Eur Urol. 2011;59:1-6. 4. Mattei A, Thoms M, Ferrari M, La Croce G, Danuser H, Schmid HP and Engeler D. First report on joint use of a Da Vinci® Surgical system with transfer of surgical know-how between two public hospitals Urol Int. 2014;93(1):1-9

Sunday, 22 March 10.30-12.00: Thematic Session 4 Localised prostate cancer- Hot topics State-of-the-art lecture

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Sunday, 22 March 2015

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Improving therapeutic management of NMIBC En-bloc resection – The future standard of care? To date transurethral resection of bladder tumours (TURBT) is the cornerstone of treatment for non-muscle invasive bladder carcinoma (NMIBC)1. However, there is evidence of a high rate of tumour recurrence after primary resection. About 50-70% of all patients will have a recurrence after their initial treatment2. Despite all technological advances, NMIBC therefore continues to represent a challenging pathology. The comparably insufficient therapeutic management of NMIBC might be associated with the limitations of conventional TURBT techniques and with an inadequate accuracy of standard white light cystoscopy (WLC)3. It has been observed that almost 81% of the tumours recurred at the site of previous resection, which indirectly hypothesizes that the technique of resecting the tumour is not adequate4. Studies suggest that “en-bloc” resection could end the poor oncological safety profile of the “incise and scatter” principle behind the transurethral resection. The question to address is whether this technique is feasible for all NMIBC patients. gastrointestinal surgery, the tumour is elevated from the bladder with a submucosal fluid cushion. By elevating the mucosa, the resection level is raised and the risk of perforation of the muscularis is reduced. Initial study results prove the feasibility of waterjet hydrodissection for removing bladder tumours. In contrast to conventional TURBT, this new technique allows the pathologist to assess the entire lamina propria and the resection edges due to the en-bloc resection and to determine invasiveness as well as R0 Successful management of NMIBC not only relies on versus R1 resection10. Another technique, using a adequate initial resection but also on accurate front-firing green-light laser to en-bloc enucleate histological diagnosis. Understaging can adversely bladder tumours has recently being published and affect the survival of the patient. The risk of tumour was demonstrated to be effective and safe for understaging by initial TURBT was discovered by treatment of NMIBC. Moreover, it may improve the investigation of cystectomy specimens. It is known accurate valuation of tumour stage and prediction of that as much as 40% of clinically T1 tumours are postoperative prognosis, although long-term upstaged to pathologic muscle-invasive disease5. Even outcomes and prospective clinical trials are needed11. though conventional TURBT, where tumour is removed in piecemeal, has been in practice for many While the objective of en-bloc resection is the removal years, issues like absence of detrusor in of the tumour in its vertical extension and a more histopathology report and incomplete resection accurate pathological evaluation after the resection, continue to plague the adequacy of TURBT. HAL-guided blue-light cystoscopy helps to ensure the complete removal of the tumour in its lateral Based on the current knowledge of the recurrence extension. The combination of both techniques process, there is evidence to suggest that a significant therefore might be instrumental in removing the percentage of recurrences result from residual tumour tumour complete in order to lower recurrence rates. left behind at resection or growth of previously undetected lesions6. HAL-guided blue-light cystoscopy Tumour visibility – Decisive to visualize tumour (BLC) increases the detection rate for small or margins indistinct lesions that can go unseen under cystoscopy An important factor that influences the outcome of the with white light alone7. Findings of a recently initial TURBT is the visibility of tumours. HAL-guided published study suggest that performance of blue-light cystoscopy improves visualisation of HAL-guided TUR-BT can be of prognostic importance8. tumours at first TURBT, helps the urologist to identify Data from this retrospective analysis demonstrate that tumour margins and confirms complete clearance of HAL guided TUR-BT in bladder cancer patients, who lesions. As a result, the amount of tumour that is later progressed to requiring RC, significantly surgically removed is increased, and the risk of increased the three year overall survival (p=0.037) and tumour recurrence is reduced. Also, HAL-guided the median three year recurrence free survival blue-light cystoscopy can be used to confirm the (p=0.002). efficacy of treatment and to identify any previously missed or recurrent tumours. Improved detection and Improving the quality of initial tumour removal reduced risk of recurrence is in turn associated with lower overall costs in managing bladder cancer The so called en-bloc resection technique is one of the ways to improve the quality of initial tumour compared to WLC12. The 2014 update of the EAU removal. The idea behind this approach is to Guidelines also acknowledges the clinical value of completely remove the tumour without incision and BLC. The guidelines recommend the use of scattering of the tumour tissue. By not “touching” the fluorescence-guided resection, as being more tumour it is assumed that the resection results and sensitive than conventional white-light cystoscopy for the recurrence rates can be improved. The first detection of tumours.13 reported en-bloc resection of bladder tumours was described by Ukai and colleagues in 2000. Ukai used “En-bloc” resection – State-of-affairs a modified loop, which was cut in half, trimmed and In 2014 Kramer et al. reviewed the currently available bent to form a ‘‘J’’9. They made a circular incision data and found no randomized controlled clinical around the tumour keeping a distance of about 5 trials dealing with en-bloc resection of bladder mm. Subsequently, the tumour was bluntly dissected tumours14. Most of the publications were based on from the bottom considering the incision line. prospective observational trials with less than forty Including the detrusor muscle was requisite while patients. They arrive at the conclusion that any performing the resection and at the end, the tumor available energy source can be used, since en-bloc was retrieved in one piece. This has been the basic resection is a methodical approach. In cases of small concept of en-bloc resection since then. tumours less than 1 cm, “en-bloc” removal by standard single wire resection loop is the most Different principles of en-bloc resection of bladder indicated approach, as it prevents tumoral cells from tumours using alternative energy resources (e.g. scattering by extracting the lesion in a single piece. In holmium laser, thulium laser and the water-jet these situations, a special attention must be given to HybridKnife®) have been published in the last years. the complete and deep resection of the tumoral base while including part of the underlying muscular layer All the techniques have in common that a circular in the specimen. incision of the mucosa, with a safety margin, surrounding the tumour is achieved and that Nevertheless, though the appeal for en-bloc resection subsequent blunt en-bloc preparation of the complete is evident, attention must be paid to the current limitations of this approach. The feasibility of en-bloc tumour, including detrusor muscle, is performed. resection still is depending on tumour size and Waterjet hydrodissection (HybridKnife®) is a new location. Furthermore, technical equipment like technology for removing superficial bladder tumours. extraction bags still have to be improved. With this technique, already established in endoscopic

Currently available studies on en-bloc resection provide encouraging data on the reduction of the recurrence rate typical of non-muscle invasive bladder tumours. New techniques to achieve en-bloc resection like the water-jet HybridKnife® system are constantly studied in further trials15. HAL-guided cystoscopy holds promise in assisting en-bloc resections by helping to visualize tumour margins and confirming complete clearance of lesions12. HAL- guided en-bloc resection of bladder

Nevertheless, even though the feasibility of en-bloc resection has been demonstrated it still cannot be applied to all tumours and is currently considered to be experimental since available data is extremely heterogeneous illustrating a lack of standardized protocols14.

Interview with Prof. Fred Witjes (Radboud UMC, Nijmegen, The Netherlands)

The aim of initial TURBT is to remove all visible tumours and obtain tissue for accurate histological diagnosis. Conventional TURBT involves piecemeal resection of the tumour, which runs counter to established oncological principles of removing any tumour intact and if possible in a non-touch technique. The high rate of recurrence begs the question as to whether TURBT should be modified to provide en-bloc resection of the specimen.

Sunday, 22 March 2015

tumours may represent a potential option for selected patients and may help to overcome the limitations of a conventional TURBT.

Do you think the concept of “incise and scatter” during standard TURB needs to be changed since it is against the basic principle of oncological surgery? “If possible, yes. One limiting factor of the surgical ‘incise and scatter’ technique is that it might contribute to tumour recurrence. En-bloc resection of tumours would be far preferable and demands further development and evaluation.” How can this approach influence the bladder cancer therapy? “Still randomized controlled clinical trials dealing with en-bloc resection are missing. If it indeed lowers the recurrence rates (probably not progression rates) it should become the new standard in smaller tumours (let say a bit over 1 cm maximum).” For which patient group en-bloc TURB is feasible and safe (according to guidelines)? “The concept of en-bloc resection has appeal; however, its application is limited by the size of the tumour and to me this also is the central selection criterion. The higher the grade the less willing I would be to incise the tumour, so the better it should be if the resection is en-bloc. Moreover, we should clearly visualize a tumour in case of an en-bloc resection. For that, HAL guidance seems ideal.” Is en-bloc transurethral resection better than conventional techniques in terms of recurrence and progression? “Theoretically it would make sense that the resection results and the recurrence rates can be improved with en-bloc resection but this has not been comprehensively proven yet. However, en-bloc techniques allow for more accurate pathologic staging of initial tumour (>90%). This better possibility for pathological assessment is a clear advantage of this approach.”

About Innovators in BC® While the number of active participants is constantly growing and after a very fruitful first year the Innovators in BC® will again present the “Bladder Cancer Topic of the Year” at this year’s EAU meeting in Madrid. Urologists and oncologists from several countries once more voted for the bladder cancer topic they believe should be further discussed and high on the agenda in 2015. Innovators in BC® (www.innovators-in-bc.com) aims to change the way doctors and healthcare professionals look at bladder cancer. The main objective of this website is to provide science based information in order to raise awareness of bladder cancer in general, and to share information, experience and material with in-depth educational background. Its content has been compiled by medical professionals and is updated regularly by providing news about bladder cancer, summaries of congresses, current studies and publications. The website shares educational material for doctors, such as slide kits and patient cases. Moreover, improving early detection and intervention cystoscopy and resection could reduce the risk of subsequent recurrence and progression, for the patients’ benefit. The potential of Innovators in BC® will increase with its number of

Does currently available data allow for any conclusion about en-bloc resection of urothelial cancer? “The performance of TURBT is constantly evolving; various techniques using different kinds of loops and laser have been described and studied. The feasibility of en-bloc resection has been demonstrated as well. However, en-bloc resection still cannot be applied to all tumours and is currently only preferable for selected patients. Therapy always should be tailored in accordance with the particularities of each case.”

users. As a “living tool” the website requires the active participation and engagement of urologists and oncologists who could edit new content and raise the interest of the audience. Innovators in BC® is a restricted area for medical practitioners only from Austria, Belgium, Czech Republic, France (www. innovators-in-bc.fr), Germany, the Netherlands, Spain and Switzerland, developed by Ipsen. Without any commercial purpose the platform aims to be neutral and independent. References 1. Sureka et al., Indian J Urol. 2014; 30(2):144-149 2. Thomas et al., Eur Urol Suppl 2008; 7:524-528 3. Filbeck et al., J Urol. 2002; 168(1):67-71. 4. Grimm et al., J Urol. 2003; 170:433-437 5. Dutta et al., J Urol. 2001; 166(2):490-3. 6. Brausi et al., Eur Urol. 2002; 41:523-531 7. Burger et al., Eur Urol. 2013 Nov;64(5):846-54 8. Gakis et al., World J Urol 2015, article in press 9. Ukai et al., J Urol. 2000; 163(3):878-9 10. Nagele et al., World J Urol. 2011; 29(4):423-7 11. He et al., J Endourol. 2014; 28(8):975-9 12. Witjes et al., Eur Urol. 2014; 66:863-871 13. Babjuk et al., EAU 2014; April 2014. 14. Kramer et al., Min Inv Ther.2014; 23:206-213 15. Fritsche et al., J Endourol 2011;25: 1599-603

EUT Congress News

Are there useable molecular markers for prostate cancer? There is an urgent need for well-annotated biorepositories for marker validation Prof. Guido Jenster Professor of Experimental Urological Oncology Department of Urology Erasmus Medical Center Rotterdam (NL)

There is no doubt that we need more and better markers to determine risk, presence, aggressiveness and therapy response of prostate cancer (PCa). Besides physical symptoms such as palpable irregularities upon digital rectal examination (DRE), current indicators range from molecular (e.g. PSA), histo-pathological (e.g. Gleason grade) to imaging markers (e.g. CT, bone scan). From the clinical point of view, progress in all these marker areas has been modest. In the past decade, many new promising markers and assays have been published, but few made it into the clinic. The funnel from marker discovery to validation and clinical implementation is ruthless. Particularly for molecular marker research in the last decade, a feeling of continuous excitement for the novel developments contrasts their limited clinical impact. Challenges for molecular markers For the molecular markers, it has become clear that we are very good at discovering novel candidates. Technological progress, particularly in the –omics area of next-generation sequencing and mass spectrometry, continuously provides new options for higher throughput and higher content DNA, RNA, protein and metabolite detection. Besides finding new markers, these technologies also unlock the use of small amounts and new types of patient samples such as circulating tumor cells (CTCs), extracellular vesicles, circulating tumor RNA/DNA in urine and serum and formalin-fixed paraffin-embedded (FFPE) cancer biopsy sections. Unfortunately, the enthusiasm from technology development and promising novel markers does not encompass the validation phase. The major challenge we currently encounter is that candidate markers are not or cannot be validated in independent cohorts. Reasons for not being able to perform a validation include the lack of samples with the right clinical follow-up, robust detection assays (e.g. lack of good antibodies) and finances to validate all candidate markers. The reason why most of the candidates fail in the validation phase varies. Very often, the discovery phase is performed on a high number of molecules (all genes or thousands of peptides and metabolites) with a limited number of samples per group.

