EUT Congress News - Monday 27 March by European Association of Urology (EAU)

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32nd Annual Congress of the European Association of Urology

Monday, 27 March 2017

London, 24-28 March 2017

Activating patients is key to enhanced recovery Plenary Session 3: Redefining contemporary bladder cancer care By Loek Keizer

more empowered and they will move around more. Our data shows that ERAS can make massive changes Prof. James Catto (GB) was one of the closing speakers to patient care with no change to the cancer outcome.” of the third Plenary Session at EAU17, speaking with Win-win great enthusiasm about the post-cystectomy ‘ERAS’ Speaking after the session, Catto explained that approach to patient care. Plenary Session 3 was another key part of this approach has to do with mainly focused on bladder cancer and featured case challenging dogmas. “In some cases we do more discussions, debates and state-of- the-art lectures. harm than good. Things like bowel preparation, Enhanced Recovery After Surgery, or ERAS, is a traditional pain relief techniques, changes in fluid pragmatic approach to patient care that can be intake: these are big changes for the patient without summarised in three core philosophies: “Do as much any clear benefit. I tell my patients that their body will as possible outside of the hospital; do as little as be running a marathon. We want a well-fed and fit patient, not one that is already tired and weak from possible to the patient; and activate the patient,” Catto summarised. “Cystectomy patients are generally fasting going into surgery.” elderly, not in good shape, and smokers. By encouraging ‘pre-habilitation’, we prepare patients This approach is certainly not limited to Sheffield: for surgery and a better recovery, for instance by “We might have started with this approach relatively getting them to walk for one to two hours every day.” early some 10 years ago, and we’ve perhaps applied it more systematically. Generally speaking we’re all on the same page, worldwide. There was a randomised “Following surgery, patients are also activated relatively soon. To reduce discomfort, use of trial in Germany five years ago, and in turn we learned lessons from other surgical disciplines. A lot nasogastric tubes and non-essential drainage should of the early lessons were learned from Swedish be minimised. Even by dressing patients in their colorectal surgeons.” regular clothes after a few days, they already feel

low-grade bladder tumours. Prof. Maximilian Burger (DE) defended the EAU Guidelines’ recommendations for a five-year follow-up period, arguing that cystoscopy doesn’t harm patients, it is the safest way to avoid recurrence, and crucially, pathologists’ assessments are sometimes wildly divergent and cannot always be trusted blindly.

Profs. Rouprêt (FR) and Palou (ES) chaired Plenary Session 3 on the third day of EAU17

Aside from having fitter patients who are more comfortable due to less invasive recovery, there are advantages for hospitals too. Particularly in the UK, where budgets are limited in the NHS, urologists can do more work with the same resources. Guidelines on BCa: EAU or NICE? The realities of costs were also a big theme in the debate about follow-up beyond 12 months for

Mr. Hugh Mostafid (GB) in turn defended the NICE recommendations, stating that they take cost into account from the outset, achieving maximum results with limited resources: “Whereas the EAU Guidelines are about achieving ideal medical results, NICE deals with the realities of the NHS.” Mostafid also pointed to data showing that follow-up may also be useful beyond five years, arguing that the five-year cut-off could be considered arbitrary, being based on retrospective, non-randomised data. Questions by moderator Prof. Brausi (IT) about specific hypothetical cases (for instance, a heavy smoker) caused both debaters to agree that their respective guidelines were just that: guidelines that leave enough space for urologists to make exceptions at their discretion on a case-by-case basis.

Updates on managing Expert challenges expert Benign Prostatic Enlargement Emerging treatments challenge standard approaches By Joel Vega Emerging treatment strategies and unresolved diagnostic issues in Benign Prostatic Enlargement (BPE) were taken up yesterday during Plenary Session 4 where a mix of state-of-the-art lectures, debates and case discussions provided a comprehensive update to functional urology specialists. “The aim of this session is to provide not only a comprehensive update on emerging novel therapies for BPE but also to identify areas where issues remain unresolved and examine those that offer innovative approaches,” said EAU Secretary General Prof. Chris Chapple (GB) who co-chaired the meeting with Prof. Piotr Radziszewski (PL). Whether there is still a role for urodynamics in BPE was the focus of a debate between Prof. Matthias Oelke (DE) and Mr. Nikesh Thiruchelvam (GB) who both gave persuasive arguments for their respective positions; pro (Oelke) and con (Thiruchelvam). “Urodynamic investigations are only useful if the investigation changes treatment philosophy and predicts treatment outcome,” said Oelke, who then proceeded to argue for the benefits of the procedure. Oelke said 40% of patients have residual LUTS and need drug treatment within less than five years after the operation. He also noted in his key messages that up to 50% of patients have detrusor underactivity and that prostate operations do not help in the long-term. Furthermore, he said that only 60% of patients have BPO before their prostate operation, whilst 70% of patients are satisfied with prostate surgery. “To remain realistic and practical, urodynamic studies are indicated in a subset of patients before prostate surgery, mainly those with suspected detrusor underactivity or detrusor overactivity (or nocturia),” Monday, 27 March 2017

At Thematic Session 2, ‘Expert Challenges Expert,’ specialist surgeons presented opposing surgical treatments, aiming to provide either a critique or an alternative view of a standard procedure; a format which led to an engrossing session covering salvage prostatectomy and the extent of primary lymph node dissection (ePLND). “We have asked the speakers to present a solid and persuasive case, one that will not only challenge but provoke their opponents to re-think their views. This session will therefore serve as a critique of how we view our own surgical techniques,” said Prof. Bob Djavan (AT) who co-chaired the session with Prof. Gunter Janetschek (AT).

C. Chapple and P. Radziszewski chair the BPE session

said Oelke as he noted that this is in accordance with the EAU Guidelines for Male LUTS. Providing the opposing view, Thiruchelvam stressed that well-constructed research and evidence is “essential justification for an intervention.” “This does not exist for urodynamics in treating men with BPE,” he said. He also noted there are adverse events and variability issues with the test. Moreover, he mentioned there are non-invasive options. Following the debate, a vote by show of hands indicated there are still more who do perform urodynamics than those who do not. Moderator Prof. Henry Woo, however, glossed over the vote and declared, tongue-in-cheek: “it’s an even vote”, which triggered amused laughter from the audience. The session also presented a case discussions that touched on treatment dilemmas in enlarged prostates and LUTS; a state-of-the-art lecture on emerging techniques; a debate on surgical techniques involving the use of electricity, light and water; symptom management following surgery for bladder outlet obstruction; and the American Urological Association (AUA) lecture on unresolved diagnostic issues in LUTS and BPE.

Prof. Axel Heidenreich (DE) argued for open salvage prostatectomy and discussed his surgical techniques as well as pre-surgical preparation, outcomes and complications. He showed videos of the crucial steps

necessary to reduce complications since salvage prostatectomy is known to be more technically demanding than primary prostatectomy. “Radical salvage prostatectomy (RSP) depends on patient selection, and functional outcome depends on the type of radiation therapy and the surgeon’s expertise,” said Heidenreich as he pointed out that particularly with complications, the surgeon’s expertise plays a crucial role.

“In good hands, RSP is the only second-line local therapy with long-term cancer control,” he added. Prof. Declan Murphy (AU) gave the opposing view and pushed for robotic salvage prostatectomy, saying that “experience is what matters, not the surgical approach.” “Open salvage radical prostatectomy (RP) is an excellent option if the surgeon is very experienced. But the same applies for robotic salvage prostatectomy,” argued Murphy. By Joel Vega

Provide sustainable patency.

Resonance

M E TA L L I C U R E T E R A L S T E N T

MEDICAL

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EAU Consensus on key topics

Available ESU Courses

Updates on MRI, testosterone and focal therapies

Interested participants should register at the Registration Area ESU Course 37 Practical management of non-muscle invasive bladder cancer (NMIBC) 08:30 - 11:30- Room 12, Capital suite (Level 3) ESU Course 39 Small renal masses: From concepts to tips and tricks in daily management 08:30 - 11:30- Room 15, Capital suite (Level 3) ESU Course 41 Post-surgical urinary incontinence in males 12:00 - 14:00- Room 10, Capital suite (Level 3) ESU Course 43 General neuro-urology 12:00 - 15:00- Room 12, Capital suite (Level 3) ESU Course 48 Video and imaging urodynamics 15:30 - 17:30- Room 12, Capital suite (Level 3) ESU Course 49 Paediatric urology for the adult urologist - 2 14:30 - 17:30- Room 14, Capital suite (Level 3) ESU Course 51 How will immunotherapy change the multidisciplinary management of urothelial bladder cancer? 15:30 - 17:30- Room 16, Capital suite (Level 3)

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

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

Advertising L. Schreuder

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Regarding LUTS, Mirone said there is consensus that TTH can be given to patients with mild to moderate LUTS. “Further research in men with severe LUTS is needed. Caution should be exercised for men with significant prostatic enlargement and significant residual urine in the bladder,” he added.

Plenary Session 3 opens with the EAU Consensus segment

impairments in fertility, ranging from oligozoospermia to even azoospermia. “TTH should not be used by hypogonadal (infertile) men who have an active wish to conceive children or undergo infertility treatment,” he said. Mirone also discussed the risks of TTH such as mammary carcinoma. “Careful monitoring with clinical assessment is warranted during TTH in men with pre-existing cardio vascular disease (CVD), he said,

On prostate cancer (PCa), the prevailing opinion is that current evidence does not support a link between TTH and a higher risk of developing PCa. “However, sufficiently powered trials with long-term follow-up are needed to reach definitive conclusions,” Mirone said.

Dr. Jochen Walz (FR) gave the EAU consensus on MRI which states that “it is essential that MRI is done by dedicated experts and with high-quality images.” Expertise, training, standardization and quality need to be assured when MRI is to be used in daily practice, according to Walz.

On male fertility, men wishing to preserve their fertility should be informed that TTH may cause

Regarding MRI before first biopsy, Walz reported that there is no consensus that MRI is the gold standard.

Colophon

However, MRI is standard for repeat biopsy, said Walz, whilst emphasizing that “quality, expertise, training and standards are of utmost importance.” “Targeted biopsies provide more precise information about grade and size,” Walz reported. “New definitions for cancer significance are necessary for targeted biopsies.” Meanwhile, Dr. Henk Van Der Poel (NL) gave the EAU Consensus report on focal therapy. One of the questions he raised was whether the benefits of primary focal therapy outweigh the possible harms of secondary salvage treatment. “Better understanding of the toxicity of secondary treatments after focal therapy is needed and assessments of these should be part of prospective analyses,” noted Van Der Poel. “Focal therapy of any sort appears promising but remains investigational, with uncertainties surrounding outcome definitions, follow-up and re-treatment criteria,” he said.

EBU: Raising the level of urological education

By Erika de Groot

Knowledge of overexpressed oncogenes and the importance of the transcription factor ETS-related gene (ERG) and cytokines in relation to individualised therapy in prostate cancer, were examined yesterday during the “Personalised medicine in urological oncology” session chaired by Professors Zoran Culig (AT) and Jack Schalken (NL).

Standards in training and education for urologists were the core topics of the “Postgraduate Training in Education in European Urology” session held yesterday. The Special Session, chaired by Prof. Arnaldo José Figueiredo, (PT) and Prof. Athanasios Papatsoris (GR), was a collaborative session of the European Board of Urology (EBU), the EAU, and national urological organisations.

Dubrovska hopes that in the future the use of well-characterised cancer stem cell markers in clinical studies may facilitate tumour diagnostics, patient prognosis, and prediction of response in order to direct the selection of end-treatment. She also expects that radiation will be used in conjunction with markers to specifically target cancer stem cell population.

Lay-Out/Printing D. Blom G. Smit

“Obesity and poor general health are the main causes of late-onset male hypogonadism (LOH). Weight loss and improved lifestyle are important measures for men with hypogonadism, since these will lead to normal testosterone and reduce associated health risks,” Mirone said. “Testosterone has beneficial effects on sexual functions. Testosterone therapy (TTH) may increase the effect of PDE5 inhibitor monotherapy in men with LOH.”

Dr. Anna Dubrovska (DE) kicked off the Thematic Session. She discussed that through the potential employment of cancer stem cells as a biomarker for tumour radiocurability, a high total number of cancer stem cells can be indicative for high intrinsic radioresistance of prostate tumour. Additionally, cancer-stem cell-related biomarkers such as tumour size can be indicative of the total number of cancer stem cells.

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

No part of European Urology Today (EUT) may be reproduced without written permission from the Communication Office of the European Association of Urology (EAU). The comments of the reviewers are their own and not necessarily endorsed by the EAU or the Editorial Board. The EAU does not accept liability for the consequences of inaccurate statements or data. Despite of utmost care the EAU and their Communication Office cannot accept responsibility for errors or omissions.

Prof. Vincenzo Mirone (IT) gave the overview on testosterone supplements, discussing their impact in four areas, namely: Erectile dysfunction (ED) and libido; Lower Urinary Tract Symptoms (LUTS); prostate cancer; and male fertility.

Thematic Session 1 looks into promising therapies

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

Disclaimer

Testosterone therapy, Magnetic Resonance Imaging (MRI) and focal therapy were the topics highlighted in three EAU Consensus statements presented yesterday during Plenary Session 3, with the presenters giving current views on how these procedures can help provide optimal treatment.

Personalised medicine in prostate cancer

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

EUT Editorial Office PO Box 30016 6803 AA Arnhem The Netherlands T +31 (0)26 389 0680 F +31 (0)26 389 0674 communications@uroweb.org

By Joel Vega

Dr. Giuseppina Carbone (CH) stated that aberrant expression of the transcription factor ERG produces profound changes in cell phenotype and has a relevant impact on tumour progression. The degree and the intensity of the ERG-induced alterations varies depending on the cell context. She added that ERG methylation is a critical modification in ERG positive prostate tumours, enabling the activation of a pro-tumourigenic and pro-metastatic programme. Carbone disclosed that the discovery of EZH2-inuced ERG methylation opens new opportunities for development of therapeutic strategies for ERG fusion positive prostate cancer. She said that knowledge of the intermolecular dynamics suggests potential approaches for direct ERG targeting. ERG methylation can be

Ebhardt: “Using systems pharmacology in target proteomics reveals common escape mechanisms from targeted treatment.”

triggered by several events and discovering these mechanisms is a significant priority in the near future. Although there are dozens of cytokines and cytokine receptors, it seems that IL-6-mediated activation of STAT3 is a principal pathway implicated in promoted tumourigenesis, according to Prof. Anders Bjartell (SE). He stated that STAT inhibitors, particularly direct inhibitors of STAT3, may be a promising way to target tumour cells, the tumour microenvironment, and the immune system, in order to obtain an effective anti-tumour therapeutic response. While the preclinical evidence on direct STAT3 inhibition justifies further development of novel small molecule therapeutics, there are currently no direct STAT3 inhibitors under clinical trial for cancer therapy. Dr. H. Alexander Ebhardt (DE) delivered his associated abstract presentation and concluded that “using systems pharmacology in target proteomics reveals common escape mechanisms from targeted treatment.” Closing the session, Dr. Hendrik Borgmann (DE) stated that the novel AR inhibitor ODM-201 shows promising efficacy in the second-line therapy scenario of Enzalutamide-resistant prostate cancer both in vitro and in vivo. In addition, the findings paved the way for clinical trials evaluating ODF-201 in patients with Enzalutamide-resistant prostate cancer.

“What links us all is the education and assessment of urologists for the sake of our patients. The EBU is part of a larger network, the European Union for Medical Specialists (UEMS), linked to the Council of Europe. Furthermore, the EBU is closely involved with the EAU, because we pursue the same purposes in increasing knowledge and optimising the practice of medicine,” said Figueiredo. In his presentation “Standards for teaching and teachers in urology”, Mr. Jan Nawrocki (GB) described what qualities a good medical educator should possess. In terms of values, they should promote quality of patient care and prioritise the needs of patients and learners. They should maintain and update knowledge of subject areas and pedagogy with a complete understanding of their teaching roles and responsibilities. Furthermore, the educator should be able to motivate and inspire learners, plan and provide effective programmes, and use appropriate technology. “To have the best care and outcome for patients, they deserve the best doctors. To have the best doctors, they should have the best education and training. The best education requires the best teachers,” concluded Nawrocki. Regarding the topic of competence-based training and revalidation, Dr. Artur Antoniewicz (PL) stated there is limited evidence to support the inclusion of virtual reality surgical simulation into surgical training programmes. Monday, 27 March 2017

More attention for renal and bladder cancers Thematic Session 6 examines immunotherapeutic options Changing treatment paradigms Of the six speakers at Thematic Session 6, Dr. Friedrich-Carl Von Rundstedt (DE) and Dr. Shahrokh Shariat (AT) spoke as urologists, whilst the rest of the speakers were expert oncologists.

By Loek Keizer In a busy late-morning thematic session, chaired by Profs. Maria De Santis (GB) and Markus Kuczyk (DE), urologists and oncologists alike presented six state-of-the-art lectures on renal cell and urothelial cancer. Kuczyk noted a shift in focus to these two topics in recent years, following a period in which urological audiences would be more likely to leave the room when the subject was broached.

Congress news. . . . . . . . . . . . . . . . . . . . . . . . 1 Congress highlights . . . . . . . . . . . . . . . . . . 2/3 Targeted molecular surgery . . . . . . . . . . . . . . 4 Current and future biomarkers in

“In most European countries, systemic treatment of these two types of cancer is not performed by urologists but oncologists. But as urologists, even if we don’t perform the treatment ourselves, we have to understand how the patient will be treated. At the moment the ‘immunotherapy train’ is leaving the station with regards to bladder cancer. If urologists miss this development, I fear we soon may not be able to follow how our oncologist colleagues treat our patients.”

further educate urologists and to be practicechanging to a certain extent. But the oncological issues are always emphasised a little, even at a urological congress like this.”

Kuczyk commended the Annual EAU Congress for providing a good balance of oncological and other topics in its scientific programme. “Urologists have interesting surgical strategies for treatment which are demonstrated here. As [Scientific Congress Office Chairman Prof.] Arnulf Stenzl says, we want to

“A multidisciplinary approach is currently followed by all modern cancer centres in Germany and Europe. Contemporary cancer treatment can only be established on the basis of a multidisciplinary approach, and it’s an integral part of all cancer guideline recommendations.”

From left: Dr. Thomas Powles, Prof. Kuczyk, and Prof. De Santis

Several major trends became apparent throughout the session. “We are now introducing immunotherapy in the first-line treatment of renal cell cancer (RCC),” Luczyk summarised. “In contrast to bladder cancer, we combine immunotherapy with conventional therapeutic options in the form of TKIs. When we subdivide patients according to PD-L1 expression, we see a more favourable response to therapy and a high efficacy in those patients expressing these immune checkpoints.” “Dr. Von Rundstedt raised an interesting point regarding cytoreductive nephrectomy, specifically when patients reveal metastatic disease at first diagnosis. Cytoreductive nephrectomy is an established treatment option in this situation, but at the moment we do not know its optimal timing. In case TKI is applied prior to surgery, there is some concern that these patients have a several-week treatment interruption. They might develop tumour progression in the meantime and decrease overall survival rate. This might be better with immunotherapy but this is an interesting question.”

castration resistant prostate cancer. . . . . . . . .6 ReproUnion . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Urogenital tuberculosis - still actual. . . . . . . 10 PI-RADS in clinical practice. . . . . . . . . . . . . . . 11 Holmium laser. . . . . . . . . . . . . . . . . . . . . . . 12 Radical cystectomy. . . . . . . . . . . . . . . . . . . . 13 Extracorporeal Shock Wave Lithotripsy (ESWL). . . . . . . . . . . . . . . . . . . . . 14 The urologist: Primary gatekeeper of men’s health . . . . . . . . . . . . . . . . . . . . . . 15 MRI-targeted prostate biopsies?. . . . . . . . . . 16 The EAU’s standpoint on meshes. . . . . . . . . 19 Emergency ureteroscopy. . . . . . . . . . . . . . . . 20 Urological implications of male

Day 3 Award Gallery

hypogonadism. . . . . . . . . . . . . . . . . . . . . . . 22 How can microbiome affect the urinary tract?. . . . . . . . . . . . . . . . . . . . . . . . 23 Implementation of high quality prostate MRI. . . . . . . . . . . . . . . . . . . . . . . . . 24 Learn and advance through ESU. . . . . . . . . . 27 mpMRI as the new guide. . . . . . . . . . . . . . . 29 Urothelium: A dynamic structure with excellent communication skills. . . . . . . 30 Unlocking the potential of social media . . . . 31

First Video Prize: J-L. Bonnal (Lomme, France)

Second Video Prize: G. Simone (Rome, Italy)

Third Video Prize: F. Porpiglia (Turin, Italy)

Second Prize Best Abstract (Oncology) J. Bedke (Tuebingen, Germany)

First Prize Best Abstract by a Resident: D. Thurtle (Cambridge, United Kingdom)

Second Prize Best Abstract by a Resident: M. Haahr (Odense, Denmark)

Third Prize Best Abstract by a Resident: T. Seisen (Boston, United States of America)

European Urology Resident’s Corner Award: T. Arends (Nijmegen, The Netherlands)

EUSP Best Scholar Award 2017: F. Castiglione (Cologno Monzese, Italy)

YUO Campbell Team Challenge Quiz Winner 2017: A.K. Czech (Krakow, Poland)

Best abstract presented by a Young Academic Urologist in 2017 H. Borgmann (Mainz, Germany)

Do not miss this today: Posters & Videos - The Prize Winners Special presentations on stage at the e-Poster Area at 11.00 Best Paper published by Young Academic Urologist in 2016 F. Sanguedolce (London, United Kingdom)

Monday, 27 March 2017

ESUI Vision Award 2017 Dr. M. Abdel-Gawad (Al-Ain, United Arab Emirates) Supported by INVIVO CORPORATION

Advanced virtual robotic procedural training at ESU/ERUS HOT Course 28, Sunday

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Targeted molecular surgery PSMA-radioguided surgery for lymph node dissection in prostate cancer Dr. med. Tobias Maurer Senior Attending Physician Klinik und Poliklinik für Urologie Technical University of Munich (TUM) Munich (DE)

In case of biochemical failure after primary treatment, salvage therapy options might be considered in selected prostate cancer patients – especially when they present with good performance status. However, in these cases early and reliable detection of recurrent disease is crucial. Here, anatomical imaging like computed tomography (CT) or Magnetic Resonance Imaging (MRI) as well as positron emission tomography (PET) using radiolabeled choline-derivatives show severe limitations and often underestimate the extent of metastatic spread. Recent advances in PET imaging of prostate cancer utilizing 68 Gallium-labelled ligands of the prostate-specific membrane antigen (PSMA) have made it possible to detect recurrencies even at low PSA values since most prostate cancer cells exhibit a significant overexpression of PSMA at the cell surface1-3.

(low PSA at recurrence, solitary lesions) and that follow-up is still limited. Due to restricted availability, higher costs and increased radiation exposure of patients as well as medical staff by 111Indium, PSMA ligands were further chemically modified to be labelled with the widely available and cheap 99mTechnetium isotope that also shows a better radiation profile5. In a just recently presented series (ESUI 2016, Milan) we combined the results of 111Indium- or 99mTechnetiumbased PSMA-radioguided surgery of 56 consecutive patients with recurrent oligometastatic localized prostate cancer on preoperative PSMA PET (PSA median: 1.29ng/mL, range: 0.19 – 13.90ng/mL) that underwent surgery at our institution from April 2014 to March 2016. Results from intraoperative gamma probe measurements of resected tissue samples were compared to findings of postoperative histological analysis. Best PSA response without additional treatment was determined eight to 16 weeks following PSMA-radioguided surgery, and prostate cancer-specific treatment-free survival was evaluated. In total, 247 separate histological specimens were evaluated, and 97 specimens contained metastatic lesions at histological analysis. All lesions (except one) visible on preoperative PSMA PET were also detected during PSMA-radioguided surgery. Intraoperatively, 84 and 144 tissue specimens were correctly identified as cancerous or cancer-free, while six and 13 tissue specimens were false positive and false negative by intraoperative gamma probe measurements.

Follow-up information was available for 55 of the 56 patients. Postoperative PSA reduction >50% and Figure 1: PSMA PET showing a suspicious paracaval lymph node >90% were observed in 44 of 55 (80%) and 29 of 55 (53%) patients. In 34 of 55 (62%) patients, a PSA drop below 0.2ng/mL was In a subset of these patients solitary subcentimeter observed. 15 of 55 (27%) patients received further lymph node metastastases can be observed outside prostate cancer-specific treatment after median 110 the usual lymph node dissection template (Figure 1). days after PSMA-radioguided surgery (range: 48 – 454 Thus, even with the help of intraoperative frozen section analysis precise detection and resection can days), the remaining 40 (73%) patients remained be challenging. To overcome the difficulty of exact treatment-free at a median follow-up of 195 days intraoperative localization of metastatic lymph nodes, (range: 43 – 591 days). we recently described the novel surgical technique of PSMA-radioguided surgery. In conclusion, comparable to medical targeted therapies, PSMA-radioguided surgery enables For PSMA-radioguided surgery PSMA ligands similar “targeted molecular surgery” as it allows intraoperative to those used for PET imaging are radioactively and specific detection of metastatic prostate cancer labelled with γ-emitting isotopes like 111Indium or tissue. Especially for intraoperative detection of small or 99m Technetium and are injected intravenous one to two atypically located metastatic lymph nodes PSMAdays prior to surgery4,5. Intraoperatively, a γ-probe is radioguided surgery might be useful and might used to detect these small unobtrusive and/or therefore be beneficial in regard to tumor control. atypically located metastatic lymph nodes6. After removal, ex vivo measurements with the γ-probe of Greater patient cohorts as well as long-term resected lymph node tissue can immediately confirm follow-up are needed to confirm these initial, but the presence or absence of metastatic prostate cancer encouraging results. Also – as mentioned above – the lesions (Figure 2). However, it is advisable not only to necessary extent of lymph node dissection during remove the suspicious lymph node on preoperative PSMA-radioguided surgery needs to be clarified. PSMA-PET imaging, since further microscopic prostate Adequate patient selection on the basis of PSMA PET cancer deposits that are too small to be identified by imaging and clinical parameters as well as dedicated PET might still be present. The extent of dissection in and subtle tissue resection, however, will always these salvage cases, on the other hand, is still a matter remain the fundamental basis. of debate. References In a first feasibility study in five prostate cancer 1. Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, patients with evidence of metastatic lymph nodes Linhart HG, Eder M, Eisenhut M, Boxler S, Hadaschik BA, PSMA-radioguided surgery (using 111Indium-labelled Kratochwil C, Weichert W, Kopka K, Debus J, Haberkorn PSMA ligands) enabled intraoperative detection of all U. The diagnostic value of PET/CT imaging with the (68) (even small) suspicious lymph nodes on preoperative Ga-labelled PSMA ligand HBED-CC in the diagnosis of PET imaging. Furthermore, in two patients PSMArecurrent prostate cancer. Eur J Nucl Med Mol Imaging. radioguided surgery revealed additional lesions of 2015 Feb;42(2):197-209. doi: 10.1007/s00259-014-2949-6. 2-4mm nearby the known metastatic lymph nodes PubMed PMID: 25411132; PubMed Central PMCID: that were not detected on imaging preoperatively6. PMC4315487. However, follow-up of these individually treated patients is mandatory to determine the value of this new technique. Several patients that underwent PSMA-radioguided surgery for recurrent prostate cancer experienced a complete biochemical response (postoperative PSA value below <0.2ng/mL) without PSA relapse at further follow-up7,8. Admittedly, it has to be stated that these patients were highly selected 4

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2. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, Graner FP, Kübler H, Haberhorn U, Eisenhut M, Wester HJ, Gschwend JE, Schwaiger M. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015 May;56(5):668-74. doi: 10.2967/ jnumed.115.154153. PubMed PMID: 25791990. 3. Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, Bolton D, Lawrentschuk N. Sensitivity,

Figure 2: Ex-vivo measurement of resected tissue specimens during PSMA-radioguided surgery

Specificity, and Predictors of Positive (68)Ga-Prostatespecific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016 Dec;70(6):926937. doi: 10.1016/j.eururo.2016.06.021. Review. PubMed PMID: 27363387. 4. Schottelius M, Wirtz M, Eiber M, Maurer T, Wester HJ. [(111)In]PSMA-I&T: expanding the spectrum of PSMA-I&T applications towards SPECT and radioguided surgery. EJNMMI Res. 2015 Dec;5(1):68. doi: 10.1186/s13550-0150147-6. PubMed PMID: 26608882; PubMed Central PMCID: PMC4659791. 5. Robu S, Schottelius M, Eiber M, Maurer T, Gschwend J, Schwaiger M, Wester HJ. Preclinical evaluation and first patient application of 99mTc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. J Nucl Med. 2016 Sep 15. pii: jnumed.116.178939. [Epub ahead of print] PubMed PMID: 27635024. 6. Maurer T, Weirich G, Schottelius M, Weineisen M, Frisch B, Okur A, Kübler H, Thalgott M, Navab N, Schwaiger M, Wester HJ, Gschwend JE, Eiber M. Prostate-specific membrane antigen-radioguided surgery for metastatic

lymph nodes in prostate cancer. Eur Urol. 2015 Sep;68(3):530-4. doi: 10.1016/j.eururo.2015.04.034. PubMed PMID: 25957851. 7. Maurer T, Schwamborn K, Schottelius M, Wester HJ, Schwaiger M, Gschwend JE, Eiber M. PSMA Theranostics Using PET and Subsequent Radioguided Surgery in Recurrent Prostate Cancer. Clin Genitourin Cancer. 2016 Oct;14(5):e549-e552. doi: 10.1016/j.clgc.2016.05.020. PubMed PMID: 27318956. 8. Rauscher I, Düwel C, Wirtz M, Schottelius M, Wester HJ, Schwamborn K, Haller B, Schwaiger M, Gschwend JE, Eiber M, Maurer T. Value of (111) In-prostate-specific membrane antigen (PSMA)-radioguided surgery for salvage lymphadenectomy in recurrent prostate cancer: correlation with histopathology and clinical follow-up. BJU Int. 2016 Nov 10. doi: 10.1111/bju.13713. [Epub ahead of print] PubMed PMID: 27862863.

Monday, 27 March 10.30-10.50: Thematic Session 10, Lymph node surgery in uro-oncology: Semi-Live

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Monday, 27 March 2017

N OW EN R O L L I N G Phase III Trials in Patients with: High Risk Non-Metastatic Castration Resistant Prostate Cancer (nmCRPC)

www.clinicaltrials.gov (NCT02200614)

Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

www.clinicaltrials.gov (NCT02799602)

For further information on these trials please contact:

clinical-trials-contact @ bayer.com

Trial Sponsors: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire, RG14 1JA, UK Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland Bayer and the Bayer cross are registered trademarks of Bayer. ÂŠ Bayer. February 2017. UKMED01170028