However, focusing on cancer-derived extracellular vesicles (e.g. exosomes), CTCs, cancer tissue or on DNA mutations or RNA expression unique to cancer (fusion genes, deletions, cancer-associated transcripts, etc.), might have a chance of success. Once markers have been validated and the assays optimized and CE-marked/FDA-approved, there is no guarantee they will be implemented in the clinic. Many issues affect the use of an assay, including the proven added-value, cost and reimbursement, ease of use, marketing and enthusiasm of the clinicians. If the proven added-value is very strong, worries about the other issues dissolve. If the added-value is limited, all other factors that play a role in adopting a new marker test, will determine its fate. Molecular markers Molecular markers used in common clinical practice are few, but their impact is high. Particularly prostate-specific antigen (PSA) is a major determinant in the diagnosis and monitoring of prostate cancer. The majority of validated molecular markers however, are not frequently used in clinical practice (Table 1). For risk assessment, single nucleotide polymorphisms (SNPs) have been identified in large genome-wide association studies (GWAS)1. Typically, each individual SNP has a limited discriminatory value, but as a panel might reach useful hazard ratios. In contrast, high hazard ratios are observed with BRCA2 and HOXB13 germline mutations. However, these hereditary cancer-associated mutations are very rare. Marker identification and validation has mainly concentrated on the diagnosis and prognosis of PCa. Unnecessary biopsies and overtreatment rightfully remain the main objectives. An overwhelming number of proteins, metabolites and RNAs have been investigated and proposed as markers. As mentioned above, most are not fully validated or failed to be independently validated by others. A selection of the markers that have been substantiated or are close to independent validation are listed in Table 1. Although often not fully clear yet, their added value to clinical practice is not expected to be at the breakthrough level. Combined however, some of the proposed marker profiles certainly deserve our attention2,3. Of interest are RNA profile assays for biopsies available from Genomic Health and Myriad4,5 and based on radical prostatectomy samples from GenomeDX Biosciences6. Their prognostic value needs to be further established in daily practice but their basis of gene expression differences directly measured in PCa tissue is solid.

Of interest are established and emerging molecular agents for nuclear imaging7. Again, technological developments in radiotracers, model systems and The variability in serum/urine content, tumor mutational PET/SPECT/CT scanning drive progress in this field and an increase in their implementation to detect and variation (heterogeneity) and expression levels of RNA and protein in tissue between men is simply too high to monitor PCa metastases is expected. escape the ‘noise in the system.’ Preventing this problem is not easy, but can be reduced by using larger The lack of robust predictive markers is a sign of our cohorts of samples during discovery and focusing on limited knowledge on the detailed molecular changes of therapy resistance. Only recently, some clear cancer-derived and cancer-specific markers. A generic search for protein or metabolite changes in urine or examples demonstrate progress in this field. The serum among a hundred men is futile. androgen receptor (AR) is the major target of Table 1: Common and emerging molecular markers for prostate cancer Type of marker

Most common current markers

Less commonly used and emerging molecular markers

Future molecular markers SNPs, other polymorphisms and germline mutations determined by genome sequencing after birth

Risk

Family history, urinary symptoms, age, race

SNPs, rare germline BRCA2 and HOXB13 mutations, PSA at age 40-50

Diagnostic

PSA, DRE, biopsy histo-pathology and in case of doubt AMACR/p63 or ERG IHC, imaging (MRI, CT, TRUS)

Prostate Health Index (PHI), PCA3, TMPRSS2DNA mutations and RNA expression (e.g. ERG, marker profiles of differentially PCa-associated transcripts) determined by expressed and mutated genes in urine and NGS of DNA/RNA from urine or biopsies blood

Prognostic

Oncotype DX (Genomic Health), Polaris (Myriad), Decipher (GenomeDX), PTEN, Gleason score (biopsy), extend of disease in cMYC and expression of other oncogenes biopsies, imaging (CT, MRI bone scan), after and tumor suppressor genes in tissue prostatectomy pT stage, Gleason grade and (biopsies), miRNA profiles in serum, urine surgical margins and tissue, imaging (PSMA [ProstaScint], Bombesin, FDG, CXCR4)

Predictive

Monitoring

PSA, imaging (MRI, CT, bone scan)

DNA mutations and (small) RNA expression determined by NGS of DNA/RNA from blood, urine or biopsies. Novel imaging agents for PET/SPECT. IHC of protein profiles on biopsies

Androgen receptor variants (indicating resistance to hormonal therapy), mutations in DNA repair genes (indicating PARP inhibitor sensitivity)

DNA mutations and RNA expression determined by RT-PCR or NGS of DNA/RNA from blood (CTCs, Exosomes, cell free), urine or biopsies

EpCAM capture and molecular characterstics of CTCs, imaging (PSMA [ProstaScint], Bombesin, FDG, CXCR4)

Number and type of extracellular vescicles. DNA mutations and RNA expression from cell free DNA and exosomal RNA from blood. Novel functional imaging agents for PET/SPECT

*Abbreviations: IHC, immunohistochemistry; SNP, single nucleotide polymorphism; NGS, next generation sequencing; DRE, digital rectal examination

EUT Congress News

hormone therapy and presence of AR amplification and mutations in castration resistant PCa (CRPC) have been known for many years. More recent is the discovery that splice variation between exons 3 and 4 can result in constitutively active receptors that are unaffected by hormonal therapies. As could be expected, the presence of AR variants in CTCs is a marker for the lack of response to enzalutamide and abiraterone8. A second example is the association between tumor-associated mutations in DNA repair genes such as BRCA1/2 and PALB2 and the increased sensitivity of the tumor to PARP inhibitors9. In normal cells, the inhibition of part of the DNA repair mechanism by PARP inhibitors is compensated by their slow growth and other DNA repair systems. When these are inactive through specific mutations in BRCA1/2 or PALB2, the cancer cells cannot cope with the accumulation of double-strand breaks and eventually perish. Mutations and loss of expression of various DNA repair-associated genes are therefore markers for the sensitivity of tumors to PARP inhibitors. Future of molecular markers The powerful technology developments are and will remain the main driver for progress in the field of marker research. Technological improvements further result in our ability to measure more parameters using less patient material. This allows us to perform marker analysis on the most limited material such as cell free or circulating tumor DNA (cf/ctDNA), CTCs and extracellular vesicles isolated from blood and urine. Taking biopsies of primary or metastasized PCa to establish tumor status is expected to be supplemented or even replaced by investigating the tumor-released cells (CTCs) and vesicles. Different types of vesicles are produced by (cancer) cells and the larger apoptotic vesicles contain DNA fragments (cf/ctDNA) while small exosomes carry cytoplasmic proteins and RNA10. Much research is directed towards the isolation of PCa-derived vesicles from blood and urine to determine the tumor status by the DNA, RNA and proteins they release. Dependent on cost developments of next generation sequencing (NGS), the measurement of single or panels of markers will be replaced by sequencing of the whole genome and transcriptome. The future in which recurrent tumors are sequenced to determine optimal treatment is near. This will be followed by sequencing of diagnostic biopsies, ctDNA and exosomal RNA for the diagnosis, prognosis, therapy response and monitoring of disease. For discovery and validation of novel markers, these efforts are established and ongoing. Clinical implementation, as mentioned, is mainly dependent on the added clinical value, costs and reimbursement. With respect to the type of markers, there is a clear bias towards DNA and RNA as compared to protein and metabolites. DNA and RNA can be easily and highly amplified and specific detection using PCR and NGS is straight forward. Although mass spectrometry is undergoing similar technological breakthroughs as NGS, implementing this technology in a clinical setting for protein and metabolite detection is more cumbersome. Protein detection using classical methods such as ELISA and immunohistochemistry (IHC) depend on specific antibodies, which are still not always available and laborious to generate. With the assay technologies in place, the limiting factor remains the molecular markers. It is expected that diagnostic and monitoring markers will be identified that have high specificity and sensitivity. Since our knowledge of DNA mutations in PCa is exponentially increasing through the many sequencing efforts, detecting cancer from changes in DNA and RNA extracted from urine or blood is feasible. Knowing the patient-specific DNA mutations, allows for the monitoring of disease via cf/ctDNA and CTC-DNA in blood. Much harder is resolving risk assessment, prognosis and therapy response predictions. If the majority of PCa tumors are caused by random mutations (just bad luck), informative risk markers will not exist for most men. For prognostic and predictive markers, knowledge on the biology of the disease is essential, but far from comprehensive. In addition, heterogeneity within and among tumors is a problem for the identification of common markers and, therefore, panels of markers have to be designed.

Technology developments, particularly in next generation sequencing, drive biomarker research

New possibilities Technology developments, particularly in next generation sequencing, drive biomarker research and create new possibilities to detect more factors in limited amounts of patient sample. For example, changes in cell-free DNA and RNA from extracellular vesicles extracted from urine and blood will become important future personalized diagnostic and monitoring markers. A proportion of the new generation prognostic, predictive and imaging (PET/SPECT) markers will be based on our increasing understanding of PCa biology and therapy resistance. Due to the high variability among tumors, sensitive markers will not consist of a single factor, but will be a panel of parameters. Although many novel candidate markers have been discovered, their validation and implementation fall behind. The need for well-annotated biorepositories for marker validation is high. Importantly, researchers, clinicians, funding agencies, health insurance companies and private partners should invest more in assessing promising markers in retrospective tissue banks and in daily routine. References 1. Choudhury AD, Eeles R, Freedland SJ, Isaacs WB, Pomerantz MM, Schalken JA, Tammela TL, Visakorpi T. The role of genetic markers in the management of prostate cancer. Eur Urol. 2012 Oct;62(4):577-87. 2. Sartori DA, Chan DW. Biomarkers in prostate cancer: what’s new? Curr Opin Oncol. 2014 May;26(3):259-64. 3. Canfield SE, Kibel AS, Kemeter MJ, Febbo PG, Lawrence HJ, Moul JW. A guide for clinicians in the evaluation of emerging molecular diagnostics for newly diagnosed prostate cancer. Rev Urol. 2014;16(4):172-80. 4. Knezevic D, Goddard AD, Natraj N, Cherbavaz DB, Clark-Langone KM, Snable J, Watson D, Falzarano SM, Magi-Galluzzi C, Klein EA, Quale C. Analytical validation of the Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics. 2013 Oct 8;14:690. 5. Cooperberg MR, Simko JP, Cowan JE, Reid JE, Djalilvand A, Bhatnagar S, Gutin A, Lanchbury JS, Swanson GP, Stone S, Carroll PR. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol. 2013 Apr 10;31(11):1428-34. 6. Klein EA, Yousefi K, Haddad Z, Choeurng V, Buerki C, Stephenson AJ, Li J, Kattan MW, Magi-Galluzzi C, Davicioni E. A Genomic Classifier Improves Prediction of Metastatic Disease Within 5 Years After Surgery in Node-negative High-risk Prostate Cancer Patients Managed by Radical Prostatectomy Without Adjuvant Therapy. Eur Urol. 2014 Nov 12. pii: S0302-2838(14)011257. 7. de Jong M, Essers J, van Weerden WM. Imaging preclinical tumour models: improving translational power. Nat Rev Cancer. 2014 Jul;14(7):481-93.

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at EUT@uroweb.org for a complete listing. Sunday, 22 March 07.30-10.55: Plenary Session 2 Prostate Cancer

Sunday, 22 March 2015

Insulin resistance, obesity and LUTD Conclusive findings on the links between metabolic syndrome and LUTD need more research Prof. Jan-Erik Damber Department of Urology Institute of Clinical Sciences University of Gothenburg Gothenburg (SE)

Overactive bladder Overactive bladder (OAB) is a syndrome defined by the storage symptoms of increased micturition frequency, urgency with or without urinary incontinence, and nocturia17. Animal studies suggest a link between the MetS and OAB20-22. When it comes to clinical evidence of a link between the MetS and OAB, evidence is still scant.

Selective aspects of the MetS, such as type 2 diabetes23,24,25, reduced HDL cholesterol25, raised triglycerides25, BMI26 and hypertension26, have been Co-Author: Jan Hammarsten, Gothenburg (SE) linked to a risk of OAB. A recent report has found an association between the MetS as defined by a health The role of tissue resistance to the actions of insulin organization and OAB in diabetic women27. In another for certain chronic disorders was first described more recent report, this link between the MetS and OAB than 70 years ago1. It was not until the late 1980s, was only found in females and not in males28.One however, that it was discovered that insulin interesting observation is that obesity, diet and resistance and its major endocrine aberration, lifestyle factors, known to be associated with the compensatory increased insulin level, represent a MetS, such as smoking and the consumption of unifying link between type 2 diabetes, coronary carbonated drinks, were linked to the onset of OAB in artery disease, hypertension, obesity and women in a prospective multivariate model29. The dyslipidaemia2,3,4,5. molecular mechanisms behind this proposed connection between the MetS and OAB remain to be This cluster of disorders is nowadays referred to as further elucidated. the metabolic syndrome (MetS). The MetS is prevalent in countries with Western civilization lifestyles. LUTS Approximately 34-39% of the adult population in the Epidemiological data show an increasing prevalence Unites States suffers from the MetS with just about of LUTS as men grow older30. It has been reported equal prevalence in men and women6. that one third of the Swedish male population over 50 years suffers from LUTS using IPSS-score31. In recent years, a debate has been going on whether LUTS are The MetS has been described as one entity characterized by a defect in the insulin-mediated an aspect of the MetS or not. However, the reports are glucose uptake. The primary metabolic abnormality is inconsistent. mainly localized to the muscle, adipose tissue and the liver of these patients, leading to an insulin resistance Another view claims that stress conditions, via increased activity of the sympathetic nervous system and a secondary hyperinsulinemia7. This defect may occur at any time throughout the patient’s life, and hypothalamic-pituitary-adrenal axis, are involved in the pathophysiology of LUTS8,15,16. In a recent study, perhaps as early as during the fetus stage, during childhood, puberty or later3. we have shown that only three out of 16 established aspects of the MetS were linked to LUTS (Table 3)32. In fact, a low adiponectin level, which is an established This disturbance may be conditioned by genetic, hormonal or lifestyle factors or a combination of these aspect of the MetS, was inversely linked to LUTS. These findings do not support the hypothesis that LUTS is an factors3. The patient may have this disturbance for decades without knowing anything whatsoever about aspect of the MetS. The study rather supports the hypothesis that stress conditions with increased activity its existence. On the basis of available know-how, suddenly and unexpectedly, the complications of MetS of the sympathetic nervous system are involved in the pathophysiology of LUTS. The most important finding emerge. These complications could be any of the diseases and conditions we associate with MetS such of the study was that serum serotonin showed an as Type 2 diabetes, hypertension, dyslipidaemia, inverse independent correlation with LUTS. obesitas or any other disease or condition depending on the genetic disposition as suggested by De Fronzo In recent years there have been many reports, showing a link between depressions as measured by and Ferrannini3. questionaries’ and LUTS as measured by IPPS score33. The possibility of a link between the MetS, on the one Depression is characterized biochemically by a serum hand, and prostate diseases has been explored for low serotonin level34. Thus, the study offers a almost 20 years8. A more recent notion is that the hypothesis on a neurotransmitter mechanism, by MetS is linked to other important clinical conditions in which depression and LUTS are linked. urology, such as male hypogonadism, nephrolithiasis, overactive bladder (OAB) and erectile dysfunction Prostate cancer (ED)9. When it comes to these clinical conditions, Also the link between insulin resistance and prostate cancer has been extensively studied29-32. The overall however, research has been going on for a shorter period of time and evidence is still sparse. The impression from these studies is that the link between present article focuses on the link between the the MetS and aggressive, lethal cancer is more robust urological aspects of the MetS and lower urinary tract than the link between the MetS and incidental dysfunction (LUTD) based on the perspective of a prostate cancer9. The results are, however, conflicting. clinician. Some studies show a link between some aspects of Benign prostatic hyperplasia The link between insulin resistance and BPH has been Table 1: Compilation of established aspects of the extensively studied. In our studies, 22 established metabolic syndrome, which have been shown to be aspects of MetS out of 23 came out as risk factors for risk factors for BPH in our reports BPH (Table 1)8,10-14. A low testosterone level, which is an established aspect of the MetS, however, did not Fasting serum insulin(8,10,11,12,13) come out as risk factor for BPH. A high-fasting plasma Free oestradiol (13) insulin level was the most consistent risk factor in Testosterone/oestradiol quotient (inverse) (13) these risk factor analyses. However, insulin resistance Sex hormone-binding globuline (inverse)(13) is associated with multiple biochemical and endocrine Body length (10,12) aberrations, among others, Vitamin D deficiency, Body mass index (8,10,11,12,13) which in a subsequent study came out as a stronger Body weight (10,11,12,13) risk factor for BPH than insulin. The overall conclusion emerging from these findings is that insulin resistance and its aberrations have a trophic effect on the prostate inducing an enlarged prostate gland. This enlarged prostate gland constitutes the static component of the bladder outlet obstruction due to BPH. It is also well established that the insulin resistance induces an increased sympathetic activity. Two publications by McVary et al15 and Ulrich et al.16 could confirm an association between the sympathetic activity and BPH. These findings suggest that insulin resistance not only induces an enlarged prostate gland, causing a static component of the bladder outlet obstruction, but also an increased sympathetic activity, causing dynamic component of the bladder outlet obstruction. Sunday, 22 March 2015

Waist measurement (8,10,11,12) Hip measurement (8,10,11,12) Waist/hip ratio (8,10,11,12) Fat body mass (13) Lean body mass (13) Type 2 Diabetes (8,10,11) Atherosclerotic disease manifestations (12) Prostate cancer (12) Treated hypertension (8,10,11) Systolic blood pressure (8,10,11,12) Diastolic blood pressure (10,11,12) HDL-cholesterol (inverse) (8,10,11) Uric acid (12) Alanine aminotransferase (12) 25-OH Vitamin D (inverse) (14)

Figure 1: Visualize the large surface of a sea and consider it as a representation of the clinical horizon. Far down beneath the sea’s surface, one would find the metabolic syndrome as a defective insulin-mediated glucose uptake, i.e. insulin resistance. Suddenly and unexpectedly the complications emerge at the horizon. The complications could be any of the diseases and conditions we associate with the metabolic syndrome. New data suggest that LUTD might be linked to insulin resistance and are aspects of the metabolic syndrome.

Table 2: Distinction regarding aspects of the metabolic syndrome in men with the metabolic syndrome and corresponding aspects in men with LUTS

Body height Body weight Body fat Body mass index Trunk fat mass Total body fat mass Systolic blood pressure Diastolic blood pressure Triglycerides HDL-cholesterol Fasting serum insulin Fasting serum glucose Diabetes or fasting serum glucose >7.0 Adiponectin Total oestrogen Free testosterone C-reactive protein Prostate gland volume

Men with the metabolic syndrome are characterized by increased increased increased increased increased increased increased increased increased reduced increased increased Increased prevalence reduced increased reduced increased increased

MetS including obesity, and prostate cancer. There are also accumulating data showing that type 2 diabetes, the final stage of MetS, in some ways appears to be protective for the occurrence of incident prostate cancer35. Medical care implications With respect to LUTD, the proposed association with MetS would mean that any physician confronted with a patient with these disorders should consider the possibility that the patient also has type 2 diabetes, hypertension, dyslipidaemia or some other aspect of the MetS. Conversely, a physician who is confronted with a patient with the above conditions should consider the possibility that the patient may have some urological problems.

5. 6.

Men with LUTS are characterized by unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged increased unchanged increased unchanged reduced unchanged increased

multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 14, 173-94 (1991). Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA and Stern MP. Prospective analysis of the insulinresistance syndrome (Syndrome X). Diabetes. 41, 715-89 (1992). Reaven GM. Syndrome X: 6 years later. J. Int. Med. 236 (Supplement 736), 13-22 (1994). Golden SH, Robinson KA, Saldanha I, Anton B and Ladenson PW. Prevalence and incidence of endocrine and metabolic disorders in the United States: A comprehensive study. J Clin. Endocrinol Metab. 94, 1853-1878 (2009). Krotkiewski M. Role of muscle capillarization and morphology in the development of insulin resistance and metabolic syndrome. Press Med 1994;23:1353-1356 Hammarsten J, Högstedt B, Holthuis N and Mellström D. Components of the metabolic syndrome – risk factors for the development of benign prostatic hyperplasia. Prostate Cancer Prostate Dis. 1, 157-162 (1998). Hammarsten J, Peeker R. Urological aspects of the metabolic syndrome. Naure Review Urology. 2011 2;8(9):483-494. Hammarsten J and Högstedt B. Clinical, anthropometric, metabolic and insulin profile of men with fast annual growth rates of benign prostatic hyperplasia. Blood Press. 8, 29-36 (1999).

Another implication is that measures can be taken to reduce the metabolic disturbance and, consequently, slow down the progression of LUTD. In our view, men concerned about their urologic health should be informed about these findings, although definitive knowledge of the associations between MetS and LUTD needs further research. The proposed link between insulin resistance, obesity and other aspects of the MetS must, of course, be confirmed by continued cross-sectional, prospective and interventional studies.

References

Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at EUT@uroweb.org for a complete listing.

1. Himsworth H. Diabetes mellitus: a differentiation into insulin-sensitive and insulin-insensitive types. Lancet 6, 127-30 (1936). 2. Reavan GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 37, 1595-1607 (1988). 3. DeFronzo RA and Ferrannini E. Insulin resistance. A

10.

Sunday, 22 March 10.30-12.00: Thematic Session 3 Male LUTS, State-of-the-art lecture

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Immunotherapy in renal cell cancer Checkpoint inhibition action is expected to demonstrate better overall survival in kidney cancer patients smallpox virus is used as a vector to deliver the 5T4 antigen. The TRIST trial failed to demonstrate any benefit in median overall survival in comparison to placebo as a first-line treatment (20.1 vs. 19.2 months; TROVAX vs. control)4.

Prof. Dr. Jens Bedke Dept. of Urology Eberhard Karls University Tübingen Tübingen (DE) •

With the discovery of novel targeted drugs, and their introduction into the clinical routine within the last decade, the management of metastatic renal cell carcinoma (mRCC) has been revolutionized. It is now based on various agents with specific targets within the signalling cascades of the mammalian target of rapamycine (mTOR) and the vascular-endothelialgrowth-receptor (VEGF) VEGF pathway. Despite the magnitude of well-established substances and these new small molecule inhibitors and the high success rate of a prolonged progression and overall survival due to the new mTOR and VEGF directed agents, mRCC still remains an incurable condition. For years, patients with a metastatic RCC have been restricted to the treatment of immunotherapy with the activation of a non-specific immune response by the application of cytokines, namely interleukin-2 (IL-2) and interferon-alpha (IFN-α). The moderate efficacy of cytokine therapy is well known, but the rate of complete or partial remissions is about 12.9% in 99 analysed study arms in the combined data of a meta-analysis. Out of these reported remissions (12.9%) 28% were complete responders1. Currently, in RCC a transformation from the ancient unspecific therapy with cytokines to rather specific approaches, which directly target the renal cell cancer cell and the tumour microenvironment is observed2. One of the underlying principles in specific immunotherapy is that tumours express antigens the so called tumour-associated antigens (TAAs) that are recognized by (cytolytic) T lymphocytes (CTLs) derived from the tumour-bearing patient. The described approaches of active immunotherapy have in common that TAAs shall activate naïve T cells, which then target the tumour3. Several randomized immunotherapy trials have been reported and are on its way in the adjuvant or metastatic setting: •

•

AGS-003 (Argos Therapeutic, NC, USA) is a dendritic cell-based (DC) vaccine of the patient´s own antigen coding amplified tumour RNA and synthetic CD40L RNA. A phase 2 trial 21 first-line mRCC patients (poor and intermediate risk) treated with AGS-003 and sunitinib showed a median PFS was 11.2 months and OS 30.2 months. Currently, AGS-003 is explored in a phase 3 trial in advanced RCC patients (ADAPT, n=450 patients) randomized to AGS-003 with sunitinib vs. sunitinib alone as a first-line treatment (NCT01582672). Vitespen (Oncophage®; Antigenics Inc., MA, USA) is an autologous tumour-derived heat shock protein Gp96 preparation (NCT00033904) and Reniale® (Liponova, Hanover, Germany) is an autologous DC vaccine. Both vaccines were used in adjuvant RCC trials, but failed to achieve general market status. Trovax (MVA-5T4; TroVax™, Oxford BioMedica, Oxford, UK) is a single tumour antigen vaccine of 5T4, which was used in combination with first-line standard of care in the TRIST trial (NCT00397345). MVA-5T4 is a non-mutated self-antigen expressed in the placenta, but also overexpressed in RCC. The modified vaccina Ankara virus, derived from the