Monday, 27 March 2017

EUT Congress News

Current and future biomarkers in CRPC Society of Urologic Oncology Lecture Prof. Christopher P. Evans Chairman, Department of Urology University of California Davis School of Medicine Sacramento (USA) This article is based on the inaugural Society of Urologic Oncology (SUO) lecture at this congress. This is an exchange lectureship developed between the SUO and EAU as part of an effort to foster education, collaboration, exchange and integration between our memberships. The lectureship exchange began with the EAU lecture at the SUO annual meeting held in San Antonio. On December 2, 2016 Professor James Catto, Sheffield University, presented the results of the PROTECT trial to the SUO attendees. It was a timely and excellent presentation, which was well received by the audience. This presentation will discuss the rapidly evolving area of biomarkers in castration-resistant prostate cancer (CRPC). In castrate sensitive prostate cancer, there has been a rapid introduction of genomic tests that add predictive value to Gleason grade and other clinical parameters for stratification of patients to decide; if prostate cancer exists, is it safe to undergo active surveillance, and is there need for salvage therapy. In CRPC the initial response to androgen deprivation therapy (ADT) has been one of the most prognostic indicators of survival. In 2006, Maha Hussein demonstrated that the PSA nadir after seven months of ADT significantly stratified patient survival.1 The PSA nadir and corresponding survival was respectively; <0.2, 77 months; 0.2 to 4.0, 44 months, >4.0, 13 months. This indicates that some patients have primary resistance to ADT. This observation is mimicked in the CRPC setting where between 25-33% of patients being treated with abiraterone or enzalutamide have no significant response after three months of therapy.2,3 As such, two Stand Up to Cancer Dream Team awards to multi-institutional groups of investigators have sought to better understand resistance mechanisms in CRPC. New CRPC histologies and gene signatures The SU2C “West Coast Dream Team” consisted of UCSF, UCLA, UC Davis, UCSC, University of British Columbia and Oregon Health Sciences University and the lead principal investigators were Eric Small and Owen Witte. CRPC patients who had progressed after chemotherapy and abiraterone and/or enzalutamide treatment underwent CT-guided core biopsies of metastatic lesions. After 3.5 years, 300 biopsies have been obtained. Figure 1 shows the distribution of the biopsies as of July 2016. Figure 2 shows two histologic discoveries made from the biopsy cohort. While pure adenocarcinoma was found in 39%, a small cell neuroendocrine variant was identified in 12% and as discussed below it has a different molecular profile than typical small cell neuroendocrine prostate cancer. Thus, we refer to as treatment-induced small cell neuroendocrine cancer (t-SCNC). Secondly, a new variant of CRPC was identified; intermediate atypical carcinoma (IAC) which occurred in 29% of patients. IAC was validated by a panel of blinded pathological experts. Both IAC and t-SCNC were aggressive phenotypes and combined the survival was less than

half of adenocarcinoma (p=0.018). However, clinical features that generally distinguish classic SCNC (prior high Gleason Score, visceral metastasis, low serum PSA levels) had similar distribution across the three histologic types. Surprisingly, androgen receptor (AR) amplification and nuclear localization was found to be similar across all histologic subtypes, between 53-58% (figure 3). Furthermore, AR-V7 splice variants were detected in all evaluable histologic groups. Neither the absolute AR-FL expression level nor the ratio of AR-V7/AR-FL differed by histology. Serum neuro-endocrine marker levels were similar in Intermediate Atypical Carcinoma and t-SCNC. Gene expression signatures were derived by supervised analysis using dichotomous selected histologies (e.g. t-SCNC vs. adenocarcinoma). For each dichotomy, a 50-gene and full gene set signature was developed. The 50-gene signature sets strongly distinguished between t-SCNC and adenocarcinoma and between IAC and adenocarcinoma. Thus, these new histologic types and their genomic signatures are potential new biomarkers in CRPC. Androgen axis The androgen axis contains two areas of potential biomarker development. First, the steroidogenic pathway for the conversion of cholesterol to dihydrotestosterone and beyond relies on a series of biosynthetic enzymes. While abiraterone inhibits the CYP17-hydroxylase and CYP17-lyase enzymes, it is known that others are upregulated with resistance to abiraterone. The backdoor pathway in which DHEA is converted to DHT without passing through testosterone is driven by three primary enzymes; AKR1C3, HSD3ß and SRD5A1. It was previously shown that these three, and in particular ADR1C3, are increased with abiraterone resistance. We’ve recently demonstrated that resistance to enzalutamide also results from increased AKR1C3, a mechanism we could suppress with indomethacin in both abiraterone and enzalutamide models.4,5 As such, we see levels of AKR1C3 as a potential biomarker and have preliminarily measured AKR1C3 transcripts in whole blood with higher levels in abiraterone and enzalutamide treated patients. Regarding the AR component of the androgen axis, it is now well known that truncated or spliced AR is associated with resistance to abiraterone or enzalutamide. Emmanuel Antonarakis has reported that mRNA expression level of AR-V7 as measured in circulating tumor cells correlates with treatment resistance to abiraterone or enzalutamide.6 On the other hand, Antonarakis has shown in 37 taxane treated patients that AR-V7 status does not statistically differentiate response to taxane chemotherapy.7 This observation has been confirmed by others, included Howard Scher who measured nuclear AR-V7 protein by the EPIC platform and found that the CRPC patients who had AR-V7 positive CTCs treated with taxanes had a much lower risk of death than those on abiraterone or enzalutamide.8 The likelihood of having detectable AR-V7–positive CTCs increased by line of therapy; 3% prior to first-line therapy, 18% prior to second-line therapy and 31% prior to third or subsequent lines of therapy. While the development, validation and commercialization of AR-V7 assays is ongoing by a couple of vendors, at the time of this article it appears to be available via the Johns Hopkins Pathology Laboratory as a send out test. As of January 2016, the EPIC test is commercially available in California and is expected to be available in other states later in 2017. Recently, Phil Kantoff and colleagues have reported

Figure 3: Clinical features that generally distinguish classic SCNC (prior high GS, visceral mets, low serum PSA levels) have similar distribution across histologies

that the quantity of prostate specific antigen (PSA) and AR-V7 transcripts detected in the blood is inversely associated with time-to-treatment failure (TTF) and overall survival (OS) in CRPC patients who were treated with abiraterone acetate and/or enzalutamide treatment.9 PSA-positive patients had a shorter time-to-treatment failure than PSA-negative patients. Patients with a higher-AR-V7 transcript level had a shorter TTF with abiraterone and enzalutamide in univariate analysis. However, in multivariable models, the association with TTF remained significant in the enzalutamidecohort, but statistically insignificant in the AA-cohort. In both cohorts, there was potential prognostic value of both PSA and AR-V7 RNA expression on OS. The patients with detectable PSA transcripts and high AR-V7 predicted for the poorest OS. New observations regarding AR To date there is little known about the regulation of AR expression itself. The AR belongs to the family of nuclear receptors and nuclear orphan receptors. In the literature, it has been reported that the retinoic orphan receptor expression levels are increased in CRPC.10,11 Recently, we validated this finding of ROR- γ levels by IHC staining and discovered that ROR- γ regulates the expression of AR.12 From the cBioportal/TCGA, study of 150 metastatic prostate cancer samples reported by Dan Robinson, it was noted that ROR- γ was amplifies in 6% of patients.13 In a more advanced CRPC cohort of patients from cBioportal/TCGA study of 107 mCRPC and neuroendocrine prostate cancer samples, reported by Himisha Beltran, ROR- γ was amplified in 36% of patients.14 ROR- γ is involved in the expression of IL-17 and immune diseases and a compound has been developed to inhibit it. Through structure-guided screening, we then developed new antagonists of ROR- γ and found that they specifically inhibited ROR- γ and as a result AR. Using CRISPR-Cas9 technology, we found a ROR responsive element 2.3kb from the transcriptional start site in AR. Both compounds administration and mutation of this site ablated AR expression. The inhibitors were very effective in inhibiting in vivo tumor growth of both AR-V7 and enzalutamide resistant tumors. This is both an exciting finding for therapy, and biomarker development. Biomarker identification in CRPC is undergoing rapid discover and development. New histologic, genomic and mechanistic discoveries are enhancing both therapeutic and biomarker approaches to CRPC.

References 1. Hussain M et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2006 Aug 20;24(24):3984-90. 2. de Bono JS et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. 3. Scher HI et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97. 4. Liu C. et al. Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer. Cancer Res. 2015 Apr 1;75(7):1413-22. 5. Liu C. et al. Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. Mol Cancer Ther. 2016 Oct 28. pii: molcanther.0186.2016. [Epub ahead of print] 6. Antonarakis ES et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38. 7. Antonarakis ES et al. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Oncol. 2015 Aug;1(5):582-91. 8. Scher HI et al. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA Oncol. 2016 Nov 1;2(11):1441-1449. 9. Qu F et al. Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer. Clin Cancer Res. 2016 Aug 3. doi: 10.1158/1078-0432.CCR-16-1070. [Epub ahead of print] 10. Chandran UR et al. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer. 2007 Apr 12;7:64. 11. Grasso CS et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012 Jul 12;487(7406):239-43. 12. Wang J et al. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med. 2016 May;22(5):488-96. 13. Robinson D et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-28. 14. Beltran H et al. Divergent clonal evolution of castrationresistant neuroendocrine prostate cancer. Nat Med. 2016 Mar;22(3):298-305.

Monday 27 March 11.05-11.20: Thematic Session17, Controversies in metastatic prostate cancer

Figure 2: Non-adenocarcinoma histologies (t-SCNC and IAC) compromised 43% of all biopsies

Figure 1: West Coast Stand Up to Cancer Dream Team Sites of mCRPC Biopsy Acquisition (as of 7 / 28 / 16; n = 264)

EUT Congress News

Monday, 27 March 2017

ReproUnion A strategic platform for future EAU and EC partnerships Jens Sønksen Professor of Urology Herlev and Gentofte Hospital University of Copenhagen Copenhagen (DK)

ReproUnion is the brand name for a large and inter-disciplinary collaboration between specialties within all aspect of reproductive medicine, including urological andrology, situated in the Greater Copenhagen area. It is a unique public and private partnership where 12 individual research organisations and hospitals, together with Ferring Pharmaceuticals A/S, work across different organisational boundaries. Because of its bi-national nature (Sweden and Denmark), the program was financed by European Union (EU) inter-regional funds within the Horizon 2020 framework program. The main challenge is not only to foster worldclass research in the individual participating units but also to create synergies between the many different competencies in the region. The goal is to deliver the best and most holistic treatment and service to Danish and Swedish infertile couples and individuals.

“These new challenges can only be met through a central and efficient role of the entire urological community. The EAU must and will fill this position.” Synergies are difficult to achieve between medical professionals More than one hundred people are engaged in ReproUnion. The medical profession is very competitive. Members strive for the same positions, funds and other opportunities. Creating synergies is easily said but much more difficult to achieve in practice. You must be able to generate mutually beneficial relationships between the parties in a program like ReproUnion. Our organization has many different stakeholders and disciplines that traverse national borders. Although Denmark and Sweden share roots and heritage, the research and organisational cultures and traditional research funding mechanisms are different, and the complexity of the program is ever increasing. Many national and international connections are generated and momentum is key to secure the ambitious vision – to become one of the world’s leading centres of reproductive medicine. Clear goals are a must The long-term goal of ReproUnion was made were very clear from the beginning—that of seamless international collaboration. It was communicated that funds to individual research projects would only be made available if collaboration with other groups were clearly established, together with specific initiatives to secure bi-nationality in all aspects of the projects. Even clear intentions like these must be reinforced in day to day operations. If that is not done, the groups will tend to revert back into the normal behavioural pattern of isolated, single-group project management. ReproUnion created a neutral unit to manage the program To oversee this multicentre/multinational goal, an innovative organisational initiative – The Management Unit – was designed. This entity has the responsibility for the entire program, and secures synergy and bi-nationality in all activities. It has the authority together with the Executive Board to change priorities in the program and eventually stop a project if the basic expectations are not fulfilled. It serves as a neutral focal point of entry for all external stakeholders and reports to the EU on a regular basis. The Unit is responsible for the entire budget and it runs the internal and external communication as well as the international branding of the program. Monday, 27 March 2017

Access to a high volume of treatments and national registries are key factors With the access to more than 5,000 IVF treatment cycles annually in ReproUnion, the total volume of patients becomes very attractive for industry partners from a clinical research perspective. The high-volume gives an opportunity to run several large clinical trials within the three-year program period. Access to large national registries with clinical data and biomaterial from more than 200,000 thousand fertility treatments and procedures gives a unique opportunity for epidemiologists and clinicians to combine interventions with outcome data from these registers in a scale not seen anywhere else. When databases from the two countries are combined, access to follow-up data from several million individuals can be achieved. In ReproUnion this asset is used to make a follow-up on more than 200,000 women who have had IVF treatment, to study the relation between infertility and Demographic changes, including longer life expectancy, will increase the economical health burden in Europe disease morbidity later in life and several other purposes. develop at an accelerating pace alongside societal Globalisation together with digitalisation will open attitudes marked by ever greater demands. The new opportunities but also demands. Patients will ReproUnion was funded with a significant amount council states that smart solutions are needed to ask for advice and treatment irrespective of of money overcome these challenges. The EU recommends geographical location. Healthcare will in the future ReproUnion has a budget of more than 15.4 million transnational collaboration with a focus on the use of euros (2015-2018). The EU supports the program with be delivered through new tools independent on EU funds for research, where Member States cannot distance. 50% of its funds, whereas the other half is shared solve problems alone and where collaboration is between public and private contributions. This needed. Programs need to focus on international significant amount of money has allowed the program These new challenges can only be met through a collaboration with researchers outside Europe, and to initiate 24 Ph.D. or post-doctoral research projects central and efficient role of the entire urological focus must be on mobility of both young and senior within many different areas of reproductive medicine community. The EAU must and will fill this position. researchers. including urological andrology. EAU has done a great job in the past Healthy aging, non-communicable diseases and The EAU has done a great job in the past. The ReproUnion focuses on the next generation personalised medicine are among the five vertical organisation has supported ground-breaking The program has the aim to efficiently educate the areas of top priority for EU and of the most interest next generation of both clinicians and scientists within research and development through grants and for the EAU. Beside these topics, the council fellowships. Member groups have developed all disciplines of reproductive medicine. This is done stresses the future importance of “big” data. Future evidence-based international guidelines, that clearly by running practical and theoretical training courses health research will increasingly rely on integration communicate and deploy updated knowledge about for post-graduate students, research seminars, of large datasets to provide the evidence base for diseases and their treatment. The international presentation sessions and conferences, where realisation of personalised medicine and future scientific community has formed networks of domestic and international attendees meet. health policies. scientists to facilitate knowledge-sharing. The EAU Several international scientists have been attracted to runs ambitious education programs where young Such datasets range from high-throughput “omics” urologists learn state-of-the-art diagnosis and the region to spend time to participate in research analyses of human specimens to electronic health treatment mentored by older colleagues. Strong ties activities within the program. Recently, EAU and records, personal monitoring devices, population and exist between the many national urology societies ReproUnion have provided funds for new research patient registries, and data on environmental and the EAU, all striving to have the highest political fellowships aimed for young members of EAU exposure, nutrition, lifestyle and socioeconomic status. expanding the international outreach of the program. impact as possible. Free Fertility Counseling fights the low birth rate Free and open fertility counseling is provided, where young men or women either alone or as couples can get a personal clinical evaluation of their current and future fertility capacity to take personal and pro-active action in their family planning. A declining fertility rate is present in most developed countries. In Scandinavia, the rate is approximately 1,68 children per female and has been declining the last 50 years. This development possesses a major threat to the demographic development where more than 50 % of the population will be older than 60 years in 2050. That is why ReproUnion addresses these issues through a targeted public campaign to generate and expand the general awareness of these issues especially among the youngest part of the populations. Interregional EU funds are ready to support research Inter-regional funds from the EU have not in the past been targeted towards traditional research. These funds are not like traditional sources that typically are given to individual projects or groups of scientist. The overall purpose of interregional programs like Interreg V is to support regional growth, job creation and wealth. Global development trends may change the health care environment European urology faces great challenges in the future. Demographic changes, including the expected increase in life expectancy, will increase the economical health burden in Europe based on rise in the incidences of urological cancers as well as benign urological diseases associated with advancing age. Infertility and low birth rates continue to be major challenges for all developed countries. Economic pressure on private and public health care providers will call for innovations and new ways to deliver health care to an aging population, where individuals are brought up to expect more individualised treatment, empowerment and active involvement in treatment decisions.

EAU will meet the future well-prepared Organisations that are based on memberships and sponsors must continuously adapt to changes in the environment. If an organisation is perceived too remote and out of touch with member needs, it will lose influence and impact in the long run. EAU will develop new paradigms based on previous achievements.

Great opportunities for EAU EU does not support individual specialities like urology, but requires that future society challenges are addressed in any program seeking central support. Inter-disciplinarity is crucial and links exist between all themes. In public health, the programs need to focus on a holistic integration with other research areas.

The new paradigms: more cross-disciplinarity; digitalisation requires new skills; global rather than just European network are key to future success; efficiency in public-private partnerships can create new opportunities; fast documentation; implementation of new technologies to improve quality without increasing health care costs; and active patient involvement and empowerment that will change physicians role in society.

This political agenda holds great opportunities for the EAU to play a central role in the future implementation of European healthcare politics. Early diagnosis and efficient treatment of common urological diseases like prostate cancer are dependent on genetic screening and development of sensitive and specific biomarkers for guidance and monitoring. Urological andrology are important elements fighting infertility and low-birth rates to concur the unfortunate demographic trend.

“Many societies compete for the same EU funds, but the EAU can gain a competitive advantage if new and innovative ways to collaborate across borders and boundaries are explored...”

The ReproUnion model may show a way Many societies compete for the same EU funds, but the EAU can gain a competitive advantage if new and innovative ways to collaborate across borders and boundaries are explored and offered to members. The key to success for any program lies its implementation. ReproUnion represents such an innovative organisational design that focuses on the most important issues for a successful implementation. ReproUnion experiences can easily be translated to handle complex inter-disciplinary and multinational research initiatives for EAU.

European Union has set the priorities The European Union has already set the agenda for the future European health care. Horizon 2020 is the biggest EU Research and Innovation programme ever with nearly 80 billion euros of funding available over seven years in addition to the private investment that this money will attract. This program will soon come to its end, but it will be followed by a new research program enrolled in the total EU budget that needs to be passed in 2018 or 2019. European Medical Research Council, which sets the health care priorities for the community for 2018-2020, claims that technology continues to be

The future starts today. The ReproUnion model has shown its value and is worthwhile for urology actors to pursue in their future endeavours for funding. ReproUnion is proud to be affiliated with the EAU and is ready to share ambitions and efforts with all EAU members. Monday 27 March 11.30-11.45: Thematic Session 12, Male hypogonadism – What role for Testosterone Replacement Therapy (TRT)?