The results of these trials are promising, but none of the vaccines has gained general market status in Europe or the U.S. despite on-going phase III trials for AGS-003 and IMA901. Unfortunately, the immune system can be controlled and edited by local or systemic environments to prevent an effective T cell activation at checkpoints of T cell activation. Immunosurveillance and immunoediting The hypothesis of immunosurveillance and the concept of immunoediting both describe the biological immunological approach of cancer development. The original concept of the immunosurveillance hypothesis formulated by Sir Macfarlane Burnet and Lewis Thomas postulates that small accumulations of tumour cells developed within the body. These tumour cells provoke an effective cellular immune reaction, which protects from neoplastic disease and leads to the regression of the tumour with no signs of clinical existence5,6. Later on, this hypothesis was reformulated to the concept of immunoediting, which consists of three phases, elimination, equilibrium and tumour escape. The elimination corresponds to the immunosurveillance. In the equilibrium the immune system allows the selections and promotion of different tumour cells with the capacity to survive the immune attacks. In the escape phase, the immunologically sculptured tumour leads to an uncontrolled outgrowth of tumour cells within the immunocompetent host and the tumour becomes clinically apparent7. Thereby, the tumour has different mechanisms to render itself “invisible” to the host´s immune system and to silence immune cells. Theses tumour-driven mechanisms of immune suppression includes the down regulation of HLA molecules and/or tumour associated antigens (TAA), which leads to a decreased immunogenicity or the induction of suppressive cytokines like IL-10 or TGF-β. These cytokines can lead to recruitment of regulatory T cells (Tregs), myeloid derived suppressor cells (MDCS) or tumour-associated M2 macrophages which can act as immunosuppressors. Therefore, agents called immunomodulators or checkpoint inhibitors, which counteract tumourinduced immunosuppression are an external editing of the immune system to potentially shift tumour growth from the escape phase to the equilibrium state or towards tumour elimination.

RCC cell

Normal cell RNA

IMA901 (Immatics, Tübingen, Germany) is a synthetic peptide vaccine consisting of nine fully defined TAA-derived T-cell epitopes. 68 HLA-A*02+ mRCC patients after at least one previous therapy were randomized to receive single-dose cyclophosphamide (Cy, 300 mg/m2) vs. no pre-treatment, three days prior to the start of IMA901 + GM-CSF (75μg). Progression-free survival was similar in both study groups (+Cy vs. -Cy), but for median overall survival there was a trend for a prolonged survival in the +Cy arm vs. the –Cy arm (23.5 vs. 14.8 months, HR=0.57, p=0.090; NCT00523159). Currently, IMA901 is investigated in the IMA901 multiPeptide vaccine Randomized INTernational study (IMPRINT) phase 3 trial, in which 340 HLA-A*02+ patients have been randomized in a 3:2 fashion to receive IMA901 plus sunitinib vs. sunitinib alone as a first-line treatment for metastatic clear cell RCC (NCT01265901).

Protein

T-cell

MHC-I

Tumor-associated protein

Figure 1: Processing and presentation of tumour associated antigens on HLA class I molecule on the cell surface3

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Checkpoints and the regulation of the immune system Activated T cells eliminate pathogens and tumour cells, but an exaggerated activation provokes autoimmune disorders. To understand the biology of checkpoint inhibition, it is of importance to figure out the control of T cells with its activating and inhibitory co-receptors, which are major regulators of T cell response and mediate tolerance to “self.”

In order to prime, e.g. to activate Dendritic cell Anti-CTLA-4 mAB T cell naïve T cells, the antigenIpilumab presenting cell (DC/APC) must Tremelimumab present the TAA in the correct CD80/86 major histocompatibility CTLA-4 complex molecule (´signal one´) + CD80/86 CD28 in the presence of a co-stimulus, e.g. the expression of CD80 (B7-1) and CD86 (B7-2). A high PD-L1 expression of such costimulatory molecules is RCC cell achieved by the activation of Anti-PD1 mAB APCs. If the co-stimulatory Nivolumab signal is not present, the DC cells might present the antigen on to the CD8+ T cell as a tolerogenic signal, which is also Figure 2: Checkpoint modulation of CTLA-4 and the PD1-PDL1 axis in renal cell carcinoma3 mediated through PD-1 (CD279) and CTLA-4 (CD152) (Figure 1). This phenomenon termed treatment of nivolumab 3mg/kg every three weeks. peripheral tolerance is influenced by the antigenCombination therapy was either nivolumab 3mg/kg specific tolerogenic role of DCs. plus ipilimumab 1mg/kg (N3+I1, n=21) vs. nivolumab PD-1/PD-L1 axis 1mg/kg plus ipilimumab 3mg/kg (N1+I3, n=23). Programmed death 1 (PD-1) is a key immune Responses were higher in the combination than checkpoint receptor expressed by activated T cells, reported for each monosubstance11. The encouraging results of this phase 1 study led to the initiation of a where it terminates immune responses upon antigen stimulation to avoid massive immune destruction. The phase 3 study in mRCC patients as a first-line treatment with the combination of nivolumab 3 mg/kg with two ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) are expressed in peripheral and tumour tissue. Here, PD-L1 ipilimumab 1 mg/kg compared to sunitinib monotherapy (CheckMate 214, NCT02231749). seems to be selectively expressed by tumour cells and cells in the tumour microenvironment, where it can Conclusion inhibit cytokine production and the cytolytic activity of PD-1 positive, tumour-infiltrating CD4+ and CD8+ T Checkpoint inhibition with nivolumab and ipilimumab cells. activates or inhibits co-stimulatory signals in T cell activation. This new mode of action demonstrated a PD-1 antibodies like nivolumab (BMS-936558, prolonged overall survival for melanoma patients and it Bristol-Myers Squibb, New York City, New York), is anticipated that this will also be achieved in mRCC pembrolizmab (MK-3475, Merck Sharp & Dohme Corp., patients. Nevertheless this “manipulation” of the Whitehouse Station, New Jersey, U.S.), AMP-224 immune system also leads to new, probably class(MedImmune/AstraZeneca, London, U.K), Pidilizumab specific immune related adverse events which might be (CT-011, Curetech, Yavne, Israel) and PD-L1 antibodies dose limiting. As observed so far, these immune-related like BMS-936559 (Bristol-Myers Squibb, New York City, AE lead to autoimmune reactions like hypothyroidism, New York), MPDL3280A (Genentech/Roche, Basel, hepatic dysfunction or hepatitis, sarcoidosis, Switzerland), MEDI4736 (MedImmune/AstraZeneca, endophthalmitis, gastrointestinal dysfunction like London, U.K) and MSB0010718C (MerckSerono, enteritis or myasthenia gravis. Especially the Darmstadt, Germany) are in different stages of combination of ipilimumab and nivolumab in the dose preclinical and clinical development phase 1 to 3 of I3 + N1 seemed to be dose limiting10. studies in RCC cancer entities (Table 1). Although checkpoint inhibitors are attributed to the PD-1 antibody treatment modality of specific immunotherapy it has to Nivolumab, a fully humanized anti-PD-1 antibody has be stressed that only the mode of action is specific, e.g. shown anti-tumour activity in a phase 1 study with 296 the target receptor is well defined. On the other hand, solid cancer patients. Nivolumab was given in a the provoked effector functions by the respective starting dose of 1 mg/kg and then expanded to 3 and checkpoint modulation are not well defined. It is not known against which respective tumour-associated 10mg/kg in cohorts of three to six patients, among antigens the T cells will be activated and in which theses 33 had mRCC at doses of 1 and 10mg/kg. The strength the anti-tumour immune response is objective response rate was four of 17 patients (24%) provoked. For the future, these facts warrant that treated with a dose of 1.0 mg/kg and five of 16 (31%) treated with 10.0 mg/kg. Five out of eight patients, who checkpoint modulators are not only used as a stand-alone drug, but rather in combination with a started treatment one year before analysis, had a response longer than one year. Stable disease, defined vaccination specific approach in which the immune response is direct against specific TAA and the strength as stability longer than 24 weeks, was observed in an additional nine (27%) patients8. Based on these results of the response can be measured. a large phase 3 trial of 822 patients with metastatic or advanced RCC in the second-line setting was initiated Table 1: Overview of available checkpoint modulators (CheckMate 025, nivolmab vs. everolimus). Primary for cancer immunotherapy study aim is overall survival. The study has terminated Target pathway Substance Company recruitment and is currently under follow-up CTLA-4 Ipilimumab BMS (NCT01668784). At ASCO 2014 additional study data from a dose escalation trial, a combination study of nivolumab with TKI and of nivolumab with ipilimumab were presented: In the dose ranging phase 2 study of nivolumab objective response rate was not different between the groups (20-22%; 0.3, 2 and 10mg/kg), Interestingly, most patients had their response within the first three months and complete responses were rare with a rate of 0-2%9. In a phase 2 study nivolumab was combined with the TKI sunitinib or pazopanib in mRCC. In the sunitinib arm nivolumab was escalated from 2mg/kg (n=7) to 5mg/kg (n=7) and then expanded in another 19 patients who were treatment naive. In the pazopanib arm 10 patients were treated with 2mg/kg and no further escalation as the maximum tolerated dose was reached. The efficacy was higher in the combinations than anticipated for the single agents, but severe adverse events grade III or IV occurred in 82% of the S+N arm and in 70% of the P+N2 arm10. In another phase 1 study, patients were treated with combinations of nivolumab and ipilimumab four times in three weeks intervals followed by continuous

PD-1

PD-L1

LAG-3

Tremelimumab

Pfizer

Nivolumab (BMS-936558)

BMS

Pembrolizumab (MK-3475)

Merck

AMP-224

Amplimmune

Pidilizumab (CT-011)

CureTech

MEDI4736

MedImmune/ AstraZeneca

MPDL3280A

Roche

MSB0010718C

MerckSerono

BMS-936559

BMS

IMP321

Immutep

Editorial Note: Due to space constraints the Reference List has been excluded. Interested readers can email a request for the complete list at EUT@uroweb.org. Sunday, 22 March 10.30-12.00: Thematic Session 9 Immunotherapy in urologic cancer State-of-the-art lecture

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Best Abstract Winners First Prize for the Best Abstract (Oncology) Abstract Nr: AM15-3854 Title: Discriminating metastasized from nonmetastasized seminoma using small RNA-expression in tumour tissue and peripheral blood Authors: Ruf, C.G.A.1, Port, M.2, Matthies, C.3, Meineke, V.2, Müller-Myhsok, B.4, Wagner, W.3, Schmelz, H.-U.1, Abend, M.2 Federal Armed Forces Hospital, Dept. of Urology, Koblenz, Germany, 2 Bundeswehr Institute of Radiobiology, Genomics, Munich, Germany, 3Federal Armed Forces Hospital, Dept. of Urology, Hamburg, Germany, 4Max-PlankInstitute of Psychiaty, Dept. Translational Research In Psychiatry, Munich, Germany

C. Ruf

Introduction & Objectives To better discriminate metastasized (lymphogen/ occult/both combined) from non-metastasized seminoma we investigated post-transcriptional changes on small RNA level in the primary tumour and in peripheral blood. Materials & Methods Total RNAs including small RNAs were isolated from testicular tumours and full blood, taken from cubital vein during the operation, of lymphogen metastasized (clinical stage IIb/c), occult metastasized (clinical stage I) and non-metastasized (clinical stage I) patients, five of each group. Small RNA next generation sequencing (SOLID, Life Technologies) was employed to examine post-transcriptional changes. We searched for differential small RNA expression (showing at least 50 reads and a significant > 2-fold difference) using small RNAs of non-metasized tumours as the reference group. Candidate small

RNAs were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines. Additionally we compared differential small RNA expression in tumour tissue and peripheral blood. Results Between 1.3x107 and 1.7x107 small RNA reads were detectable in tumour tissue and between 1.2x107 and 1.3x107 in peripheral blood, of which 30-32% and 73-76% remained after trimming. From these between 59-68% and 80-84% represented annotated reads and 8.6-11% (3.6-5.7x104) and 7.2-7.8% (1.6-1.7x104) respectively were annotated small RNA tags. Of them 137 small RNAs in tumour and blood showed > 50 reads and a two-fold difference to the reference. In univariate analysis we detected 32-38 and 33-35 different small RNAs which significantly discriminated lymphogen/occult/ combined metastasized from non-metastasized seminoma and among these different comparisons it were the same small RNAs in 51-88%. Eleven of the 38 and 35 differentially expressed small RNAs discriminated metastastatic status in both, primary tumour and peripheral blood (Table 1). Many combinations of two of these small RNAs allowed a complete discrimination of metastasized from non-metastasized seminoma, irrespective of the metastasis subtype, measured in either the tumour or in the peripheral blood. Conclusions Metastasized and non-metastasized seminoma can be completely discriminated with a combination of two small RNAs, irrespective of the subtype (lymphogen or occult metastasized), if measured in primary tumour or in peripheral blood. About one third of all differentially expressed small RNAs are detected in tumour tissue and peripheral blood.

First Prize for the Best Abstract (Non-Oncology) Abstract Nr: AM15-3537 Title: Adherence to European Association of Urology guidelines on prophylactic antibiotics: An important step in antimicrobial stewardship Authors: Cai, T.1, Verze, P.2, Brugnolli, A.3, Tiscione, D.1, Malossini, G.1, Luciani, L.1, Echher, C.1, Wagenlehner, F.4, Mirone, V.2, Bjerklund Johansen, T.5, Picakrd, R.6, Bartoletti, R.7 T. Cai

Santa Chiara Hospital, Department of Urology, Trento, Italy, 2University of Naples, Department of Urology, Naples, Italy, 3University of Verona, Department of Public Health, Verona, Italy, 4 Universitätsklinikum Giessen Und Marburg GmbH, Justus-Liebig-Universität Giessen, Klinik Und Poliklinik Für Urologie, Giessen, Germany, 5 University of Oslo, Department of Urology, Oslo, Norway, 6Newcastle University, Institute of Cellular Medicine, Newcastle, United Kingdom, 7University of Florence, Department of Urology, Florence, Italy 1

Results The rate of symptomatic post-operative infectious complications was not significantly different between the two periods (117/2,619 (4.5%) vs 180/3,529 (5.1%); p=0.27). The costs in period “after”, related to drugs amounted to 36,700 Euro and the indirect costs to 29,560 Euro, were statistically lower than those observed in period Introduction & Objectives “before” (76,980 Euro and 45,870 Euro) (p<0.001). The evolution of resistant pathogens has developed A total of 342 isolates from all patients with into a worldwide health crisis and adherence to symptomatic post-operative infectious complications European Association of Urology (EAU) guidelines on were reported and analyzed. The resistance rates of antibiotic prophylaxis may be an important way to E. coli to piperacillin/tazobactam (p=0.03), improve antibiotic stewardship and reduce costs. gentamicin (p=0.02) and ciprofloxacin (p=0.03) The aim of this study is to evaluate costs saving and decreased significantly during the after periods. the prevalence of antibiotic resistant bacterial strains during a period of adherence to EAU guidelines in a Conclusions tertiary referral urological institution. The adherence to European Association of Urology guidelines on antibiotic prophylaxis reduced related Materials & Methods costs and the prevalence of resistant bacteria. In January 2011, we started a protocol of adherence

Second Prize for the Best Abstract (Oncology) Abstract Nr: AM15-1240 Title: Epigenomics of penile squamous cell carcinoma

miRNA reporter assays. Dual-Luciferase® Reporter Assay system (Promega) was used to assess miRNA repression with both Let7 and mir100 reporter assays.

Authors: Feber, A.1, Arya, M.2, De Winter, P.3, Muhammad, S.4, Nigam, R.4, Malone, P.R.4, Tan, W.S.3, Rodney, S.3, Lechner, M.1, Freeman, A.5, Jameson, C.5, Muneer, A.4, Beck, S.1, Kelly, J.D.3

Results WES revealed 810 genes containing somatic mutations among the 27 tumours, with a mean somatic mutation rate of 30 per sample, representing 1.78 non-silent mutations per megabase (range 0.72-7.5). There was no significant association between mutational burden and tumour stage, grade or age, high viral load tumours had a significantly lower mutational load (P<0.05) when compared to HPV negative.

Table 1

small RNA

non versus metastasized (lymphogen and occult, n=38), tumour

non versus metastasized (lymphogen and occult, n=35), blood

p-value

fold-change

95% confidence interval

fold-change

95% confidence interval

mir-18a

0,008

4,10

1,70

9,85

0,05

2,4

1,1

5,2

mir-92a-1

0,007

2,38

1,41

4,02

0,008

2,7

1,4

5,1

mir-92a-2

0,006

2,43

1,42

4,16

0,008

2,8

1,5

5,2

mir-99a

0,001

0,18

0,08

0,40

0,01

2,5

1,3

4,6

mir-183

0,037

5,22

1,29

21,04

0,02

2,0

1,2

3,5

mir-296

0,007

3,89

1,71

8,87

0,01

2,3

1,3

4,0

mir-378a

0,028

2,32

1,19

4,53

0,01

2,4

1,3

4,3

mir-326

0,001

3,12

1,82

5,33

0,02

2,7

1,3

5,5

mir-331

0,003

2,81

1,61

4,92

0,01

3,0

1,4

6,3

mir-92b

0,016

3,93

1,48

10,40

0,02

2,5

1,2

5,0

ENST00000387347

0,013

2,84

1,39

5,79

0,03

3,0

1,3

7,3

Second Prize for the Best Abstract (Non-Oncology) Abstract Nr: AM15-2662 Title: Neurite outgrowth of pelvic neurons is stimulated by the neurotrophic peptide galanin

isolated from control and bilateral CN crush rats 48hrs after injury and subsequently cultured as a whole-mount explant in matrigel (Figure 1). Control MPGs were treated with culture medium(control), galanin (non-selective agonist) and M1145 (selective galR2-agonist). Injured MPGs were treated with Authors: Weyne, E.1, Hannan, J.L.2, Liu, X.2, De Ridder, D.1, Van Der Aa, F.1, culture medium (control), M40 (non-selective antagonist) and M871 (selective galR2-antagonist). Bivalacqua, T.J.2, Albersen, M.1 Neurite outgrowth was measured in both 1 experiments after 48hrs and 72hrs in culture. University of Leuven, Laboratory for Experimental Urology, Department of ANOVA was used to analyse differences in neurite E. Weyne outgrowth between treatments. Development and Regeneration, Leuven, Belgium, 2Johns Hopkins Medical Institutions, James Buchanan Brady Urological Institute, Department of Urology, Baltimore, United States of America Introduction & Objectives Erectile dysfunction remains a frequent sequela of radical prostatectomy (RP) due to neuropraxia of the cavernous nerves(CNs). Peripheral nerve regeneration is stimulated by the release of endogenous neurotrophic factors. Galanin is a neurotrophic factor transcriptionally upregulated 180-fold in major pelvic ganglions (MPG’s) of CN injured rats and also present in human CNs. Galanin has been shown to increase neurite outgrowth in sensory neurons mediated by galanin receptor 2 (galR2). In this study we investigate whether stimulation or inhibition of the galanin pathway influences regeneration of pelvic nerves in vitro. Materials & Methods Major pelvic ganglion (MPG) and the CN were

EUT Congress News

Figure 1

Figure 2

Results Mean neurite outgrowth of MPGs from control animals showed a trend towards increased outgrowth with

to EAU guidelines for antibiotic prophylaxis in all urological procedures. From January 2011 to October 2013 (period “after”), data from 3,529 urological procedures have been collected and compared with 2,619 procedures obtained before agreeing on the recommendations for best practice between December 2008 and December 2010 (period “before”). Data about the prevalence of bacterial resistance after starting the protocol of adherence to EAU guidelines were compared between the two periods. The direct and indirect costs related to symptomatic post-operative infectious complications and the prevalence of antibiotic resistant bacterial strains were the outcome measurements. Chisquare or Fisher’s exact tests were used.

A. Feber

1 UCL Cancer Institute, Dept. of Cancer Biology, London, United Kingdom, 2Queen Mary University of London, Barts Cancer Institute, London, United Kingdom, 3University College London, Division of Surgery & Interventional Science, London, United Kingdom, 4University College London Hospital, Department of Urology, London, United Kingdom, 5 University College London Hospital, Department of Histopathology, London, United Kingdom

Introduction & Objectives The incidence of penile cancer (PeCa) in western nations is relatively low, 0.5-0.8/100,000 in the UK and USA. This contrasts with developing nations where incidence rates vary from 2.3-8/100,000. Other than HPV driven transformation little is known about the molecular genetic alterations defining the development of PeCa. We sought to identify the somatic alterations driving the tumourigenesis of PeCa, by performing whole exome sequencing (WES) of 27 PeCa samples. Materials & Methods Sample Cohort. Informed consent was obtained from all subjects and ethical approval for this study was granted by the University College London (UCL) / University College London Hospital (UCLH) BioBank for studying Health and Human Disease (NC06.11). Whole-exome sequencing. Sequencing was performed using the Illumina TrueSeq or Nextrea exome capture kit according to the manufactures instructions and sequenced on a Hi-Seq2000 (Illumina). Reads were aligned to the human reference genome (build NCBI 37) using the BurrowsWheeler Aligner (BWA) . Varscan and Annoar were used to identify and annotate somatic alterations. GPS1 mutations. Constructs expressing Flag-tagged wild-type GPS1 were a kind gift from Ning Wei (Yale University). Mutations in GPS1 were made using the Q5® Site-directed Mutagenesis kit (NEB).

selective galR2-agonist treatment compared to control treatment (48h:453μm vs 367μm; 72h: 586μm vs 529μm; p>0.05). Inhibition of the galanin pathway in MPGs of injured rats with a selective galR2-antagonist resulted in decreased neurite outgrowth compared to control treatment (48h: 453μm vs 632μm; 72h: 477μm vs 708μm; p<0,05,p<0,01) (Figure 2) and this was more more pronounced than non-specific galanin inhibition. (48h: 607 μm vs 452 μm; p<0,05).

HPV high disease had significant enrichment TCW alterations, consistent with HPV induced APOBEC mutations. HPV low and negative disease had a significant enrichment of C>T alterations at CG dinucleotides, which correlates with a significant (P< 0.001) decrease in DNA methylation when compared to high viral load samples and matched normal tissue. Of the 810 mutated genes, 137 (17%) were recurrent alterations; 756(93%) have previously been identified as mutated in other tumour types. Of the recurrent mutations, TP53, FAT1 and the G-protein pathway suppressor CNS1(GPS1) were validated in an independent cohort of 70 PeCa samples. Of the novel genes identified, CSN1, was mutated in 11% and 14% of cases respectively. Recapitulation of CSN1 mutations resulted in the translocation of CSN1 to the cytoplasm and co-localization with AGO1 and AGO2-positive P-bodies and resulted in a significant inhibition of miRNA-mediated gene repression. Conclusions This study represents the most comprehensive analysis of the genetic alterations in PeCa thus far. PeCa appears mutationally quiet, suggesting that penile cancer development is driven by an intricate pattern of alterations. The identification of a strong CpG mutation signature in HPV negative tumours may suggest that changes to the epigenome (directly or indirectly) represent the major mechanism in the development in this disease. Furthermore, the identification of CSN1 mutation, and its role in aberrant miRNA processing, suggests aberrant miRNA regulation may play a key role in PeCa pathogenesis. Conclusions Inhibition of the galanin pathway in pelvic ganglion neurons resulted in decreased neurite outgrowth, whereas galanin stimulation increased neurite outgrowth in vitro. The neurotrophic action of galanin is mediated through galR2. Galanin is an important component of endogenous CN regeneration and strategies increasing galanin production could be advantageous in EF recovery following RP.

Sunday, 22 March 2015

Third Prize for the Best Abstract (Oncology) Abstract Nr: AM15-3405 Title: Extended vs limited pelvic lymphadenectomy during radical prostatectomy for intermediate- and high-risk prostate cancer: A prospective randomized trial Authors: Lestingi, J.F.P.L. 1, Pontes Jr, J., Borges, L.L., Ravanini, J., Guglielmetti, G.B., Cordeiro, M.D., Coelho, R.F., Nahas, W.C.

J. Lestingi

Institute of Cancer of State of Sao Paulo - General Hospital - University of Sao Paulo, Dept. of Urology, Sao Paulo, Brazil

Introduction: The role of extended pelvic lymph node dissection (ePLND) in treating prostate cancer (PCa) patients remains controversial, mainly by the lack of prospective randomized trials. Materials & Methods Since May 2012 until October 2014, in a single institution, 216 patients with D’Amico intermediate or high risk PCa (≥ cT2b or ≥ PSA 10 ng/mL or Gleason score ≥ 7), absence of bone metastasis and no previous radiotherapy or hormonal treatment were prospectively randomized to undergo extended or limited PLND in proportion 1:1 during radical prostatectomy. The pre-defined model of ePLND involved bilaterally chains: Obturator, external iliac, internal iliac, common iliac and pre-sacral, while the limited pelvic lymphadenectomy (lPLND) was basically represented by the obturator chain bilaterally. The surgical specimens were analyzed according to the guidelines of the College of American Pathologists,meach chain being analyzed separately. All patients signed a free and informedconsent. The study was conducted according to the protocol approved by the local committee on ethics in human investigation and is registered in Clinical Trials #NCT01812902.