EUT Congress News

ADVERTORIAL This article is written and funded by

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

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

UKHEX00164 February 2017

EUT Congress News

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

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

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

Prescribing Information Hexvix® (hexaminolevulinate) Presentation: Hexvix 85mg, powder and solvent for solution for intravesical use. Pack of one 10mL glass vial containing 85mg of hexaminolevulinate as 100mg hexaminolevulinate hydrochloride as a powder and one 50mL polypropylene or glass vial containing solvent. After reconstitution in 50mL of solvent, 1mL of the solution contains 1.7mg hexaminolevulinate which corresponds to an 8mmol/L solution of hexaminolevulinate. Indications: This medicinal product is for diagnostic use only. Hexvix blue light fluorescence cystoscopy is indicated as an adjunct to standard white light cystoscopy to contribute to the diagnosis and management of bladder cancer, in patients with known or high suspicion of bladder cancer. Dosage and Method of Administration: Hexvix cystoscopy should only be performed by healthcare professionals trained specifically in Hexvix cystoscopy. The bladder should be drained before the instillation. Adults (including the elderly): 50mL of 8mmol/L reconstituted solution is instilled into the bladder through a catheter. The patient should retain the fluid for approximately 60 minutes. Following evacuation of the bladder, the cystoscopic examination in blue light The new French Guidelines recommend blue-light should start within approximately 60 minutes. The cystoscopic examination should not be performed more than 3 cystoscopy for the first bladder cancer resection in the hours after Hexvix is instilled in the bladder. Also if the retention time in the bladder is considerably shorter than majority of patients and for consecutive TURBs in one hour, the examination should start no earlier than after 60 minutes. No minimum retention time has been many patients. This facilitates the most correct staging identified making examination non-informative. For optimal visualisation it is recommended to examine and map the entire bladder under both white and blue light before any surgical measures are initiated. Biopsies of all and grading, which is crucial for the optimal follow-up and management of the patient. In contrast mapped lesions should normally be taken under white light and complete resection should be verified by switching to blue light. Only CE marked cystoscopic equipment should be used, equipped with necessary filters to allow both to the former version of the Guideline the update standard white light cystoscopy and blue light (wavelength 380-450nm fluorescence cystoscopy). Children and includes the situations in which diagnosis with BLC adolescents: There is no experience of treating patients below the age of 18 years. Contraindications: Hypersensitivity can reduce the risk of recurrence. A cost-effectiveness to the active substance or to any of the excipients. Porphyria. Warnings and Precautions: The possibility of study applied to the French system revealed a QALY hypersensitivity including serious anaphylactic/anaphylactoid reactions should always be considered. Advanced gain (an economic indicator aiming to estimate the life support facilities should be readily available. Post-marketing experience with repeated use of Hexvix does not value of life) for the use of fluorescence guided TURB indicate that it represents a risk when used in follow-up in patients with bladder cancer however no specific with HAL starting with the first TURB of any NMIBC7,8. studies have been conducted. Hexaminolevulinate should not be used in patients at high- risk of bladder According to Morgan Rouprêt, Professor of Urology at inflammation, e.g. after BCG therapy, or in moderate to severe leukocyturia. Widespread inflammation of the bladder should be excluded by cystoscopy before the product is administered. Inflammation may lead to increased the Pitié-Salpétrière Hospital, University Paris, and porphyrin build up and increased risk of local toxicity upon illumination, and false fluorescence. If a widespread one of the authors of the Guidelines, “the strong level inflammation in the bladder becomes evident during white light inspection, the blue light inspection should be of evidence associated with the newest data incorporated avoided. There is an increased risk of false fluorescence in the resection area in patients who recently have into the European Guidelines for the use of blue light undergone surgical procedures of the bladder. Interactions: No specific interaction studies have been performed with hexaminolevulinate. Pregnancy and Lactation: There are no or limited data on the use of hexaminolevulinate cystoscopy should result in an increased level of in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to the reproductive urological care for the management of patients with toxicity. As a precautionary measure, it is preferable to avoid the use of Hexvix during pregnancy. It is unknown bladder cancer in France.” whether hexaminolevulinate/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast- feeding should be discontinued during the treatment with Hexvix. Animal studies do not indicate effects on female fertility. Male fertility has not been investigated in animals. Undesirable effects: Most of the reported adverse reactions were transient and mild or moderate in intensity. The most frequently reported adverse reactions from clinical studies were bladder spasm (2.4%), dysuria (1.8%), bladder pain (1.7%) and haematuria (1.7%). Other commonly (>1/100 to <1/10) reported adverse reactions are: headache, nausea, vomiting, constipation, diarrhoea, urinary retention, pyrexia and post-procedural pain. Prescribers should consult the SPC in relation to other side effects. The adverse reactions that were observed were expected, based on previous experience with standard cystoscopy and transurethral resection of the bladder (TURB) procedures. Overdosage: No case of overdose has been reported. No adverse events have been reported with prolonged instillation times exceeding 180 minutes (three times the recommended instillation time), in one case 343 minutes. No adverse events have been reported in the dose-finding studies using twice the recommended concentration of hexaminolevulinate. There is no experience of higher light intensity than recommended or prolonged light exposure. Pharmaceutical Precautions: This medicinal product must not be mixed with other medicinal products. For single use only. Hexaminolevulinate may cause sensitisation by skin contact. The product should be reconstituted under aseptic conditions using sterile equipment. Any unused product should be discarded. Legal Category: POM. Basic NHS cost: Hexvix 85mg £375 per vial. UK Marketing Authorisation Number: Hexvix 85mg: PL34926/0017. UK Marketing Authorisation Holder: Ipsen Ltd., 190 Bath Road, Slough, Berkshire, SL1 3XE, UK. Tel: 01753 627777. Date of preparation of PI: October 2015. Ref: UK/HEX00036(1) Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to the Ipsen Medical Information Department on 01753 627777 or medical. information.uk@ipsen.com Hexvix® is the property of Photocure. Monday, 27 March 2017

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15.02.2017 14:44:32

EUT Congress News

Urogenital tuberculosis - still actual Single, standard approach is insufficient to combat UGTB Prof. Ekaterina Kulchavenya Novosibirsk TB Research Institute Novosibirsk State Medical University Novosibirk (RU)

Prof. Truls E. Bjerklund Johansen Oslo University Hospital Dept. of Urology Oslo (NO)

Kidney tuberculosis (KTB) is defined21 as an infectious inflammation of the kidney parenchyma, caused by Mtb or M. bovis. There are four stages to be considered: Stage 1: TB of kidney parenchyma (non-destructive form, KTB-1) Stage 2: TB papillitis (small-destructive form, KTB-2) Stage 3: Cavernous kidney TB (destructive form, KTB-3) Stage 4: Polycavernous kidney TB (widespreaddestructive form, KTB-4) Complications of kidney TB are chronic renal failure, fistula, high blood pressure21. Awareness of KTB is important when patients present with unexplained urinary tract abnormalities, especially immunosuppressed patients and those coming from TB-endemic areas20. The risk of TB is significantly increased in chronic kidney disease. Dialysis and renal transplant patients appear to be at a higher risk of TB, in part related to immunosuppression along with socioeconomic, demographic, and comorbid factors22-23.

Co-authors: R. Bartoletti, G. Bonkat, F. Bruyere, T. Cai, M. Cek, M. Grabe, D. Kholtobin, B. Köves, T. Perepanova, A. Pilatz, K. Rennesund, V. Smelov, Z. Tandogdu, P. Tenke, B. Wullt, K. Naber, and F. Wagenlehner on behalf of ESIU

Urinary tract TB Urinary tract TB (UTTB) includes TB of pelvis, ureters, bladder, and urethra. UTTB first appears as an oedema, the next stages are infiltration, ulceration and fibrosis. UTTB is always secondary to KTB.

Tuberculosis (TB) remains one of the world’s deadliest communicable diseases and is an increasing global health problem. In four years (from 2012 until 2015) the incidence of new TB cases worldwide increased from 8.6 million people to 10.4 million people (+20.9%), and the mortality increased from 1.3 million in 2012 to 1.5 million in 2014 (Table 1)1-5. Thus, TB remained one of the top 10 causes of death worldwide.

Bladder TB is divided into four stages21: Stage 1: tubercle-infiltrative Stage 2: erosive-ulcerous Stage 3: spastic cystitis (symptoms similar to those of overactive bladder) Stage 4: contracted bladder (non-functioning)

In 2015, there were an estimated 480,000 new cases of multidrug-resistant TB (MDR-TB) and an additional 100,000 people with rifampicin-resistant TB who were also newly eligible for MDR-TB treatment. India, China and the Russian Federation accounted for 45% of the combined total of 580,000 cases. Given that most deaths from TB are preventable, the death toll from the disease is unacceptably high. Urogenital tuberculosis Urogenital tuberculosis (UGTB) is defined as an infectious inflammation of the urogenital system and its organs in any combination, caused by Mycobacterium tuberculosis (Mtb) or M. bovis. By definition it includes both urological and gynecological TB (female genital TB). In the preantibiotic era, the prevalence of UGTB was huge. Every fifth urological in-patient in France had UGTB and more than a third of all pyonephrosis was due to TB. In that period, UGTB patients were mostly young people, about equally male and female6. Today, the proportion of UGTB of all extrapulmonary TB forms varies depending on region, epidemic situation, co-morbidity, awareness, time period etc. Some authors consider UGTB to be the third most common form of extrapulmonary TB accounting for 15-20% and even 40% of extrapulmonary TB7-10. In Italy UGTB represents about 27% of all extrapulmonary localizations of TB and may be due either to a disseminated infection or to a primary urogenital localization11. In Europe, UGTB is diagnosed more often in immigrants than in the native population12. Although UGTB is one of the most common forms of extrapulmonary TB in countries with epidemic TB, the proportion of UGTB is lower in countries with low incidence rates of TB13-14. UGTB was lowest among all extrapulmonary sites in Korea15. Of 135 patients with extrapulmonary TB diagnosed in Korea between 2006 and 2013 only six (4.4%) had UGTB16. Among 415 Polish patients diagnosed with extrapulmonary TB, 58 (14.0%) had UGTB17. In Turkey UGTB was diagnosed in 5.4% of all extrapulmonary sites18. Surprisingly, in Bangladesh the proportion of UGTB was also low19. UGTB is often underestimated by clinicians because of few and non-specific symptoms and insidious disease courses13. Reported statistics may therefore be falsely low. Kidney TB Renal TB infection is often underdiagnosed in health care centers, and it can manifest itself as part of a disseminated infection or as a localized urogenital disease20. 10

EUT Congress News

Stages 1-2 of bladder TB may be cured with anti-TB therapy. Complex supplementary treatment is indicated for bladder TB stage 3. Fourth stage means shrinked bladder and cystectomy is needed24.

Figure 1: Cured cavernous prostate tuberculosis with calcified caseation and secondary prostate cancer

Prostate TB To estimate the value of prostate biopsy for diagnosing UGTB, 93 men with suspected prostate TB were enrolled in a prospective study25. All underwent standard ultrasound-guided core prostate biopsy under local anaesthesia. The biopsy cores were examined by pathomorphology, polymerase chain reaction (PCR) and TB culture. Among all patients 38.7% had a TB history and 33.3% had active TB in other locations, mostly pulmonary. Common complaints were pain in the prostatic area (96.8%), and dysuria (79.6%). Leucospermia was found in 73.1% and haematospermia in 51.6% of patients. Prostate specific antigen (PSA) was normal (less than 4.0 ng/ ml) in 81.7% and in the remaining18.3% of patients the average PSA value was 7.2 ± 1.25 ng/ml (±SD) (range 4.0–9.6 ng/ml). Histological inflammation was found in 94.6%, fibrosis in 65.6%, intraprostatic neoplasia (high grade PIN) in 9.7% and prostate cancer in 5.4% of patients. TB inflammation with Pirogov-Langhans cells was seen in 24.7% of patients. PCR of the biopsies further revealed human papilloma virus in 10 patients (10.7%), Ureaplasma urealyticum in two patients (2.2%) and Mtb was found in five patients (5.4%). Mtb culture was positive in six patients (6.4%).

Thus, prostate biopsy confirmed the diagnosis of ‘prostate TB’ in 32 patients (34.4%), 23 by histology, six by culture and five by PCR (among them, two also had positive culture)25. A recent study showed that chronic prostate inflammation accelerates prostate cancer progression, promotes initiation of diverse malignancies, enhances basal-to-luminal differentiation, and accelerates initiation of prostate cancer originating from basal cells26. TB inflammation is chronic, and may provoke development of cancer27. Case report A 72-years old patient cured from pulmonary and prostate TB complained seven years later of dysuria. PSA was 11ng/ml. Prostate biopsy revealed prostate cancer and the patient underwent prostatectomy. Large prostate caverns with calcified caseation were found (Figure 1). Active TB inflammation was not found. Therefore, in patients with a history of TB and elevated PSA levels, prostate biopsy is indicated as in any other circumstances to diagnose or rule out prostate cancer. While pulmonary TB patients mostly have a low body mass index, 41% of patients with prostate TB had metabolic syndrome and obesity24 (Figure 2). Male genital TB and infertility Fertility problems could be the first sign of male genital TB in high-risk areas, because TB epididymitis may be a cause of infertility. Obstructive azoospermia as a result of male genital TB has been reported28. Analysis of ejaculate in patients with UGTB showed normal sperm parameters only in a quarter of patients, among the others oligo-and asthenozoospermia were found. No improvement in the quality of the ejaculate was seen after anti-TB therapy29. TB and sexual dysfunction The role of pulmonary TB in the development of sexual dysfunction in men is largely unknown. To evaluate this aspect, we conducted a comparative study30 of 105 newly diagnosed patients with pulmonary TB and 37 healthy volunteers aged 18 to 39 years. All patients underwent routine clinical examination and completed the questionnaires IIEF (International Index of Erectile Function) and NIH-CPSI (Chronic prostatitis symptoms index). All tests were performed at base-line and after three and six months of standard anti-TB chemotherapy with four drugs (isoniazid, rifampicin, streptomycin, pyrazinamide). Significant disorder of all sexual components and the quality of life index was ascertained in patients with TB. Patients with pulmonary TB showed deterioration of all measured sexual parameters, such as sexual desire, orgasm, frequency of spontaneous erections, in spite of absence of any related diseases of the urogenital system. The degree of dysfunctions in the group of patients with cavernous pulmonary TB was significantly higher than in infiltrative TB30. During anti-TB therapy, we saw an improvement of the patients` general condition, disappearance or reduction of clinical symptoms, and a decreasing a number of leucocytes in the prostatic secretion and ejaculate. Restoration of libido was also noted during the anti-TB therapy. An improvement of self-estimated erectile function on the IIEF Scale was registered. However, the recorded improvement in libido, frequency of spontaneous erections, emotional state and sexual activity after three months of therapy were still significantly lower than in the group of healthy volunteers (p<0,0001). Six months of anti-TB therapy did not improve the results further. On the contrary, there was a decrease score of some criteria (frequency of spontaneous erections, proportion of successful attempts of sexual intercourse, orgasm intensity). Another study has shown serious disorder of ejaculatory function provoked by anti-TB therapy24,29. As well, we have to keep in the mind that UGTB may be sexually transmitted24.

Table 1: WHO reports on TB statistics [1-5]. Year Patients diagnosed with TB (millions) Patients died from TB (millions) HIV-positive patients died from TB (thousands)

2012 8.6 1.3 320

2013 9.0 1.5 360

2014 9.6 1.5 400

2015 10.4 1.4 400

Figure 2: Patient with prostate TB and metabolic syndrome

Challenges in UGTB UGTB is a multivariate disease and one standard approach is not suitable. To optimize the management of UGTB, a commonly accepted classification is needed and the different clinical characteristics of the various forms of UGTB have to be carefully considered. As with all other infections, attempts should be made to cure UGTB with antibacterial therapy. In case of advanced stages surgery may be required as well. Physicians should bear in mind that in addition to functional deterioration of the organs involved, such as renal insufficiency, bladder shrinkage, and infertility, TB by itself may also cause impaired sexual function which might be improved by adequate anti-TB therapy. However, patients with pulmonary or UGTB must be carefully informed about the risk of infecting their partners during sexual activity. Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. References 1. WHO. Global tuberculosis report 2012. Geneva: World Health Organization, 2012. http://www.who.int/tb/ publications/global_report/en/index.html (accessed Dec 27, 2012). 2. WHO Global tuberculosis report 2013, available on http://www.eurosurveillance.org/ViewArticle. aspx?ArticleId=20615 3. WHO Fact sheet N°104, Reviewed March 2014, available on http://www.who.int/mediacentre/ factsheets/fs104/en/ 4. WHO Global tuberculosis report 2015: who.int›tb/ publications/global_report/en/ 5. Global tuberculosis report 2016. WHO/HTM/TB/2016.13. World Health Organization Geneva 2016 6. Marion, G. Traite d’Urologie. Masson, Paris, 1940. 7. Sourial MW, Brimo F, Horn R, Andonian S. Genitourinary tuberculosis in North America: A rare clinical entity. Can Urol Assoc J. 2015 Jul-Aug;9(7-8):E484-9. doi: 10.5489/ cuaj.2643. 8. Kumar S, Kashyapi BD, Bapat SS. A rare presentation of tuberculous prostatic abscess in young patient. Int J Surg Case Rep. 2015;10:80-2. doi: 10.1016/j.ijscr.2015.03.028. Epub 2015 Mar 18. 9. Sanches I, Pinto C, Sousa M, Carvalho A, Duarte R, Pereira M. Urinary Tuberculosis: Serious Complications May Occur when Diagnosis is Delayed. Acta Med Port. 2015 May-Jun;28(3):382-5. Epub 2015 Jun 30. 10. Bacci MR, Namura JJ, Lera AT. Complicated urinary infection and extrapulmonary tuberculosis. BMJ Case Rep. 2012 Dec 17;2012. pii: bcr2012007553. doi: 10.1136/ bcr-2012-007553. 11. Toccaceli S, Persico Stella L, Diana M, Taccone A, Giuliani G, De Paola L, Valvano M, De Padua C, Di Biasio G, Ranucci C, Orsi E, La Torre F. Renal tuberculosis: a case report. G Chir. 2015 Jan-Feb;36(2):76-8. 12. Lenk S. Genitourinary tuberculosis in Germany: diagnosis and treatment. Urologe. 2011; Dec;50(12):1619-27. 13. Kulchavenya E. Extrapulmonary Tuberculosis: are statistical reports accurate? Therapeutic Advances in Infectious Disease, 2014; 2(2) 61-70: DOI: 10.1177/2049936114528173 14. Kulchavenya E. Epidemiology of urogenital tuberculosis in Siberia. American Journal of Infection Control 2013;41(10):945-6 15. Ji Yeon Lee. Diagnosis and Treatment of Extrapulmonary Tuberculosis Tuberc Respir Dis 2015;78:47-55

Monday 27 March 10.45-11.00: Thematic Session 16, Killer bacteria and viruses in urology

Monday, 27 March 2017

PI-RADS in clinical practice Including differential diagnosis in prostate imaging Prof. Harriet C. Thoeny Inselspital Universitätsspital Bern Dept. of Diagnostic Radiology Berne (CH)

cancer (Gleason > 7, volume > 0.5 ml, extracapsular extension or seminal vesicle infiltration) with a high likelihood. Findings on mpMRI are reported on a five-point scale based on a combination of imaging features on T2-weighted (T2w) MRI, DW-MRI and dynamic contrast-enhanced MRI (DCE-MRI) for each particular lesion addressing the likelihood of the presence or absence of clinically significant prostate cancer.

Most prostate cancers ( >70%) are located in the peripheral zone of the prostate. DW-MRI is the Multiparametric MRI (mpMRI) of the prostate based dominant sequence for prostate cancer detection in on prostate imaging reporting and data system the peripheral zone. DW-MRI shows the Brownian version 2 (PI-RADS v2) is widely used in clinical motion in the extracellular extravascular space and practice in many centers in Europe and far beyond. provides information on the cell density of the underlying lesion. It is therefore a very sensitive and These guidelines aim to promote global standardization, specific method to detect prostate cancer mainly in to diminish variation in image acquisition, interpretation the peripheral zone. and reporting of prostate mpMRI and to improve detection and localization of clinically significant “...mpMRI based on PI-RADS v2 is prostate cancer in treatment naïve prostates. It does however, not address detection of recurrence of prostate an excellent tool to detect or exclude cancer after radical prostatectomy or radiotherapy, clinically significant prostate cancer imaging in patients under active surveillance or evaluation of other parts of the body. with a high likelihood.” mpMRI can be performed on any clinical scanner (1.5 and 3T); however prostate MRI on a 3T MRI without endorectal coil is preferred in most centers. Emptying of the rectum before MRI is suggested to avoid air in the rectum that may hamper image interpretation due to artifacts especially for diffusion-weighted MRI (DW-MRI). Anti-peristaltic agents are recommended to reduce bowel motion artifacts. PI-RADS v2 standardises and improves communication between radiologists and urologists to detect or exclude clinically significant prostate

A typical prostate cancer in the peripheral zone is detected as a focal lesion with impeded diffusion, meaning a high signal intensity lesion on the high b-value image (b-value of > 1000sec/mm2) and a hypointense lesion on the corresponding Apparent Diffusion Coefficient (ADC) map. On T2w images these tumors are hypointense and show focal enhancement on DCE-MRI. mpMRI is excellent in detecting significant prostate cancer in the peripheral zone with a detection rate of more than 90%. Detection of prostate cancer in the transition zone is more challenging. The dominant sequence to detect prostate cancer in the transition zone is T2w showing the typical erased charcoal sign with impeded diffusion on DW-MRI and focal enhancement on DCE-MRI.

Figure 1: MR images of the prostate (3T, no endorectal coil) of 74-year old man with rising PSA of 8.0ng/ml. T2w shows a hypointense lesion in the right posterolateral peripheral zone at the midlevel with broad contact to the capsule and irregular borders suspiciuous for extracapsular extension. This lesion shows focal enhancement on the dynamic contrast-enhanced (DCE-MRI) images. On diffusionweighted MRI this lesion is hyperintense on the image acquired at a b-value of 2000 sec/mm2 and is hypointense on the corresponding ADC map. There is a high likelihood that this lesion corresponds to a clinically significant prostate cancer (PIRADS V). Histology after radical prostatectomy showed a pT3a and a Gleason score of 4+5=9. Please note typical signs of BPH in the transition zone with enhancement, but no impeded diffusion.

Definition of PIRADS scores PIRADS 1: clinically significant prostate cancer is highly unlikely to be present PIRADS 2: clinically significant prostate cancer is unlikely to be present; benign pathology e.g. benign prostatic hyperplasia (BPH), prostatitis PIRADS 3: the presence of clinically significant prostate cancer is equivocal PIRADS 4: clinically significant prostate cancer is likely to be present (size < 1.5cm) PIRADS 5: clinically significant prostate cancer is highly likely to be present (size >1.5cm, extracapsular extension or seminal vesicle infiltration independent of the tumor size) Up to four lesions have to be mentioned in the standardized report and the index lesion corresponding to the largest lesion or the lesion with extracapsular extension or seminal vesicle invasion has to be noted. Lesions corresponding to PIRADS 1 or 2 do not need to be included in the conclusion and its mention is facultative. Suspicious lesions should be noted on a sector map according to the exact anatomical localization. In the written report peripheral zone, transition zone and anterior fibromuscular stroma have to be divided into base, mid-level and apex; posterior, anterior, lateral as well as right and left. Presence or absence of extracapsular extension and seminal vesicle infiltration should always be mentioned. Suspicious lymph nodes and bone lesions are also part of a correct radiological report on prostate MRI.

Figure 2: MR images of the prostate (3T, no endorectal coil) of 77-year old man with rising PSA of 5.78ng/ml. On T2w central hyperintensity after TUR-P. The rest of the prostate is diffuse hypointense. On DCE-MRI there is focal enhancement in the right lateral peripheral zone. On diffusion-weighted MRI this lesion is hyperintense on the image acquired at a b-value of 2000 sec/mm2 and is hypointense on the corresponding ADC map. There is a high likelihood that this lesion corresponds to a clinically significant prostate cancer (PIRADS V). MR/TRUS-fusion guided biopsy showed a Gleason 4+3=7 on histology.

Monday, 27 March 2017

Several studies have shown good to excellent inter-reader agreement in the assessment of PIRADS lesions > 4. The most challenging lesions are those reported as PIRADS 3, meaning that the presence of clinically significant prostate cancer is equivocal. To improve the correct diagnosis of cancer in PIRADS 3 lesions, a lot of research is going on including quantification of DW-MRI. Not all visible lesions on mpMRI correspond to cancer and to make the correct diagnosis of a benign pathology all available sequences including morphology and function have to be taken into account. Differential diagnoses Benign prostatic hyperplasia (BPH) shows typically hypo-or hyperintense well-delineated nodules with a hypointense rim in the transition zone leading to enlargement of the prostate. As a consequence, the peripheral zone can become smaller or nodules can protrude into the peripheral zone mimicking prostate cancer if image interpretation does not take into account T2w sequences and findings are only based on functional techniques. Also BPH nodules can show impeded diffusion on DW-MRI and focal enhancement on DCE-MRI. In these cases the correct diagnosis can only be made based on T2w sequences. Prostatitis/inflammation has a high prevalence around the world, is often clinically silent and can also lead to an elevated PSA. In contrast to cancer lesions, prostatitis is often a more diffuse process and can present as a hypointense lesion on T2w with slightly impeded diffusion, however, to a lesser extent than tumors. ADC measurement can be helpful to differentiate tumor from inflammation with the latter showing a higher ADC value compared to prostate cancer. Prostatitis often shows diffuse enhancement. Granulomatous prostatitis, however, also shows focal enhancement and impeded diffusion such as significant prostate cancer and based on imaging these entities can’t be separated. In these cases knowledge of previous BCG instillation can help to suggest this potential differential diagnosis. Normal findings such as the normal central zone presenting as a hypointense lesion in the posterior base of the prostate should not be interpreted as

Figure 5: MR images of the prostate (3T, no endorectal coil) of 65-year old man with rising PSA of 9.5 ng/ml. On T2w images there is a small hypointense lesion in the anterior fibromuscular stroma in the apex on the right side. On diffusion-weighted MRI this lesion is hyperintense on the image acquired at a b-value of 1000 and 2000 sec/mm2 and is hypointense on the corresponding ADC maps. There is likelihood that this lesion corresponds to a clinically significant prostate cancer (PIRADS IV). MR/TRUS-fusion guided biopsy showed a Gleason 3+3=6, 11 mm on histology.

cancer. Furthermore, the normal ductus deferens might mimic seminal vesicle infiltration for an unexperienced reader.

“Indication to perform mpMRI is often a negative previous biopsy; however, the use of mpMRI before biopsy is increasing in many institutions.”

Figure 3a: MR images of the prostate (3T, no endorectal coil) of 57-year old man with rising PSA of 9 ng/ml. On T2w there is diffuse hypointensy of the entire prostate. On DCE-MRI there is focal enhancement in the right lateral peripheral zone at the midlevel. On diffusion-weighted MRI this lesion is hyperintense on the image acquired at a b-value of 2000 sec/mm2 and is hypointense on the corresponding ADC map. There is a high likelihood that this lesion corresponds to a clinically significant prostate cancer (PIRADS V). MR/TRUS-fusion guided biopsy showed a Gleason 3+4=7 on histology.

Indication to perform mpMRI is often negative previous biopsy; however, the use of mpMRI before biopsy is increasing in many institutions. Main indications include rising PSA, suspicious digital rectal examination or positive family history for prostate cancer. The use of targeted biopsies by MRI or by MR/ TRUS-fusion guidance has shown promising results in detecting more clinically significant prostate cancers and decreasing the detection rate of insignificant prostate cancers. A pre-requisite to achieve these excellent results is optimal MR images, experienced and dedicated radiologists and discussion of each case prior to biopsy between radiologist and urologist (if the urologist performs the biopsy).

Figure 4: MR images of the prostate (3T, no endorectal coil) of 69-year old man with rising PSA of 5.8 ng/ml. On T2w images there is a small hypointense lesion in the anterior transition zone at the midlevel on the right side with irregular borders. On diffusion-weighted MRI this lesion is hyperintense on the image acquired at a b-value of 2000 sec/ mm2 and is hypointense on the corresponding ADC map. There is likelihood that this lesion corresponds to a clinically significant prostate cancer (PIRADS IV). MR/TRUS-fusion guided biopsy showed a Gleason 3+3=6 on histology.

Additional information based on mpMRI Several studies have shown an inverse relationship between tumor aggressiveness (Gleason score) and ADC value. This might be helpful to determine the index lesion, to perform targeted biopsy and to apply this information in the evaluation of patients under active surveillance due to a low grade prostate cancer. However, for the time being, the Gleason score based on ADC cannot be determined for each individual patient. In conclusion, mpMRI based on PI-RADS v2 is an excellent tool to detect or exclude clinically significant prostate cancer with a high likelihood. However, excellent image quality, reader experience and close collaboration between radiologists and urologists are the prerequisite for optimal patient management. Suggested literature Weinreb JC et al. PI-RADS Prostate Imaging- Reporting and Data System: 2015 Version 2, Eur Urol 2016. Steiger P, Thoeny HC. Prostate MRI based on PI-RADS version 2: how we review and report. Cancer Imaging 2016.

Figure 3b: These images show typical seminal vesicle infiltration on the right lateral side in all sequences which has been proven on histology based on MR/TRUS-fusion guided biopsy revealing a Gleason 3+4= 7 on histology.

Monday, 27 March 10.30-10.45: Thematic Session 15, MRI in prostate cancer: Optimising interpretation by urologists and radiologists; European Society of Urogenital Radiology (ESUR) Lecture, PI-RADS in clinical practice including differential diagnoses in prostate imaging

EUT Congress News

Holmium laser Space age technology with primitive problems Dr. Peter Kronenberg Hospital Prof. Doutor Fernando Fonseca Amadora (PT)

Almost half a century has passed since the world’s first urological laser procedure in 1968.1 After the introduction of the first commercial laser lithotripter in the 1980s, urological applications in the literature quickly overshadowed the use of laser lithotripsy in all other medical fields, such as gastroenterology, general surgery or ENT, to treat, for example, biliary, pancreatic, or salivary stones.2-6 Currently, laser lithotripsy is established primarily as a urological field, with 85-90% of the articles published in the last 10 years authored by urology-affiliated investigators.6 In particular, the holmium:yttriumaluminum-garnet laser (holmium laser) is extremely useful and has a wide range of applications in most urological fields, such as lithotripsy, coagulation, incisive, resection, enucleation or vaporization procedures. This versatility, associated to an excellent safety profile in any endourological setting, makes holmium laser one of the favorite tools of any urologist.

measure any significant rise in ablation volume with an increase in pulse frequency.6,7,16 In a study where total power was kept constant, low frequency using high-pulse energy settings showed a statistically significant favorable difference over high frequency using low-pulse energy settings. Besides showing a directly proportional increase in ablation volume as pulse energy rises, that study also showed how at the same power levels, low frequency using high-pulse energy settings were up to six times more ablative than high frequency using low-pulse energy settings. Even very high power settings using high frequency were surpassed by significantly lower total power settings using higher pulse energies, highlighting pulse energy as the determinant factor in ablation volume, with pulse frequency and total power playing a secondary role.17 Technological upgrade As previously mentioned and regardless of their power capabilities, until then, holmium laser lithotripters had only two parameters controllable by the urologist: pulse energy and pulse frequency. Only 20 years after their first use, did holmium laser lithotripthers get their first true technological upgrade, in 2012: the ability to change pulse length. Instead of a fixed pulse length or pulse duration (300-350 µs), thenceforth known as short pulse, the urologist could now choose a different and longer pulse length, subsequently known as long pulse (800-1200 µs).