Results Preoperative data were comparable between the groups and 28.11% of patients were high risk preoperatively. Mean and median follow-up were 14.4 and 13.4 months, respectively.

Third Prize for the Best Abstract (Non-Oncology) Abstract Nr: AM15-2196 Title: Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by NSC23766 and EHT1864, two novel inhibitors of the small GTPase Rac

On average, ePLND and lPLND yielded 18.8 and 3.5 nodes, respectively; lymph node metastases were found in 10.7% (11/103) and 4.4% (5/113) patients, respectively (p=0.08).

Authors: Wang, Y.1, Kunit, T.2, Strittmatter, F.1, Rutz, B.1, Ciotkowska, A.1, Waidelich, R.1, Liu, C.3, Stief, C.G.1, Gratzke, C.1, Hennenberg, M.1

The ePLND increased on average: Surgical time by 68.8 minutes; intraoperative complications and bleeding by 304 mL; and 26.8 hospital stay hours (p≤0,001).

LMU Munich, Dept. of Urology, Munich, Germany, 2 Universitätsklinikum Salzburg, Dept. of Urology, Salzburg, Austria, 3 Southern Medical University of China, Dept. of Urology, Guangzhou, China

There was no statistically significant difference between ePLND and lPLND groups in postoperative complications according to Clavien scale, 14.4% vs 11.1% respectively (p=0.116). Postoperatively, 126 patients (58.3%) were high risk (pT3/4 or Gleason ≥8); 56 patients (44.44%) underwent ePLND and 19.6% had positive nodes (PN) while rate of PN in lPLND group was 7.1% (p=0,036) There were no PN in postoperatively intermediate risk (pT2 or Gleason=7) patients. Positive surgical margin was similar between groups (p=0,977). Despite being higher in lPLND, there was no difference in biochemical recurrence (PSA ≥ 0.2 ng/mL) between groups (7.6% vs 10.1%, p=0.685) but this may be due to the short follow up time. Conclusions Extended lymphadenectomy is associated with increased morbidity (longer hospital stay, longer operating room time, intraoperative bleeding, intraoperative complications include obturator nerve or vascular injury) and tumour staging in patients with prostate cancer at high risk. The oncologic benefit can be demonstrated with a longer follow-up time.

Y. Wang

Introduction: Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the effect of two structural unrelated Rac inhibitors, NSC23766 and EHT1864, on 1) the control of smooth muscle tone in the hyperplastic human prostate, and 2) on cellular functions including cytoskeletal organization and growth of prostate stromal cells. Materials & Methods Experiments were carried out using human periurethral prostate tissues (n=65 patients) from radical prostatectomy and in an immortalized line of cultured stromal cells (WPMY-1). Expression of Rac isforms 1-3 was examined by RT-PCR, Western blot and fluorescence staining. A pull-down assay was performed to analyze Rac1 activity. Effects of the two Rac inhibitors NSC23766 and EHT1864 on contractility of human prostate strips were assessed in the organ bath. Cytoskeletal organization in WPMY-1 cells was visualized by Phalloidin staining, while cell growth was assessed using an EdU assay.

Results Protein and mRNA expression of Rac isoforms 1-3 was observed in prostate samples from each patient being included to this analysis, and in WPMY-1 cells. Immunoreactivity for all Rac isoforms was located to the stroma, where it colocalized with the smooth muscle marker calponin. The pull-down assay indicated a decrease in Rac1 activity after incubation of WPMY-1 cells 2 h with NSC23766 (100 μM) or EHT 1864 (25 μM). In the organ bath, both NSC23766 (100 μM) and EHT1864 (100 μM) significantly reduced contractions of prostate strips induced by noradrenaline (p<0.01 – p<0.02 for NSC23766 vs. ethanol, n=8; and p<0.004 – p<0.01 for EHT1864 vs. water, n=10), phenylephrine (p<0.01 – p<0.02 for NSC23766 vs. ethanol, n=8; and p<0.01 – p<0.04 for EHT1864 vs. water, n=7), or electric field stimulation (p<0.05 for NSC23766 vs. ethanol, n=7; and p<0.002 – p<0.02 for EHT1864 vs. water, n=6). In WMPY-1 cells, application of NSC23766 or EHT1864 induced cytoskeletal deorganization: while cellular shape of control cells was characterized by many long and thin protrusions containing bundles of actin filaments, this structure collapsed after treatment with NSC23766 or EHT1864. Finally, NSC23766 or EHT1864 reduced proliferation of WPMY-1 cells. This decline was progressive, with the rate of proliferating cells being significantly lower after 72 of incubation than 24 h after incubation. Conclusions Both Rac inhibitors, NSC23766 and EHT1864 reduce human prostate smooth muscle contraction, and impair growth of stromal cells. This indicates that Rac may be a link, connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Urodynamic effects of Rac inhibitors appear possible.

1st European da Vinci Xi Live Surgery In Urology Please join our parallel live surgeries on

Sunday, 22nd March 14:00 - 17:00 Room Milan Moderators

Walter Artibani • Verona, Italy Ben Challacombe • London, UK

Live da Vinci® Xi Partial Nephrectomy Surgery with Firefly™ Fluorescence Imaging with Live Narration Operating Surgeon Alexandre Mottrie • Aalst, Belgium

Live da Vinci® Si Advanced Prostatectomy with Extended Lymphnode Dissection Operating Surgeon Henk van der Poel • Amsterdam, The Netherlands

All surgery presents risk. While clinical studies support the use of the da Vinci® Surgical System as an effective tool for minimally invasive surgery for specific indications, individual results may vary. Patients and doctors should review all available information on non-surgical and surgical options in order to make an informed decision. For complete technical information, including indications for use and full cautions and warnings, please refer to the da Vinci Si, da Vinci Si-e and da Vinci Xi Surgical System instructions for use, Instrument & Accessory, Single-Site and Firefly instructions for use and other product information. © 2015 Intuitive Surgical, Inc. All rights reserved. PN 1016607-EU Rev A 1/15

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Sunday, 22 March 2015

1/23/15 11:44 AM

EUT Congress News

Large prostates: Knife or laser? Laser techniques abound but level of evidence has not been sufficiently assessed Dr. Jean-Nicolas Cornu Tenon Hospital, Paris (FR)

80-100 grams) is a particularly debated point, as some urologists are confident in treating those with new laser techniques, while others advocate for simple prostatectomy. What does the literature say? In the case of large prostates, today’s surgical approaches using laser devices aim either at enucleate or at vaporize prostatic issue.

Lower urinary tract symptoms due to benign prostatic obstruction (LUTS/BPO) are a common disease in men over 50 years of age. It is seen as a chronic medical condition, mostly due to an enlarged prostate gland generating bladder outlet obstruction. In case of moderate to severe symptoms and significant bother, medical intervention is required. If the vast majority of patients are treated with oral medications, a number of patients need to be surgically treated with the main objective of relief of the obstruction1. The surgical armamentarium for surgical relief of BPO has changed in the past decades with the introduction of laser therapy. Lasers (including Holmium, Greenlight™, Thulium, Diode, etc.) have been shown to be useful tools for tissue ablation (via enucleation, vaporization, or resection of the prostatic tissue), and a number of standardized techniques (HoLEP, ThuLEP, PVP) are now seen as valuable alternative to the old standard techniques (transurethral resection of the prostate (TURP) using electricity, and open simple prostatectomy (OSP))2. However, all laser techniques have not been assessed with the same level of evidence. Furthermore, the choice of the best technique for each patient (tailored treatment according to pre-operative patient characteristics) remains quite unclear. The case of “large prostates” (namely, over

Enucleation technique (whatever the type of laser considered) is based on removal of the “adenoma” by transurethral approach. Namely, after the identification of the plane between the prostatic tissue and the prostatic capsule, the adenoma is enucleated progressively and pushed in the bladder, before morcellation of the prostatic tissue once it has been switched in the bladder. This procedure is thought to be similar to what is done using the index finger during OSP. Hence, the anatomical results awaited after laser enucleation of the prostate (in terms of tissue ablation) are the same as those obtained after OSP. That said, the scientific challenge is to establish this non-inferiority of laser enucleation compared to OSP, while showing potential advantages in terms of complications (intraoperative as well as during follow-up) and costs. HoLEP has been compared to OP in several high quality studies, showing a significantly longer operating time for HoLEP, but a shorter hospital stay, a reduced risk of intraoperative and immediate post-operative bleeding/transfusion2. Efficacy and complications in the long term has been stated to be similar after HoLEP and OP, leading to a very strong statement in the current revised version of the EAU Guidelines on the treatment of benign prostatic obstruction that mention HoLEP as a standard/first choice option in patients with large prostates1.

Vaporization technique is mainly conducted using the Greenlight™ laser, to produce a photovaporization of prostatic tissue until the prostatic capsule. If Greenlight™ PVP has been compared to OP in one rather old randomized controlled trial2, its feasibility in large prostates has been mainly established in contemporary case series, with a limited number of cases and short-term follow-up. Thus, high quality evidence supporting the use of prostates over 100 mL is missing, particularly with the last version of the device (XPS 180W Greenlight™ laser). The recent introduction of Greenlight™ enucleation may put this device back in the game, but further research is necessary. What do people do in current clinical practice? Recent epidemiological data have shed new light on the issue of the use of laser and OP in current clinical practice. In France, where the National Health Insurance records allow the monitoring of the number of surgeries each year during 2004, it has been shown that the use of OP is rather decreasing with time. Indeed, while the total number of BPO surgeries remained stable over the last 10 years, the number of OPs has been reduced by a third in the last years (mainly because of the introduction of laser techniques on the market)3. These data, as well as those coming from the United States and Asia are showing that the respective share of each technique is progressively evolving, but not stabilized. Bipolar energy, laparoscopy and robotics: a third way? Besides the use of HoLEP, some other options have been established as an alternative to OP, including plasmakinetic enucleation of the prostate (PKEP) and bipolar enucleation of the prostate (TUEB). Indeed, the use of bipolar energy allows irrigation with saline instead of glycine, freeing the surgeon from any risk of TURP syndrome. However, the results published to date for big prostates,

comparing PKEP and TUEB to OP for large prostates are limited with respectively two and one randomized controlled studies, with a limited 12 months follow-up2. Some authors proposed to do OP by laparoscopic approach, either robot-assisted or not. Technical demonstrations and feasibility of these surgical options have been published, but limited evidence exists, especially regarding operative time and costs compared to OP via open approach4. Again, the results awaited are similar to those obtained with traditional OP. Conclusion OP via traditional approach is the oldest surgical option for BPO relief and stands the test of time, being still practiced all around the globe, including the western world. However, enucleation of the prostate by endoscopic approach (namely HoLEP) has come of age and is the number one alternative. HoLEP and other potential competitors (including bipolar techniques and other lasers for enucleation) will progressively turn the “gold standard” into an “old standard.” However, even within the area of “large prostates,” the treatment decision has still to take into account patient characteristics (anesthesia, cardiovascular risk), patient’s preferences and willingness to accept surgery-associated side effects, availability of the treatment, costs, and surgeon’s experience with the technique. Editorial Note: Due to space constraints the Reference List has been excluded. Interested readers can email a request for the complete list at EUT@uroweb.org. Sunday, 22 March 10.30-12.00: Thematic Session 3 Male LUTS, State-of-the-art lecture

Your single source in Endourology

Special portfolio for: Ureterorenoscopy PCNL Cystoscopy ESWL

Scan the code for further information www.richard-wolf.com/highlights/disposables

We are looking forward to your visit at our booth F 42.

Disposables by Richard Wolf

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05.03.2015 16:16:55

Sunday, 22 March 2015

Guidelines in the jungle of new media How to use, behave and interact when employing social media tools Prof. James Catto Academic Urology Unit University of Sheffield Sheffield (GB)

Dr. Kate Linton Academic Urology Unit University of Sheffield Sheffield (GB)

Social media (SoMe) has radically changed the way that people interact over the last decade. This new digital landscape includes wikis, blogs, photograph sharing sites, YouTube™, LinkedIn™ and social networking sites such as Facebook™ and Twitter™. These new digital media open up a wealth of exciting opportunities in our professional lives and are constantly evolving. The use of social media in medicine is ubiquitous and urology as a specialty has embraced it in its many forms. Using social media effectively as a clinician There are numerous ways to harness the power of social media to enhance your clinical life. Keeping up to date with new developments or newly published literature is one advantage of these new digital technologies. Twitter, a micro-blogging service can be used very effectively for this purpose. Twitter users can either follow leaders in the field that you are interested in, or search via hashtags for tweets on a particular topic.