Although all other lithotripter settings remain the same, with the same pulse frequency, the same pulse energy, and therefore the same power level, in short-pulse lithotripsy the energy delivered by a The optimal holmium laser lithotripter settings and the most appropriate laser fibers to achieve the best single laser pulse occurs during a certain period of time, while in long-pulse lithotripsy, that same lithotripsy performance is an ongoing discussion and amount of energy is distributed over a longer period are still being refined.6–8 A quick review how this of time.6 In comparison to short-pulse lithotripsy, holmium laser technology evolved and its main long-pulse lithotripsy is a bit less ablative18, but it accomplishments are summarized here. doesn’t produce so much retropulsion, fiber The main, and usually the only, adjustable parameters burn-back is significantly reduced with less cladding of the first holmium laser lithotripter are pulse energy degradation as well as less fiber tip opacification6, and pulse frequency. The total power output results and the size of resulting stone fragments also seems from the product of these two parameters: Total Power to be smaller. (W) = Pulse energy (J) × Pulse frequency (Hz). By adjusting these parameters, the urologist decides the From now on, instead of lowering the pulse energy to energy intensity that is delivered at the tip of the laser minimize retropulsion or laser fiber damage, fiber to ablate the urinary calculi.6 As expected, urologists can choose a different approach, by increases in total power, i.e. in pulse energy or pulse changing their settings to long-pulse mode, without frequency, were usually accompanied by an increase decreasing too much ablation efficiency. Further in ablation volume but by no means in a linear fashion improvements in this field led to the launching of as shown ahead. several laser lithotripters which, besides offering short and long-pulse mode, also have medium or even But, as with any new technology, some problems and ultra-short-pulse modes.19 limitations quickly became apparent. First, laser lithotripsy produces retropulsion, similar to ballistic One of the latest innovations is an entirely new form of lithotripsy, although to a lesser extent. Retropulsion is lithotripsy known as “burst laser lithotripsy”. In known to reduce lithotripsy efficacy, increase conventional laser lithotripsy each pulse is exactly the operating time and, sometimes, making ureteral same as its preceding or succeeding pulse, with the calculi inaccessible by pushing them into the renal same pulse energy, the same pulse length and also pelvis.9 And the higher the pulse energy, the greater the same time interval between pulses. However, in the retropulsion effect.9-12 Second, laser fibers suffer a burst lithotripsy, each burst is made of several burn-back effect, especially the fiber tip, that wears off individual pulses, which are fired in a very rapid faster, and whose damages are more intense at higher succession (few milliseconds from one another), each pulse energies.13 And, third, laser lithotripsy produces pulse having the same amount of energy. stone fragments, whose size and number can increase the operating time, requiring further laser lithotripsy However, that amount of energy is delivered over and/or the use of an expensive stone-removal device. increasing periods of time, i.e. with increasing pulse Some authors advocate that lowering pulse energy lengths. For example, in case of a 3-pulse-based reduces fragment size.7,14,15 Nevertheless, these burst, the first pulse is the most powerful one, first-generation holmium laser lithotripters were succeeded by a less powerful, and finally by the least powerful one. Within each second of laser emission, low-powered (usually up to 15 W maximum), with low-pulse energies (up to 1.5 J), having limited there may be several of these bursts. Initial tests frequencies (up to 15 Hz), and a fixed pulse length/ showed burst laser lithotripsy to be 60% more duration (300-350 µs). ablative than conventional laser lithotripsy at similar power levels.20 Nonetheless, other aspects such as Some manufacturers tried to overcome this by retropulsion or resulting stone fragments must still be producing more powerful lithotripters (up to 100 W), evaluated with this new lithotripsy mode. capable of higher pulse energies (sometimes up to 3,5 J), as well as producing higher frequencies (up to 50 Efficacy of outcomes Hz). However, the retropulsion and laser fiber In conclusion, as soon as the first holmium laser burn-back issues shown by the first lithotripters lithotripters appeared on the market, difficulties and continued and were even exacerbated in these limitations pertaining to that technique were lithotripters with the use of higher pulse energies. To identified. Developments and improvements in the prevent these persisting drawbacks, higher pulse technology followed, improving efficacy and reducing frequencies were advocated as the way to go. Lower some of the associated difficulties, while others pulse energies could therefore be used, and still remained to be addressed. achieve higher power outputs (e.g. 0.6 J x 50 Hz = 30 W), without damaging the laser fibers considerably, The foreseeable future could well include a very reducing retropulsion to some extent, and also giving high-frequency rotating-pulse-length burst laser the impression of lowering the number of large stone lithotripter. But regardless of any upcoming fragments. technological innovation, the surgical technique and approach of each individual urologist to a urinary The increase in pulse frequency and the consequent stone still weights on the outcome of the procedure. increase in total power were also expected to increase An ancient scalpel in prudent hands succeeds better ablation volume. However several studies did not than the best laser scalpel in inexperienced ones… 12

EUT Congress News

Advances in holmium laser lithotripters have improved efficacy and reduced some technical drawbacks (Photo: EUT Archives)

References 1. Parsons RL, Campbell JL, Thomley MW. Carcinoma of the penis treated by the ruby laser. J. Urol 1968; 100(1):38–9. 2. U.S. Corporate News: News from Candela Corporation. Laser Medicine and Surgery News and Advances 1988; 6(5):24–5. 3. Ritchey M, Patterson DE, Kelalis PP, Segura JW. A case of pediatric ureteroscopic lasertripsy. J Urol 1988; 139(6):1272–4. 4. Hofmann R, Hartung R. Use of pulsed Nd:YAG laser in the ureter. Urol Clin North Am 1988; 15(3):369–75. 5. Coptcoat MJ, Ison KT, Watson G, Wickham JE. Lasertripsy for ureteric stones in 120 cases: lessons learned. Br J Urol 1988; 61(6):487–9. 6. Kronenberg P, Traxer O. Update on lasers in urology 2014: current assessment on holmium:yttrium-aluminumgarnet (Ho:YAG) laser lithotripter settings and laser fibers. World J Urol 2015; 33(4):463–9. 7. Sea J, Jonat LM, Chew BH et al. Optimal power settings for Holmium:YAG lithotripsy. J. Urol. 2012; 187(3):914–9. 8. Patel AP, Knudsen BE. Optimizing use of the holmium:YAG laser for surgical management of urinary lithiasis. Curr Urol Rep 2014; 15(4):397. 9. Kronenberg P, Traxer O. V1718 LASER FIBERS, PULSE ENERGY AND RETROPULSION-WHAT WE CAN SEE AND WHAT WE CAN’T. The Journal of Urology 2013; 189(4):e707. 10. Kang HW, Lee H, Teichman JMH, Oh J, Kim J, Welch AJ. Dependence of calculus retropulsion on pulse duration

during Ho: YAG laser lithotripsy. Lasers Surg Med 2006; 38(8):762–72. 11. Blackmon RL, Irby PB, Fried NM. Comparison of holmium:YAG and thulium fiber laser lithotripsy: ablation thresholds, ablation rates, and retropulsion effects. J Biomed Opt 2011; 16(7):71403. 12. Lee H, Ryan RT, Kim J et al. Dependence of calculus retropulsion dynamics on fiber size and radiant exposure during Ho:YAG lithotripsy. J Biomech Eng 2004; 126(4):506–15. 13. Kronenberg P, Traxer O. Are we all doing it wrong? Influence of stripping and cleaving methods of laser fibers on laser lithotripsy performance. J. Urol. 2015; 193(3):1030–5. 14. Spore SS, Teichman JM, Corbin NS, Champion PC, Williamson EA, Glickman RD. Holmium: YAG lithotripsy: optimal power settings. J Endourol 1999; 13(8):559–66. 15. Corbin NS, Teichman JM, Nguyen T et al. Laser lithotripsy and cyanide. J. Endourol. 2000; 14(2):169–73. 16. Chawla SN, Chang MF, Chang A, Lenoir J, Bagley DH. Effectiveness of high-frequency holmium:YAG laser stone fragmentation: the “popcorn effect”. J. Endourol 2008; 22(4):645–50. 17. Kronenberg P, Traxer O. In vitro fragmentation efficiency of holmium: yttrium-aluminum-garnet (YAG) laser lithotripsy - a comprehensive study encompassing different frequencies, pulse energies, total power levels and laser fibre diameters. BJU Int. 2014; 114(2):261–7. 18. Wezel F, Häcker A, Gross AJ, Michel MS, Bach T. Effect of pulse energy, frequency and length on holmium:yttriumaluminum-garnet laser fragmentation efficiency in non-floating artificial urinary calculi. J. Endourol. 2010; 24(7):1135–40. 19. Kronenberg P, Traxer O. 1035 Ultra-short, short, medium and long-pulse laser lithotripsy performance. European Urology Supplements 2016; 15(3):e1035. 20. Kronenberg P, Traxer O. 941 Burst laser lithotripsy – a novel lithotripsy mode. European Urology Supplements 2016; 15(3):e941.

Tuesday 28 March 10.53-11.00: Plenary Session 7, Stones

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

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

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

www.urochm.rcsed.ac.uk Monday, 27 March 2017

Radical cystectomy Intestinal injuries: How to solve them?

In any case of rectal full-thickness injury, we recommend adequate decompression of the lacerated bowel and establishment of sufficient pelvic drainage. It is our practice to dilate the anal sphincter manually immediately after the bowel repair and to place a Radical cystectomy (RC) continues to be a procedure rectal tube at the end of the surgery while a patient is of choice for muscle invasive bladder cancer1. still in theatre. This approach decreases intraintestinal Although improvements in surgical technique, as well pressure within the affected segment of the bowel and as in pre- and postoperative care for patients on the rectal suture line which if not reduced can undergoing this type of surgery that have been result in repair dehiscence with further serious introduced over the last 30 years reduced the consequences. Following rectal injury repair, we mortality and morbidity rates, RC is still associated recommend to drain the pelvis in an effort to minimise with significant rate of complications. the risk of pelvic abscess formation. We prefer to place a drainage tube through a direct stab wound in the Morbidity related to RC and urinary diversion occurs perineum if urethrectomy has not been performed, in up to 40% of all patients2,3. Intestinal injury rate whereas in case of urethral resection drain should which has decreased in the last three decades and in course through the urogenital diaphragm. Optimal pelvic drainage is direct and dependent. Aggressive contemporary series accounts for up to 10% of all complications in individuals operated for muscle postoperative nutrition in all patents with colonic repair in the form of parenteral hyperalimentation is invasive bladder cancer, has potentially grave consequences if not recognised early4-7. critical, as the period of starvation is prolonged and individuals are in acute catabolic state. Rectal injury Inadvertent rectal injury from radical cystectomy most Postoperative bowel leak commonly occurs during one of two parts of the Postoperative bowel leak should be suspected in dissection i.e. in the development and transection of patients who present with fever, wound infection and the most distal portion of the lateral bladder pedicles leukocytosis on the fifth to seventh postoperative day or as the dissection plane between the bladder and/ or in individuals with delayed return of bowel or prostate gland and the rectum is being established. function temporarily associated with these events or The latter scenario is more frequent and results from when the signs of clinical peritonitis or sepsis are improper entrance into the plane or an obliteration of present. In any of these cases, an aggressive search antecedent factors such as fibrosis around the for a drainable intra-abdominal collection with anterior vaginal cuff and rectum in women who had computed tomography (CT) scan with water-soluble previously undergone hysterectomy. oral contrast agent is indicated. CT not only helps to localise an enteric fistula but also provides additional As unrecognised colonic injury can lead to a significant information about the presence of potential distal potential sequelae with intra-abdominal sepsis and intestinal obstruction that may have contributed to the death, it is imperative that any and all intestinal injuries enteric fistula formation, and if not recognised and are recognised intraoperatively so that the rectifying addressed will adversely affect bowel repair. steps can be taken promptly and serious postoperative consequences are hence avoided. Therefore, after Management of postoperative enteric fistula in patients bladder removal the rectum needs to be carefully who underwent radical cystectomy poses a clinical inspected. Diligent intraoperative inspection of the dilemma since the rationale for the approach to follow anterior and lateral rectal walls is of utmost importance can only be supported by scattered low-level evidence. and if this is inconclusive we recommend insufflating There are two ways of approaching the complication: the rectum with air while the pelvis is filled with fluid. emergency laparotomy and conservative management9. This maneuver helps to delineate the site of injury Personal experience of the authors of this paper with which is indicated by appearing air bubbles. postoperative bowel leak is limited to only several cases. However, we are of the opinion that embarking In case of intestinal tear adequate repair must be on a trial of conservative management should be performed. This may involve either primary closure limited only to those cases with an adequate drainage and/or colostomy formation. Several factors including of the intestinal leakage through the surgical wound or the ones that may significantly impair healing in the a drain tract, in clinically well patients with no signs of cystectomy patients, and thus needs to be considered clinical peritonitis or evidence of the systemic when choosing management of iatrogenic rectal injury inflammatory response syndrome (SIRS) or sepsis, and include patient’s nutritional status, presence of no associated abscess on CT. diabetes mellitus, previous irradiation or pelvic surgery, colonic inflammatory disease, degree of faecal Total parental nutrition should be introduced in all contamination, infection, patients prognosis, difficulty individuals treated conservatively, as it has been of the procedure and type of urinary diversion planned. shown to increase the spontaneous closure rate by inducing bowel hypoactivity and to provide better nutritional preparation of the patient for reoperation if In case of a simple serosal injury we over-sew the the fistula fails to close spontaneously10. The reported defect with 3-0 Vicryl suture. If the rectum is perforated (i.e. full-thickness lesions), we perform a success rate for spontaneous closure of enteric fistula two-layer primary repair. Following wound edges within six weeks of conservative management reaches debridement a running 3-0 polydioxanone (PDS) 50%. The remainder of patients requires elective suture is used to close the mucosa and attention is fistula repair with re-establishment of intestinal tract paid to invert mucosal edges into the bowel lumen continuity. This should be performed not earlier than while performing this step. An interrupted inverting three to four months following the RC9. muscular layer closure with 3-0 Vicryl suture is used to complete the repair. Whenever possible, we cover Immediate relaparotomy is indicated in patients with the repair with a greater omental apron particularly if evidence of clinical peritonitis, SIRS or sepsis with orthotopic neoblader is to be constructed. As soon as proven or suspected intraperitoneal abscess the continuity of bowel is reestablished we irrigate amenable to percutaneous drainage or in which the pelvis with saline to minimise the degree of faecal percutaneous drainage has failed9. Moreover, contamination and dilute the bacterial inoculum. emergency laparotomy should also be considered in Additionally, each patient receives a broad-spectrum patients with intraabdominal syndrome or in whom intravenous antibiotic therapy. the primary surgery was performed by an unknown Monday, 27 March 2017

or untrusted surgeon. The aim of emergency relaparotomy is to control the source of contaminating infection by cleansing the abdominal cavity and pelvis of any loculated abscess by using copious irrigation, adequate drainage of the pelvis and peritoneum and formation of proximal enterostomy. In very selected cases, i.e., in a stable, minimally compromised patient, when peritonitis is macroscopically minimal, and the quality of bowel appears good, and RC was performed no more than two days earlier, resection of the affected bowel segment with primary anastomosis may be advocated9. In these patients a typical two-layer hand-sewn closure is recommended. Conclusions Intestinal injury during radical cystectomy should not be left unrecognised since even subtle has serious postoperative complications. Intraoperatively identified full-thickness rectal injury should be closed in two layers. Diversion of the faecal stream by the means of sigmoid loop colostomy should additionally be performed in complicated cases with the potential for poor healing or when the rectal defect is substantial or there is a considerable degree of faecal contamination. Further principles include bowel decompression, adequate drainage, broad-spectrum antibiotic therapy and good nutrition. Development of an intestinal leak following RC is a potentially life threatening complication and its treatment must be tailored to the individual patient. Emergency relaparotomy is indicated in the setting of peritonitis, SIRS or sepsis. Whereas, clinically well patients with no signs of clinical peritonitis or evidence of SIRS and no associated abscess on CT, and with adequate drainage of the intestinal leakage may be given a trial of conservative management. References 1. Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, Hernández V, Espinós EL, Dunn J, Rouanne M, Neuzillet Y, Veskimäe E, van der Heijden AG,

Gakis G, Ribal MJ. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur Urol. 2016 Jun 30. pii: S0302-2838(16)30290-1. doi: 10.1016/j. eururo.2016.06.020. 2. Farnham SB, Cookson MS: Surgical complications of urinary diversion. World J Urol. 2004;222:157-167. 3. Knap MM, Lundbeck F, Overgaard J: Early and late treatment-related morbidity following radical cystectomy. Scand J Urol Nephrol. 2004;38:153-160. 4. Takada N, Abe T, Maruyama S, Sazawa A, Shinohara N, Seki T, Togashi M, Nonomura K; Hokkaido Urothelial Research Cancer Group. Perioperative morbidity and mortality in patients treated by radical cystectomy: A multi-institutional retrospective study. J Clin Oncol. 2011;29(7_suppl):270. 5. Palazzetti A, Sanchez-Salas R, Capogrosso P, Barret E, Cathala N, Mombet A, Prapotnich D, Galiano M, Rozet F, Cathelineau X. Systematic review of perioperative outcomes and complications after open, laparoscopic and robot-assisted radical cystectomy. Actas Urol Esp. 2016 Nov 28. pii: S0210-4806(16)30157-7. doi: 10.1016/j. acuro.2016.05.009. 6. Hautmann RE, Gschwend JE, de Petriconi RC, Kron M, Volkmer BG. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery-only series in the neobladder era. J Urol. 2006;176(2):486-92. 7. Chang SS, Cookson MS, Baumgartner RG, Wells N, Smith JA Jr. Analysis of early complications after radical cystectomy: results of a collaborative care pathway. J Urol. 2002;167(5):2012-6. 8. Flechner SM, Spaulding JT. Management of rectal injury during cystectomy. Urology. 1982;19(2):143-7. 9. Schein M. Postoperative small bowel leak. Br J Surg. 1999;86(8):979-80. 10. Smith SJ, Austen WG Jr, Souba WW: Nutrition and metabolism. Greenfield LJ Mulholland MW Oldham KT Zelenock GB Lillemoe KD Surgery: Scientific Principles and Practice. 3rd ed 2001 Lippincott Williams & Wilkins Philadelphia 43-68.