Twitter is also useful for inter-continental interaction and crowd-sourcing opinions on a range of topics. Facebook can be used not just for keeping in touch with friends; journals such as European Urology and BJUI have a presence there, as does the European Association of Urology (EAU). Blogs (a contraction of weblog) are discussion or information websites, which can be used to discuss pertinent topics.

The BJUI have a blog that many urologists have contributed to on a wealth of topics, and is also where the blog of the monthly International Urology Journal Club #urojc is published. YouTube is a video-sharing site that can be used to share presentations, interviews and videos of surgical techniques. Getting started Start off low-key, observe for a while how others behave and interact. Ask others who are more prolific users if you need help getting started. Conferences often have help desks where you can get social media help if you are new to it. Conferences are a great place to get started, particularly with twitter as you can follow the conference hashtag, tweet about the sessions you are attending, and interact with colleagues. Often, conferences have teaching courses on how to use social media, e.g. BAUS 2013 and EAU 2014 both had social media teaching courses. For those starting in the social media world, the European School of Urology will run hands-on teaching sessions during this congress. These can be booked through the ESU office and include tutorage from various experienced urologists. How to behave One of the problems with social media platforms, and in fact all digital communication, is that they can be disinhibiting, and so communication and behavior can become more informal than in other forms of communication. There are risks regarding the use of social media and boundaries can become blurred and so now there are several publications to guide appropriate behavior. The EAU has published recommendations regarding the appropriate use of social media (Roupret et al 2014). The following are some tips:

Many of the major journals now have a twitter presence including European Urology (@EUPlatinum), British Journal of Urology International (@BJUIjournal) and The Journal of Urology (@JUrology), or 1. Generally it is advisable to use your real name associations can be followed such as the European rather than a pseudonym, particularly if you are Association of Urology (@Uroweb) or the American making it clear that you are a doctor. Urological Association (@AmerUrological). Busy 2. Make it clear that your posts represent your views clinical practice reduces the number of conferences and not those of your institution, a disclaimer in that can be attended; however, twitter can be used as your profile addresses this nicely. a way to keep up with events and breaking news from 3. You should assume that anything you post is conferences by following hashtags e.g. #EAU15 or permanent and can be referred to and published #AUA15, as a form of virtual attendance. in the future by others. Tweets are citeable and can be published in manuscripts. Journal clubs have now become global with the aid of 4. Think before you post, restraint may be required twitter, the International Urology Journal Club on regarding what you post, particularly if you are Twitter #urojc is now into its third year and shows no angry or passionate about something. Assume sign of losing momentum. As of 24th January 2015 the your employers and patients are reading it. journal club had 2,779 followers, and has produced Whatever your privacy settings, never assume several publications, including its 12-month that your posts will remain private. experience (Thangasamy et al 2014) and also letters to 5. Do not break patient confidentiality; don’t post images or comments that could lead to the editors of two journals whose papers had been identification of a patient. Although blogs and web discussed at the journal club (Linton and Woo 2014 forums can be used for discussion of clinical and Thangasamy and Woo 2014). practice, our ethical duties regarding confidentiality and privacy of patients apply to digital media as well as other forms of communication. 6. Keep strict boundaries regarding patients, don’t accept current or former patients as friends on Facebook, and if they follow you on Twitter, don’t follow them back. 7. Be cautious regarding mixing professional and personal content. Some clinicians have separate SoMe accounts for professional and personal use. Always consider what effect the posting of personal content has on your professional profile. Consider using privacy settings on personal accounts. 8. Always be honest, professional and respect the opinion of others, your behavior reflects not only on yourself but also on your profession. 9. Try to be accurate regarding your posts, citing or linking to your sources enhances your post, particularly if your post is regarding a recently published manuscript. 10. Quality is more important than quantity; posting in a timely manner enhances what you post. Figure 1: Screenshot of European Urology Twitter feed showing how manuscripts are linked and hashtags of different topics are used, so that followers of that hashtag would find the link to the manuscript.

Sunday, 22 March 2015

Most importantly enjoy the opportunities that these new digital media have to offer. Many collaborations have been formed and friendships made due to the interactions using these technologies.

Social media platforms can be disinhibiting leading users to be more informal in their communication and behavior compared to other forms of communication.

References Rouprêt M, Morgan TM, Bostrom PJ, Cooperberg MR, Kutikov A, Linton KD, Palou J, Martínez-Piñeiro L, van der Poel H, Wijburg C, Winterbottom A, Woo HH, Wirth MP, Catto JW. European Association of urology (@Uroweb) recommendations on the appropriate use of social media. Eur Urol. 2014 Oct;66(4):628-32 Thangasamy IA, Leveridge M, Davies BJ, Finelli A, Stork B, Woo HH. International Urology Journal Club via Twitter: 12-month experience. Eur Urol. 2014 Jul;66(1):112-7 Linton KD, Woo HH; Twitter International Urology Journal Club. Complications of prostate cancer treatment. Lancet Oncol. 2014 Apr;15(4):e150-1 Thangasamy I, Woo HH; Twitter International Urology Journal Club. Re: Eija Laurikainen, Antti Valpas, Pauliina Aukee,

et al. Five-year results of a randomized trial comparing retropubic and transobturator midurethral slings for stress incontinence. Eur Urol 2014;65:1109-14. Eur Urol. 2014 Sep;66(3):e55

Using social media: practical and ethical guidance for doctors and medical students. BMA 2011 Monday, 23 March 10.30-12.00: Thematic Session 19 Controversies in the management of bladder cancer Point-counterpoint session: Social media and urology

S a t e l l i t e S y m p o s i u m Saturday March 21st 2015 Chairman: N. Clarke (United Kingdom)

Alternative approaches to individualised care

in prostate and bladder cancers M. Ribal (Spain)

Do we have new markers beyond PSA for diagnosing primary prostate cancer? Professor Ribal discussed the current status of biomarkers for the diagnosis of primary prostate cancer, starting with a brief review on what is expected from a biomarker in prostate cancer. The diagnostic value of PSA was outlined and how newer developments such as Prostate Health Index might be of use clinically. Other recent biomarker approaches were discussed in detail, including urinary- (PCA3 and TMPRSS2-ERG) and tissue-based methods (Oncotype Dx and Prolaris). Professor Ribal concluded that while PSA will continue as a first-line marker, other markers such as Prostate Health Index and PCA3 are increasingly showing their usefulness in clinical settings. Looking towards the future, Professor Ribal suggested that we can only expect noninvasive diagnostic biomarkers to be improved upon.

Y. Loriot (France)

Beyond the androgen receptor – future therapeutic approaches in complex metastatic castration-resistant prostate cancer Doctor Loriot provided an overview of newer therapeutic options currently available for the treatment of metastatic castration-resistant prostate cancer and their benefits, noting limitations too, including therapeutic resistance. There was discussion that through a better understanding of molecular events behind prostate cancer, there should be focus on biomarker development, the mechanisms of resistance and targeted therapies. Doctor Loriot highlighted several new therapeutic approaches, beyond the androgen receptor, including targeting cell survival pathways and the tumour microenvironment.

J.A. Witjes (The Netherlands)

Can the combination of better tumour visualisation and en-bloc resection lower recurrence rates in NMIBC? At the start of his presentation, Professor Witjes sought the opinion of the audience on the need for innovation in treatment strategies in NMIBC. Following this, Professor Witjes reviewed many of the recent advances in tumour visualisation and en-bloc resection in NMIBC. These included blue light to improve tumour detection and facilitate complete resection, and technical developments, such as hydrojet en-bloc resection. The presentation concluded that en-bloc resection seems to be a safe and feasible option to potentially decrease recurrence rates and that optimal visualisation guided by blue light is necessary. TOPIC OF THE YEAR 2015

The Bladder Cancer Topic of the Year was voted on and announced during the IPSEN-sponsored EAU 2015 Symposium. If you would like further details regardingthe selected Topic of the Year, please visit the IPSEN booth.

EUT Congress News

Today’s European Urology Events Writing course March 22nd

‘How to write a manuscript and get it published in European Urology’.

Platinum hour

Learn the best tricks and tips form a distinguished list of world renowned authors acting as faculty. 1. How to get your manuscript published in European Urology. J.W.F. Catto, Sheffield (UK) 2. Why publishing (and publishing in European Urology) is important for you. C. Gratzke, Munich (DE) 3. Clinical research original article: How to write an article and get it published in European Urology. M.R. Cooperberg, San Francisco (US) 4. Common problems and potential solutions. J.W.F. Catto, Sheffield (GB) 5. The importance of statistical design and analysis. A.J. Vickers, New York (US)

6. How to write a basic research article to be relevant for the readers of European Urology. J-N. Cornu, Vincennes (FR) 7. How to write the perfect Twitter Text. A. Kutikov, Philadelphia (US) 8. Surgery in Motion: How to combine the best possible manuscript and video for the Surgery in Motion Section. A. Mottrie, Aalst (BE) 9. How to review a paper for European Urology. S. Boorjian, Rochester (US) 10. Questions and answers. J.W.F. Catto, Sheffield (UK) To be held in room N111-112 , from 8.30-11.30

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 #A01. Daily from 16.00 to 18.00

March 21st - 23rd

Platinum picture perfect

Please come to the European Urology booth #A01 and have your Platinum Postcard created and posted online. Daily from 10.00 to 18.00 View your picture on europeanurology.com/madrid

March 21st - 23rd

europeanurology.com 26

EUT Congress News

Sunday, 22 March 2015

ERAS care pathway aids patient’s rehab Nurses play a crucial role in ERAS programmes Maria Anna Risolo, RN Hospital San Raffaele Dept. of Urology Milano (IT)

Mechanical bowel preparation is associated with dehydration, electrolyte loss, major septic complications, prolonged hospitalisation, delayed restoration of canalisation, and increased stress (Holt et al., 2004). In the ERAS pathway, mechanical bowel preparation is absent or at least selective.

Enhanced Recovery After Surgery (ERAS) is a type of perioperative care pathway that aims to minimise metabolic stress and postoperative organ dysfunction and quickly restore the patient’s autonomy.

To achieve better control of surgical stress, ERAS patients receive a dose of glucose the night before the operation, and two hours before surgery. Fasting is only necessary from six hours before surgery for solid food, and from two hours for fluids. This reduces the patient’s sense of thirst and hunger, catabolism of fats and proteins because of gluconeogenesis, and insulin resistance, as well as loss of proteins and muscles, thus reducing length of stay (Thorell et al., 1999).

ERAS programs have been shown to reduce hospital length of stay, improve cardiopulmonary function, and lead to an earlier return of bowel function and resumption of normal daily activities (Melnyk et al., 2011).

In ERAS patients, pre-operative medication with long half-life drugs like opioids, sedatives and hypnotics, fosters post-operative recovery, mobilisation, and return to a normal diet (Moiniche, Kehlet, and Dahl, 2002).

The key concepts of all ERAS programmes are preoperative counselling, preoperative nutrition, avoidance of preoperative fasting and carbohydrate loading up to two hours preoperatively, standardised analgesic and anaesthetic criteria, and early mobilisation (Weimann et al., 2006). The components of ERAS are shown in Figure 1.

Regarding anaesthesia, analgesics and epidural anaesthetics are preferred, because they have less side effects when compared to general anaesthesia (e.g. reduction of post-operative sedation, nausea and vomiting) (Walker and Smith, 2009). Furthermore, the level of the spine in which the epidural catheter is placed allows optimising pain control (Moiniche, Kehlet, and Dahl, 2002).

Figure 1: Schematic diagram of the ERAS pathway

It is known in literature that patients receiving preoperative counselling are less anxious and report lower pain levels, require less analgesic drugs, recover faster and have shorter hospital stay (Blazeby et al., 2010).

“ERAS improves several fundamental surgical outcomes, thus reducing patient’s discomfort and hastening the resumption of their daily activities.”

In the ERAS pathway, preoperative counselling is provided at least 15 days before the patient’s admission, and allows the collection of information that will be used to set-up proper nursing strategies during the patient’s hospitalization. In this first phase, Particular attention is paid to intravenous fluids, since the patient’s role in the recovery process is also overloading the patient would increase pre-load and discussed. after-load, resulting in fluids and sodium

accumulation in extravascular spaces. This influences bowel function recovery and causes intolerance to oral fluid intake, gut micro biota translocation, oedema, mobilisation difficulties, and reduction of tissue oxygenation with possible increased risk of fistulae (Nisanevich et al., 2005).

delay the healing of surgical wounds and 90-day mortality (Melnyk et al., 2002). In conclusion, ERAS improves several fundamental surgical outcomes, thus reducing patient’s discomfort and hastening the resumption of their daily activities. Nurses play an important role in ERAS programmes. Don’t miss out on the lecture that will focus on this hot topic during this congress!

Hypothermia is strictly controlled in ERAS patients since it leads to bradycardia and to a reduction of the Editorial Note: Due to space constraints the liver’s detoxification capacity, glomerulal filtration rate, activity of coagulation factors, and cerebral blood bibliography has been excluded. Interested readers flow. It also contributes to respiratory centres can email at EUT@uroweb.org for the list. depression and triples the risk of infections (Scott and Buckand, 2006). Sunday, 22 March 14.45-16.45: Workshop 10, 16th International EAUN Meeting In ERAS pathways, early mobilisation reduces the risk of thromboembolism and prevents paralytic Market place session: Rehabilitation in urology cancer care ileus. Early feeding reduces infection rates since it prevents the onset of catabolic processes, which

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TP 51 2.0 03/2015/A-E

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Sunday, 22 March 2015

EUT Congress News

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Sunday, 22 March 2015

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3/9/15 10:12 AM

EAU Patient Information launches materials on PCa The clear and reliable information is a useful tool for doctor-patient dialogue The EAU continues to expand its tools for improving overwhelming for patients to see which option is best relations between doctors and patients in Europe and for their individual situation.” around the world. EAU Patient Information gives a comprehensive A comprehensive set of EAU Patient Information overview of all established and evidence-based leaflets on Prostate Cancer is now available online. treatment options for the various stages of prostate The leaflets can also be downloaded for offline use. cancer. Patients can find the most current information This new publication is an important milestone, given on treatment options on the easy-to-navigate website, the need for clear and reliable information on as well as in the printable leaflets. prostate cancer. By addressing possible side effects and the impact on “The prevalence of prostate cancer in the average the quality of life of each treatment modality, this urology practice makes this topic particularly suited information set helps patients to understand their for patient-oriented information,” explained Prof. treatment options better and enables them to make Thorsten Bach (DE), EAU Patient Information Project the right decision together with their doctor. Consultant. “For one thing, multiple interest groups publish information about potential treatment options For doctors, the custom-made illustrations provide an or even cures. excellent tool to talk about procedures with each patient. These publications range from serious information to low-level commercial advertisements concealed as “EAU Patient Information gives patient information. Most people are not able to distinguish between the high-quality and the a comprehensive overview of all misleading information,” Bach continued. EAU Patient Information on Prostate Cancer guarantees that the provided information is reliable and unbiased. The leaflets are written by medical doctors, nurses, and patients, and present the most up-to-date information on diagnosis, treatment, and support for prostate cancer patients. The quality of the information is ensured, as the information is completely in line with the latest version of EAU Guidelines on Prostate Cancer. The works are complemented with insights from nurses and patients, particularly in the topics of posttreatment care and support. Bach: “Another difficulty for many prostate cancer patients and the people close to them is understanding the great variety of possible treatment modalities. Each treatment pathway has its advantages and disadvantages and it can be

EUT Congress News

established and evidence-based treatment options for the various stages of prostate cancer.”

The leaflets can be downloaded as a set or separately for each stage of the disease, allowing for flexibility during the consult. “This set-up is designed to allow patients to ask the right questions during consultation,” said Bach. The initiative relies on medically-approved translations of the materials into languages as diverse as Spanish, Latvian, and Turkish, which allows more patients in Europe and beyond to benefit from the material. The first translations of Patient Information on Prostate Cancer will appear later this year. Visit the website at http://patients.uroweb.org/prostate-cancer

Sunday, 22 March 2015

What’s on in Madrid this week? Let Madrid entertain you! Madrid in March is anything but predictable. With the city’s numerous museums, world-class cuisine and entertainment, its bustling nightlife and rich cultural heritage, both first-time and veteran visitors will have a hard time planning an itinerary for a few days. Below are a few tips from Madrid’s Tourism Office on what’s happening in Spain‘s premier city:

Watch him live and listen to him singing his greatest hits: ‘Bodies’, ‘Eternity’, ‘Angels’, ‘Supreme’ and many others.

Teatralia, On-going until 29 March The best international and Spanish creations for children and younger audiences are returning to Teatralia, the International Festival of Performing Arts for Children and Young People in Madrid, with a view to fostering a love of the theatre among younger audiences. The Festival is marking its 19th edition with a Big Bang Data, On-going until 24 May four-week programme in Robbie Williams “Let Me Entertain You Tour ” concert on 25 March at the Barclaycard Center Big Bang Data is a project that explores the explosion which Teatralia will be of data brought about by the new technologies. filling the stages of Individuals generate data that are increasingly easy to Madrid with private, personal themes. In the Thyssen-Bornemisza store and process, revealing users’ behaviour and performances dedicated to the disciplines of magic, Museum, you’ll also find the woodcut illustrations consumption patterns. The project gathers the work of dance, music, puppetry, shadow theatre and artists Christopher Baker, Chris Jordan, Ingo Gunther, numerous multidisciplinary projects, 12 of which will Dufy made for Guillaume Apollinaire’s book of poems Bestiary, or The Parade of Orpheus. Erik Kessels, David Bowen, Aaron Koblin, Eric Fischer, be showing for the first time in Spain. Performances the creative staff at Near Future Laboratory and by 19 national and international companie from Ellas Crean, On-going until 12 April Bestiario, and several researchers, activists, Mexico, Argentina, Zimbabwe, Kenya, Denmark, To commemorate International Women’s Day (8 designers, teachers, analysts, cartographers, Spain, France, Italy, and the Czech Republic. March), Madrid hosts the female creation festival, engineers, architects, programmers, journalists, etc. Ellas Crean. This is a cultural event marking its 11th Raoul Dufy, On-going until 17 May edition in 2015 with a full multi-disciplinary Robbie Williams, 25 March Raoul Dufy focuses on the more intimate, selfprogramming that includes concerts, debates, theatre, Madrid is the city chosen by Robbie Williams to begin reflective works by the French painter, whose his Let Me Entertain You Tour. The Barclaycard Center best-known paintings embody a vivid sense of joie de dance, exhibitions and film screenings. The festival will be waiting for him on March 25. Ten years after vivre. The exhibition at Thyssen-Bornemisza Museum has included the participation of over 600 artists such as Yuja Wang, Cecilia Bartoli, Marianne Faithfull, Jane his last trip to Spain, Robbie will return to visit Madrid includes a group of lesser-known paintings by Dufy. Birkin, Ana María Matute, Ángeles Caso, María and Barcelona. Then the tour will take him to France, The French artist painted scenes, mostly in the Dueñas, Icíar Bollaín or Inés París. Detailed Lithuania, Russia, Poland, Slovakia, Austria and Israel, seaside, marked by the joy and pleasure of everyday among other countries. life. Later in his career, he became more interested in information at Conde Duque. White Fire, Renia Sofia Museum, On-going until 14 September With the Kunstmuseum Basel undergoing renovation, the Reina Sofía Museum (MNCARS) will run a travelling exhibition containing more than 100 masterpieces in the Swiss museum’s collections from the 19th, 20th and 21st centuries. On show are modern and contemporary paintings by artists such as Edvard Munch, Wassily Kandinsky, Pablo Picasso, Juan Gris, Fernand Léger, Georges Braque, Le Corbusier, Jean Dubuffet, Alberto Giacometti, Yves Tanguy, Max Ernst, Paul Klee, Piet Mondrian, László Moholy-Nagy, Gerhard Richter and Mark Rothko, among many others.

Temple of Debod This is an Egyptian temple dating back to the 2nd century BC, transported to Madrid’s Cuartel de la Montaña Park. The temple was donated to Spain by the Egyptian government to save it from floods following the construction of the great Aswan Dam. Works on the temple began at the beginning of the 2nd century BC at the orders of the Meroë King Adijalamani, who built a chapel dedicated to the god Amun and the goddess Isis. This chapel was decorated with high reliefs. Subsequent kings of the Ptolemaic dynasty built new rooms around the original core, thereby enlarging the temple. Where: Calle Ferraz, 1, Princesa/Free admission Info at: http:// templodedebod.memoriademadrid.es/ Source: Madrid, Official Tourism Website

In the last year the European Association of Urology (EAU) and Elsevier have successfully collaborated in various projects, under the banner of the EAU’s scientific journal European Urology. By providing freely accessible educational platforms, the aim is to increase clinical knowledge in a specific medical specialty by disseminating important new research and clinical developments more broadly.

Sunday, 22 March 2015

EUT Congress News

Nocturia: Control the cause. Restore the night.

SLEEP, E MORE C URBAN T S I D LESS

DESMOPRESSIN ORAL LYOPHILISATE

Nocturnal polyuria occurs in the majority of patients with nocturia. 1 By causing the kidneys to produce less urine, Minirin® Melt significantly reduces nocturnal voids in patients 2 by selectively acting on vasopressin 2 receptors in the kidneys to concentrate urine. Abbreviated Prescribing Information: Prescribing information and indications may vary from country to country. Contact the local Ferring representative for country specific prescribing information. Presentation: MINIRIN® Melt is presented as oral lyophilisates containing 60 μg, 120 μg or 240 μg desmopressin. The oral lyophilisates are white, round, and marked with one, two or three drop shaped figures on one side for the strengths 60 μg, 120 μg and 240 μg respectively. MINIRIN® Melt also contains gelatin, mannitol and citric acid, anhydrous. Indications: Central Diabetes Insipidus; Primary Nocturnal Enuresis in patients (from 5 years of age) with normal ability to concentrate urine; and symptomatic treatment of Nocturia in adults, associated with nocturnal polyuria (i.e. nocturnal urine production capacity exceeding bladder capacity). Dosage and method of administration: Central diabetes insipidus: The normal daily maintenance dose in adults and children is 60 μg – 120 μg administered sublingual three times daily. Primary nocturnal enuresis: The recommended dose is 120 μg – 240 μg administered sublingual at bedtime. Nocturia: The recommended initial dose is 60 μg

administered sublingual at bedtime. The dose may be increased up to 120 μg and subsequently 240 μg by weekly dose escalations. The initiation of treatment in elderly (over 65 years old) is not recommended. Contraindications: Habitual or psychogenic polydipsia (resulting in a urine production exceeding 40 ml/ kg/24 hours); A history of known or suspected cardiac insufficiency and other conditions requiring treatment with diuretics; Moderate and severe renal insufficiency (creatinine clearance below 50 ml/min); Known hyponatraemia; Syndrome of inappropriate ADH secretion; Hypersensitivity to desmopressin or the excipients. Warnings: When used for primary nocturnal enuresis and nocturia indications, the fluid intake must be limited to a minimum from 1 hour before until 8 hours after administration. Treatment without concomitant reduction of fluid intake may lead to water retention and/or hyponatraemia with or without accompanying warning signs and symptoms (headache, nausea/vomiting, weight gain, and, in severe cases, convulsions). Precautions: Severe bladder dysfunction and outlet obstruction should be considered before starting treatment. Elderly patients and patients with low serum sodium levels may have an increased risk of hyponatraemia. Treatment

For the treatment of nocturia in adults associated with nocturnal polyuria 2 with desmopressin should be interrupted during acute intercurrent illnesses characterised by fluid and/or electrolyte imbalance (such as systemic infections, fever, gastroenteritis). Precautions to avoid hyponatraemia including careful attention to fluid restriction and more frequent monitoring of serum sodium must be taken in case of concomitant treatment with drugs, which are known to induce SIADH, e.g. tricyclic antidepressants, selective serotonine reuptake inhibitors, chlorpromazine and carbamazepine, case of concomitant treatment with NSAIDs. Side effects: Primary nocturnal enuresis & diabetes insipidus: Common: Headache, abdominal pain and nausea. Very rare: Hyponatraemia. Nocturia: The most frequent during dose-titration: Headache, nausea, abdominal pain, hyponatraemia, dizziness, and dry mouth. The most frequent in long-term treatment: Headache, dizziness, peripheral oedema, micturition frequency, nausea, and weight increase. Legal category: POM. Date of preparation: May 2005. Ferring International Center S.A. Chemin de la Vergognausaz 50, 1162 Saint-Prex, Switzerland. Reference: 1. Weiss et al. J Urol 2011;186:1358-1363 2. Minirin SmPC

Minurin no está autorizado en España para la indicación de nocturia 32

EUT Congress News

Day 2 – SUNDAY- MINIRIN Nocturia Ad (HUG) v5.indd 1

Date of preparation: January 2015 MN/1919/2014/ECOc

Sunday, 22 March 2015

29/01/2015 12:01