Monday 27 March 10.45-11.00: Thematic Session 11, Complications: Radical cystectomy

LLITE T E S I UM O

S S YMP A

Dr. Tomasz Golabek Department of Urology Jagiellonian University Krakow (PL)

In complicated cases with the potential for poor healing or when the rectal defect is substantial or there is a considerable degree of faecal contamination, we prefer to perform a sigmoid loop colostomy which is easy to do and requires minimal bowel manipulations. Moreover, it can be reversed early, usually six to eight weeks following RC, if re-convalescence of the patient is uneventful and an integrity of the bowel is confirmed by contrast studies8. To create a sigmoid loop colostomy, we bring out a redundant loop of sigmoid colon through a circular stoma in the left lower quadrant of the abdomen. Next, we dissect the mesentery from the bowel for a distance of approximately 5cm to 6cm sufficient to allow the sigmoid to knuckle, and we open the antimesenteric border of the loop. The bowel is sutured to the skin after the abdominal wound is closed and dressed.

Chaired by Professor Nicholas D. James on Saturday 25th March

Treating Urological Cancers

New Twists and Turns In The Road Professor Thomas H. Lynch (Ireland) How far have we improved on prostate cancer management? Professor Lynch provided an overview of the advances in the diagnosis and treatment of prostate cancer over the past century, with a focus on the evolving role of hormone manipulation in therapeutic strategies for this disease. With cancer care moving further towards individualized medicine, recent developments and remaining challenges in the fields of robotic surgery and genetic profiling were also critically examined by Professor Lynch.

Professor Susanne Osanto (The Netherlands) Systemic therapy in RCC – current landscape and future directions Professor Osanto reviewed the latest advances in the second-line renal cell carcinoma (RCC) setting, focusing on new agents that have recently reported significant survival benefit following first-line therapies. The impact of the expanding second-line options on clinical practice guidelines was also discussed.

Professor Shahrokh F. Shariat (Austria) The future of non-muscle-invasive bladder cancer management Professor Shariat presented the latest developments aimed at improving the management of non muscle-invasive bladder cancer (NMIBC) for patients. Key topics in this field, covered by Professor Shariat, included preventive strategies, earlier and improved detection and resection of NMIBC, more accurate risk stratification, and less invasive risk-stratified follow-up. UK/DEC09547c February 2017

Prof. Piotr L. Chlosta Department of Urology Collegium Medicum Jagiellonian University Krakow (PL)

TOPIC OF THE YEAR 2017

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

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

Please visit the Ipsen booth E16

Exib. Halls S7-S10 Level 1

EUT Congress News

Extracorporeal Shock Wave Lithotripsy (ESWL) Proper ESWL training is a key to achieving better results Dr. Geert Tailly Algemeen Ziekenhuis Klina Dept. of Urology Brasschaat (BE)

In major congresses in recent years, the importance of extracorporeal shock wave lithotripsy (ESWL) as a valuable treatment modality in active stone management has been relentlessly challenged. This challenge is based mainly on perceptions and misconceptions. Treatment results with ESWL are supposedly disappointing both in terms of retreatment rates and stone-free rates (SFRs). Apart from that, and in contrast to endourological techniques, ESWL is believed to require few skills and hence is underestimated as a “serious” treatment modality. As a consequence training in and proper performance of ESWL are often neglected creating a vicious circle. The EAU Guidelines on Urolithiasis are the result of a meticulous analysis of the existing literature on stone treatment. These Guidelines specifically state that success with ESWL depends on the efficacy of the lithotripter and the following factors: size, location and composition (hardness) of the stones, patient’s habitus and the proper performance of the procedure. Results are operator-dependent and better results are obtained by experienced clinicians. According to these Guidelines, ESWL remains a recommendable treatment choice for renal stones less than 20 mm in size. While with increasing stone size SFRs both for ESWL and retrograde intrarenal surgery (RIRS) decrease, SFRs for percutaneous nephrolithotomy (PNL) remain largely unaffected. Due to the decreasing SFRs and the need for repeat sessions with increasing stone size, neither RIRS nor ESWL are recommended as first-line treatment for stones larger than 20 mm.

Newer insights in SW-physics have changed SW delivery techniques. A slower SW-rate (60-90 SW/min) reduces cavitation effects and, hence, reduces the risk of cavitation induced adverse tissue effects. This in turn improves the efficacy of every single SW hitting the stone, thus improving fragmentation and outcome: better SFR, lower retreatment rate and better Effectiveness Quotient (EQ). Apart from improving outcome, a slower SW-rate is also reported to improve cost-effectiveness (due to the lower retreatment rate). Gradually increasing the power output of the lithotripter (“voltage stepping or ramping”) improves stone comminution and reduces potential injury to the renal parenchyma. It is also recommended to start with a low voltage dose of 100-200 SW before starting voltage stepping and to have a treatment pause of one to two minutes after an initial low energy dose of ± 200 SW. One of the most important factors in SW-delivery is the coupling of the therapy head to the patient. In the original Dornier HM3 lithotripter optimal coupling was achieved by immersing both patient and SW-source in 1200 litres of degassed water. The acoustic impedance of water and human tissue being comparable there was little or no energy loss in the propagation of the SW into the patient. Modern “dry head” lithotripters use ultrasound gel as an interface between the water cushion in the therapy head and the patient. Several in vitro studies have established that air bubbles in the coupling area significantly affect energy transfer and hence disintegration efficacy. In one study by Pishchalnikov et al.1, efficiency of stone fragmentation decreased by 20-40% when only 2% of the coupling area was covered with air pockets.

“More and more patients are obese and this can constitute a challenge to ESWL. Focal distances largely exceeding SSD could possibly improve outcome in the obese.”

For stones 10-20 mm in the lower pole, ESWL is not recommended in the presence of unfavourable anatomic factors. Although fragmentation of lower pole stones rarely poses a problem, SFRs may be affected by poor clearance of the fragments from the gravity-dependent lower pole. In the absence of unfavourable factors both ESWL and endourologic techniques are equally recommended in this subgroup.

Removing air bubbles In a study by Bohris2 43% more SW were needed to fragment model stones when only 8% of the coupling interface was covered with air bubbles. During the coupling process, air bubbles are inevitably trapped in the coupling area between water cushion and patient. Until recently it proved impossible however to visually monitor the coupling area for the detection of air bubbles.

In the treatment of ureteral stones, overall SFRs after URS or ESWL are reported to be comparable. Larger stones (>10 mm) achieve earlier and higher SFRs with URS, but URS is associated with higher complication rates and a longer hospital stay. For ureteral stones smaller than 10 mm both ESWL and URS are recommended as first choice regardless of their location in the ureter.

Some newer lithotripters now have a video camera in the therapy head allowing visual monitoring of the coupling area with optically controlled removal of air bubbles from this interface. Optically controlled removal of air bubbles significantly reduces the total energy needed (number of SW and energy level) to obtain comparable treatment results3. Theoretically, this reduction in total energy applied should also reduce incidence and severity of SW-induced adverse effects.

Least invasive treatment Still, according to the Guidelines, ESWL remains the least invasive treatment modality in children.Apart from the important observation that children pass fragments more easily than adults, the indications for ESWL in children are the same as in adults.

Patiënt about to undergo an endoscopic procedure on a multifunctional lithotripter, (Photo. G. Tailly)

A good analgesia regimen during ESWL will also improve outcome. Medical expulsive therapy (MET) with α1-blockers can enhance the clearance of stone fragments. Complication rates with ESWL are very low and with the exception of a perirenal or intracapsular hematoma (<1%) complications are minor. Not unimportant also is the fact that patients tend to prefer ESWL over more invasive procedures. “Primum non nocere” is one of the pillars of the practice of medicine. In stone management this translates to choosing the least invasive method that will do the job with the lowest complication rate possible. Modern stone management should be based on a judicious combination of all available treatment modalities. This means that ESWL and endourological techniques should be complementary in rendering a patient stone free. Every stone treatment should be tailored to both the stone and the stone bearing patient. As a consequence urologists interested in advanced stone treatment should be well trained and comfortable in all modalities including ESWL. In the past, training in ESWL more often than not has been substandard. Also newer machines were all too often considered “plug and play”. Multifunctional lithotripter To offer the full range of treatment modalities and to have the possibility to perform all stone- related interventions in optimal conditions, stone centers ideally should be equipped with a multifunctional lithotripter. A modern multifunctional lithotripter needs to have a good uro-table function allowing comfortable perfomance of endourological procedures. Ideally, this

“Emergency” ESWL within a short interval after a first episode of colic offers improved fragmentation, a shorter time to achieve complete stone clearance, an increase of SFR, a reduced need for repeat ESWL sessions and a treatment of the renal colic in itself.

uro-table is accessible over 360° and has a radiolucent carbon fibre table top with a high weight bearing capacity. A videocamera in the therapy head to visually monitor the coupling interface is an advantage. The system should also offer versatile imaging modalities with simultaneous use of fluoroscopy and ultrasound. The possibility to couple the SW-source both above and under table will allow all patients to be treated in a more comfortable supine position. More and more patients unfortunately are obese and this can constitute a challenge to ESWL. According to the literature ESWL failure correlates with an increased BMI (>30) and ESWL becomes less effective as SSD (skin-to-stone distance) approaches the focal distance of the lithotripter. In obese patients the main problem is proper targeting and focusing of the stones. Focal distances of earlier lithotripters typically were 12-13 cm with 15 cm being the exception. Newer lithotripters now boast focal distances up to 17 cm. In combination with high resolution imaging systems, versatile coupling of the therapy head above and under table and positioning tricks by experienced operators, better results can be obtained even in obese patients. Continued researches in new technical developments are expected to improve the performance of lithotripters in the future: modifications of SWgeometry, Burst Wave Lithotripsy (BWL), modifications of the p- phase (tensile phase) of the SW, and techniques to rapidly eliminate cavitation bubbles as soon as they have formed. Finally, one cannot overemphasize the importance of proper training in ESWL. According to Neisius et al.4, with proper training ESWL could become the new phoenix: “If urologists make use of a more comprehensive understanding of the pathophysiology and the physics of SW, much better results could be achieved in the future. This may lead to a renaissance and encourage SWL as first-line therapy for urolithiasis in times of rapid progression in endoscopic treatment modalities.” References 1. Yuri A. Pishchalnikov, Joshua S. Neucks, R. Jason VonDerHaar, Irina V. Pishchalnikova, James C. Willliams, Jr. and James A. McAteer. Air pockets trapped during routine coupling in dry head lithotripsy can significantly decrease the delivery of shock wave energy. The Journal of Urology, Vol. 176, 2706-2710, December 2006. 2. Bohris C. Quality of coupling in ESWL significantly affects the disintegration capability – how to achieve good coupling with ultrasound gel. In: Therapeutic Energy Applications in Urology ll. Edited by C. Chaussy, G. Haupt, D. Jocham et al. New Yrok; Thieme 2010, p 61-64. 3. Tailly et al., Optical coupling control. An important step toward better ESWL. J. Endourol., Vol 28, No 11, 2014, 1368-1373 4. Andreas Neisius, Michael E. Lipkin, Jens J. Rassweiler, Pei Zhong, Glenn M. Preminger, Thomas Knoll. World J. Urol. Published online 01 August 2014

Key factors for success with ESWL are the operator and the lithotripter. For the longest time ESWL has been considered a boring and tedious procedure with little or no input from the clinician operating the machine. The complexity of SW-administration and the importance of a well-trained and experienced urologist performing the treatments, however, are largely underestimated. A basic understanding of the physics of shockwaves and a proper training in their administration should form the basis of good clinical practice in ESWL. In the early days all possible means were used to expedite the treatments: ungated SW-delivery, dual shocks, the highest possible SW-rate at the highest possible energy, etc…

Tuesday March 28 08.30-13.30: Plenary Session 7, Stones: ESWL A patient undergoing ESWL with ultrasound targeting of the stone (Photo: G. Tailly)

EUT Congress News

Monday, 27 March 2017

The urologist: Primary gatekeeper of men’s health Central role of urology in higher number of ageing men Prof. Nikolaos Sofikitis Chairman, Department of Urology Ioannina University School of Medicine Ioannina (GR)

59 years, 40% when the age is 60 to 69 years, and 50% to 100% when age is 70 to 80 years6. Sexual health is a crucial aspect of overall health and quality of life7. It has been demonstrated very vividly that interaction between erectile dysfunction and depression results in an impaired quality of life attributable to a decrease in free testosterone serum levels8 and that the decrease in testosterone levels is one of the causes of erectile dysfunction and low sexual desire9.

c) Metabolic Syndrome Co-Author: Dr. Sotirios Skouros (GR) The frequency of metabolic syndrome is known to increase with the age. In European Male Ageing According to World Health Organization in Europe in Study, 30.5 % of patients have demonstrated the year 2015 the life expectancy for males has metabolic syndrome (40 to 79 years) at the time of reached the level of 73.2 years1. Apparently, this inclusion. In addition during the follow-up period increase in longevity is accompanied by of 4.3 years, another percentage equal to 18% pathophysiologies related to ageing. developed metabolic syndrome10. A different elegant study has indicated that people with metabolic syndrome have reduced health-related Kaplan suggested the term health-related quality of life quality of life compared with those who do not to represent a variety of topics (such as general health, physical symptoms, functionality, emotional health, have this syndrome11. cognitive subjects, social paper, spiritual matters, sexual matters, financial matters, job satisfaction and Several studies have indicated a link between low life conditions) that influence the quality of life2. serum total testosterone levels and the presence of metabolic syndrome12. In fact, subnormal Taking into consideration that several of the above peripheral serum testosterone levels in an ageing topics are related with age-dependent male could cause/aggravate the symptoms of pathophysiologies of the urinary or genital tract, it is metabolic syndrome (i.e., sexual function obvious that the urologist has a role of paramount disorders, reduced fertility or disorders of the importance in the early diagnosis or in the early prostate) that direct the male to visit the urological treatment of threats of a) the quality of life or b) the life office. A cascade of biochemical events (Figure 1) per se of the ageing male. It should be emphasized develop a vicious cycle between ageing male/late that the longer the life expectancy in males becomes, onset hypogonadism and increased fatty tissue. the more important the role of urologist is designated for the health and the quality of life of the male. This d) Fertility means that the urologist is the appropriately trained Nowadays the percentage of divorced males is physician to take care of the ageing male. increasing and the age of marriage in the male becomes elevated, especially in western countries. Age-dependent pathophysiologies direct the male to Thus a significant subpopulation of ageing males visit the urologist attempt to father his own child. It is evident that Males with urinary incontinence, erectile dysfunction, the role of urologist to assist ageing males to low sexual desire, lower urinary tract symptoms, achieve paternity and to ameliorate any agemetabolic syndrome, late onset hypogonadism, dependent declines in semen quality is of prostatic cancer, and bladder cancer are very likely to paramount importance. Furthermore, it has been choose the urologist as the first physician to ask for suggested that advanced paternal age is linked to alleviation of their symptoms or information about complications in pregnancy and genetic diseases their laboratory findings. The frequency of all of the in offspring. above pathophysiologies is related to ageing. However, several of the above symptoms/diseases are An interesting study has demonstrated a longer unequivocally related to peripheral serum testosterone time to achieve pregnancy in older fathers. Indeed, levels. Looking at the frequency or the clinical the authors reported a five-fold increase in time to relevance of each of the above symptoms/ pregnancy in men over 45 years13. It has been pathophysiologies in various ages, their relationship additionally demonstrated that a) no consistent with the age becomes evident as it is listed below: relationship is present between male age and semen sperm concentration14 and b) performance a) Lower Urinary Tract Symptoms of semen analysis demonstrates lower mean Lower urinary tract symptoms are evident in 72.3% values for semen volumes, sperm motility, and of men with age larger than 50 years3,4. These sperm morphology in ageing male (Figure 2). studies indicate that the clinical relevance is On the other hand, these alterations in the latter present in about 50% of men with lower urinary tract symptoms. Strong evidence has been sperm parameters could still allow conception provided, indicating vividly a negative effect of with relative ease15. Thus, the detrimental effect of lower urinary tract symptoms across several elevated paternal age on the fertilization process domains of urinary-specific-health-related quality and embryonic capacity for implantation, as well, may not be attributable to subnormal values in of life and on the overall perception of bladder problems, general health status, and mental some of the standard parameters of semen health5. analysis but it may be due to defects in different sperm functional parameters/factors (whose b) Erectile Dysfunction values cannot be predicted by the standard Erectile dysfunction is correlated with age. The parameters of semen analysis) such as a frequency of erectile dysfunction is 1 to 10% when significant sperm DNA damage due to excessive the male age is less than 40 years, 15% when the production of reactive oxygen species (Figure 2)16, age is 40 to 49 years, 30% when the age is 50 to or sperm chromosomal aneuploidies17. Reduced Lipolysis

Male Age

Alteration in GnRH pulse frequency

Fatty Tissue

Androgens

Aromatase Activity • Leptin • Adiponectin • Resistin Figure 1: Cascade of biochemical events responsible for the development of a vicious cycle between low serum testosterone levels and increase in fatty tissue

Monday, 27 March 2017

Paternal Age

Semen ROS

Standard Semen Parameters: • Sperm Motility

Sperm DFI

Low Fertilization Rate

• % Morphologically Normal Spermatozoa

Low Pregnancy Rate

These Alterations Could Still Allow Conception

Figure 2: Rationale for impaired pregnancy rates. ROS: Reactive oxygen species. DFI: DNA Fragmentation Index

e) Prostate Cancer The risk of development of prostate cancer is 0.3% (1 in 325) when the male age is up to 50 years. This risk becomes 2.1% (1 in 48) when the age is 50 to 60 years and 5.8% (1 in 17) when the age is 60 to 70 years. Furthermore, the risk reaches the level of 10.0% (1 in 10) when the age is larger than 70 years. The lifetime risk for the development of the prostate cancer is 14.0% (1 in 7)18. Quality of life in men with localized prostate cancer is further deteriorated after the employment of either radical prostatectomy or brachytherapy19. f) Bladder Cancer Bladder cancer incidence is related to age, with the highest incidence rates being present in older males. In the UK in 2012-2014, on average each year more than 54% of cases were diagnosed in males with age of 75-year-old and over20. Age-specific incidence rates rise gradually from around age 50 to 54 in males, with a sharper rise in males from age 60 to 64. The highest incidence demonstrates a peak in men aged over 90 years.

Age is a strong and independent risk factor for the development of bladder cancer. Several demographic reports provide evidence that males aged over 65 years have 11 times the incidence of bladder cancer in general than males aged under 6521.

Age–dependent hormonal alterations reinforce the role of urologist to provide health care to the ageing male As we have stated above, the increased life expectancy for men is related with the development of various age-dependent pathophysiologies of the urinary or genital tract that have a detrimental effect on male quality of life and occasionally threat the male survival. Thus, this cascade of events raises the role of urologist as a gatekeeper for the male health. However this important role of urologist is reinforced by the mission of urologist to provide care of the symptoms or complaints of the male related to age-dependent hormonal alterations. The incidence of low peripheral serum T either with combined clinical symptoms or without the presence of clinical symptoms is 12.3 % of all men over the age of 50 years10. On the other hand, the incidence of symptomatic late onset hypogonadism is 2.1 % and would increase with age from 0.1% for men 40 to 49 years of age to 0.6% for those 50 to 59 years, to 3.2% for those 60 to 69 years, and to 5.1% for those 70 to 79 years22. As reference ranges for the lower normal value of testosterone, a cut-off of 12.1 nmol/L for total serum testosterone and for free testosterone of 243 pmol/L have been suggested23. Late onset hypogonadism can give rise or aggravate pathophysiologies/symptoms such as reduced reproductive potential, decrease in lean body mass and muscle strength, visceral obesity, decrease in bone mineral density with low trauma fractures, erectile dysfunction, fewer and diminished nocturnal erections, hot flushes, fatigue, changes in mood, sleep disturbances, metabolic syndrome, insulin resistance and type 2 diabetes mellitus, and diminished cognitive function24. Testosterone replacement in men with late-onset hypogonadism is expected to have a beneficial effect

on bone metabolism, musculature, erythropoiesis, libido, sexual satisfaction, and general mood25. Expert physician It is obvious that the urologist is the expert physician to diagnose and treat pathophysiologies of the urinary tract or genital tract that have increased frequency in the ageing male, affect the quality of life, or occasionally represent a life-threat. Several of these pathophysiologies/symptoms are related to or aggravated by age-dependent hormonal alterations. Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. References 1. World health statistics 2016: monitoring health for the SDGs. Published by WHO Pres, pp 1-126. 2. Kaplan et al.,Health status: types of validity and the index of well-being. Health Serv Res. 1976;11:478-507 3. Coyne et al, Risk factors and comorbid conditions associated with lower urinary tract symptoms: EpiLUTS. BJU Int., 2009 , 103:24-32 4. Coyne et al, The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int., 2009, 104:352-60 5. Coyne et al, The burden of lower urinary tract symptoms: evaluating the effect of LUTS on health-related quality of life, anxiety and depression: EpiLUTS. BJU Int., 2009 ,103: 4-11 6. Lewis et al. Definitions/epidemiology/risk factors for sexual dysfunction. JSM, 2010, 7:1598-607 7. Montorsi et al., Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2010;7:3572–88 8. J H Soterio-Pires et al., The interaction between erectile dysfunction complaints and depression in men: a cross-sectional study about sleep, hormones and quality of life. International Journal of Impotence Research 2016.10.1038 9. Castelló-Porcar and Martínez-Jabaloyas, Testosterone/ estradiol ratio, is it useful in the diagnosis of erectile dysfunction and low sexual desire? Aging Male. 2016,254258 10. Antonio et al., Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone.J Clin Endocrinol Metab, 2016, 101:2647-57 11. Ford and Li, Metabolic syndrome and health-related quality of life among U.S. adults.Ann Epidemiol. 2008, 18:165-71 12. Blaya et al., Total testosterone levels are correlated to metabolic syndrome components. Aging Male. 2016, 19:85-9 13. Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril. 2003;79 :1520–7 14. Conti and Eisenberg, Paternal aging and increased risk of congenital disease, psychiatric disorders, and cancerAsian Journal of Andrology (2016) 18, 420–424 15. Christopher Wu et al., The role of advanced paternal age in modern reproductive medicine.Asian Journal of Andrology (2016) 18, 425 16. Selvaratnam and Robaire, Effects of Aging and Oxidative Stress on Spermatozoa of Superoxide-Dismutase 1- and Catalase-Null Mice. .Biol Reprod. 2016, 95:60

Monday 27 March 10.45-11.00: Thematic Session 12, Male hypogonadism - What role for Testosterone Replacement Therapy (TRT)?

EUT Congress News

MRI-targeted prostate biopsies? Systematic biopsy is still essential in an era of targeted biopsies Dr. Guillaume Ploussard Saint Jean Languedoc Hospital & Institut Universitaire du Cancer Toulouse (FR)

Blinded prostate biopsies under transrectal ultrasound (TRUS) guidance lead to inherent concerns of random sampling and clinical issues of overdetection of insignificant prostate cancer (PCa) as well as under-detection of clinically significant disease. The rapid development of multiparametric magnetic resonance imaging (mpMRI) recently modified the biopsy paradigm, evolving from pure blinded biopsies to lesion-directed sampling. We all know that mpMRI performs particularly well for the detection of high-grade and large PCa and may increase the biopsy yield by targeting a suspicious lesion. Defenders of MRI as systematic pre-biopsy prostate cancer triage test highlight that the majority of tumors by MRI are low-grade organ-confined lesions and therefore, sampling of prostate gland not involved by MRI suspicious lesions may be omitted when performing biopsy. Ideally, a pre-biopsy MRI followed by targeted biopsy in positive cases or omission of random biopsies in case of negativity, would result in an increased (or at least comparable) detection rate of clinically significant prostate cancer, in a decrease of unnecessary negative biopsies and in a reduction of truly insignificant detected PCa. Abandonment of systematic random biopsies would also be possible if the index lesion that could be perfectly targeted by MRI-directed cores, reflected in all cases the global disease aggressiveness.

prostate cancer through the gland, the number of positive cores, the percent of involvement in all positive cores are well-studied prognostic factors for disease aggressiveness that pertinently influence our PCa management. By analyzing only targeted biopsies, we would omit several meaningful factors that could push for active surveillance, focal therapy, or conversely for immediate curative treatment in case of not visible but pathologically proven significant bilateral disease. The multifocality and the intratumoral heterogeneity of PCa are two important features that have to be taken into account for treatment decision, and that could be under-estimated by only index lesiontargeting biopsies. Although MRI-directed biopsies help in determining the more accurate assessment of the index lesion, this will not reflect in all cases the global aggressiveness of the disease or of the index tumor as defined at final pathology in radical prostatectomy specimens.

“MRI-targeted biopsies have shown the potential to overcome some limitations of traditional biopsy methods...” When reading the MRI and the biopsy reports, can we (and the patient) trust the radiologist and/or the urologist who were involved?

Most high-level of evidence studies assessing the impact of MRI-targeted biopsies has been published by expert teams, treating patients in high-volume academic centers. The generalization of these results may be questioned on a large scale. Learning curve that has not yet been thoroughly assessed in the literature plays a substantial role in both MRI interpretation and MRI-directed biopsy realization quality. mpMRI ideally should be reported in a sub-specialist setting and should include continuous Whether all these statements were 100% true, feedback from pathological outcomes which is rarely MRI-targeted biopsies as only biopsy technique would done by radiologists in routine. become the standard of care. However, several concerns remain and limit the wide acceptance of Standardization of data reporting using validated such a paradigm shift. systems such as the 5-point Likert-type scale and the PI-RADS systems have been developed to mitigate In case of negative MRI, do standard biopsies only interpretation variation amongst readers. Despite detect insignificant prostate cancer? Evidence suggests these refinements, and in addition to those achieved that mpMRI negative predictive values ranges from by equipments and protocols, the learning curve of the 60% to 90% for prostate cancer detection. Thus, reader and the experience of the team still influence postponing a biopsy in case of a negative mpMRI may the MRI interpretation accuracy. When performing hold a risk of missing or delaying a diagnosis of PCa. MRI-directed biopsies, the operator also faces a However, most of these missed tumors are low-grade second learning curve and the precision to sample the disease and it has been reported that from one to two target lesion depends on his own experience of the thirds of the missed tumors on mpMRI are Gleason 6 technique (although no date are available in this cancers. PCa detection rates on mpMRI depend highly regard). So, in fine, the report of MRI-targeted cores on two characteristics, Gleason grade and tumor size, should be Interpreted with caution and related to the and ranges from approximately 20% for <0.5 ml reader and operator experience. tumors with Gleason ≤6 to 100% for tumors >2ml with Gleason ≥8. Precision is crucial MRI-targeted biopsies can also be mistaken by user The main clinical issue remains the detection of small error and under-sampling. In imaging-based biopsy, foci of high-grade disease that needs to be treated precision matters. Multiple strategies were developed and may be missed by imaging. Moreover, to be to accurately target the MRI lesion. The cognitive certain that mpMRI performs correctly, mpMRI process integrates the real-time 2D-TRUS images into findings have to be formally validated against final a 3D-mental representation of MRI images and pathology on radical prostatectomy specimens, and remains the cheapest process. However, the cognitive not only against super-extended sauration template method is prone to imprecision due to the difference biopsies. Since the negative predictive value of in obliquity of acquisition planes between MRI and mpMRI is not always 100%, inevitably also highTRUS, and real-time visualization of the potential grade or significant PCa are missed by mpMRI, and target is lacking. could be sampled using the standard extended scheme in addition to targeted biopsies. Software based on TRUS/MRI volumes reconstruction and using rigid or elastic registration systems are also Up to 20% of men with no suspicious lesions or available aiming to improve biopsy precision. negative MRI-targeted biopsies harbour clinically PCa Surprisingly, although all these fusion techniques detected on random cores. When considering have been compared in terms of all PCa and clinically whole-mount section of radical prostatectomy significant PCa detection rates, no clinical study specimens as control, about 30% of high-grade measured in millimetres the actual precision of tumors and lesion > 1 cm in diameter were missed by cognitive or computer-based registration techniques. mpMRI. These rates cannot be considered as negligible. Evidence suggests that software-based MRI-US fusion targeted biopsy detected more clinically significant Intratumoral heterogeneity disease than visual targeted biopsy. However, in In case of positive MRI and positive targeted biopsies, clinical practice, given the advantage of lower costs do standard biopsies only provide useless information using visually directed biopsies, most operators do for prostate cancer management? not use software-based fusion biopsies, and then do not use the most precise targeting technique. The presence of cancerous cells and their grade assessed by the Gleason score are obviously Do standard plus targeted biopsies lead to additional fundamental for treatment decision-making. And morbidity compared with scheme included only there is no doubt that MRI-targeted biopsies improve targeted cores? The potential decrease in both cancer detection and grading (when associated complications rate by reducing the number of cores with standard biopsies). However, the extent of the sampled is unproven. A recent systematic review of 16

EUT Congress News

TRUS-guided biopsy after acquisition with the 3D TRUS probe and visualisation of the needle tract (Photo: EUT Archives)

the literature concluded that to date, serious adverse by decreasing under-sampling in repeat biopsy events after biopsies were rare and comparable setting. whatever the biopsy technique (MRI-targeted biopsies However, to date, MRI is not absolutely infallible and with or without random biopsies). MRI-directed cores do not target precisely in all cases. Previous series have demonstrated that adverse events Systematic standard biopsies remain necessary, in after biopsies were equal between sextant, extended, addition to the targeted cores, to adjust MRI misinterpretation and MRI-targeted biopsies errors, and saturation schemes without clear association linking biopsy core number and complication rate and to obtain the most accurate assessment of the entire prostate gland. Characteristics provided by increases. Thus, to date, no one can state that random biopsies still help the clinician for patient performing only two MRI-targeted biopsies reduces the occurrence of post-biopsy complications compared counseling and treatment decision-making, in addition to MRI findings, but also to age, prostate with a scheme adding random and targeted cores. volume, familial history. That’s why the urologic MRI is not infallible community on a global scale is not yet ready to give In summary, the diagnostic pathway implementing up systematic biopsies in addition to MRI-targeted mpMRI before biopsy might greatly improve the cores, in spite of the not debatable advent and role of biopsy yield (in terms of detection and disease imaging-based biopsies in clinical practice. characterization) when a suspicious lesion is demonstrated on mpMRI and a targeted biopsy Monday 27 March performed. MRI-targeted biopsies have shown the 09.15-9.30: Plenary Session 5, Management of potential to overcome some limitations of traditional prostate cancer, Systemic biopsy is essential biopsy methods, mainly by reducing false grading and

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

Monday, 27 March 2017

Bladder cancer in depth Dirk Schultheiss

3rd Course of the European School of Urology Nursing

Friedrich Moll

27-28 October 2017, Amsterdam, the Netherlands

Join us at the 3rd ESUN course in Amsterdam Are you looking for an update in the field of bladder cancer? Do you appreciate a state-of-the-art lectures and applicable recommendations from Europe’s top experts? Are you an experienced practising nurse specialist who treats bladder cancer patients and teaches other health care professionals to treat them?

50 places available

If so, you will most certainly want to join us at the 3rd ESUN Course in Amsterdam 27-28 October 2017. This course combines all the best features of an educational event – interaction, group work, latest updates and established evidence-based recommendations. We have invited renowned experts in the field, from a theoretical and practical point of view, who will train you with the purpose to help you spread the latest insights in the field. The preliminary programme consist of the following modules: Module 1 - Principles of treatment of non-muscle invasive bladder cancer Module 2 - Principles of treatment of muscle-invasive and metastatic bladder cancer Module 3a - Neoadjuvant chemotherapy & chemoradiotherapy Module 3b - Immunotherapy Module 4 - Intravesical therapy Module 5 - Patient’s perspective and unmet needs in bladder cancer Module 6 - Group work – Part 1 Module 7 - Adherence to treatment Module 8 - Prevention of bladder cancer Module 9 - Nursing role from haematuria to cancer Module 10 - Group work – Part 2

UROLOGY under the

Members, don’t forget to pick up your Congress Gift!

S WA S T I K A

Registration fee for the full course is €100 for EAUN members and €130 for non-EAUN members. The EAUN covers your hotel arrangement for one night and reimburses your flight or train ticket.

Please send an email to eaun@uroweb.org before 26 June to receive an application form, the application deadline is 30 June 2017. A selection will take place based on experience, work environment and educational background. An accreditation application in The Netherlands is pending. For more info please visit eaun.uroweb.org We are looking forward to receiving your application! The Organising Committee: Willem De Blok (NL), Bente Thoft Jensen (DK), Susanne Vahr (DK)

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

TP 59 1.0 02/2017/A-E

This course is supported with an educational grant from Medac and Bristol-Myers Squibb

Stop Guessing. Start Knowing. PDD – flexibility in visualization with IMAGE1 S

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Monday, 27 March 2017

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Pocket App free for EAU members Two new topics this year: • Renal Transplantation • Thromboprophylaxis in Urological Surgery

WEEK 2017 25-29 SEPTEMBER

Urology Week is an initiative of the European Association of Urology, which brings together national urological societies, urology practitioners, urology nurses and patient groups to create awareness of urological conditions among the general public.

Remember to pick up your copy at the EAU Booth G50

Eu ro pea n A ssociation of Urology

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New EAU guidelines available online!

Guidelines

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Join the Campaign for public awareness of urological conditions

Guidelines

European Prostate Cancer Awareness Day 27 September 2017

2017 edition

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Monday, 27 March 2017

The EAU’s standpoint on meshes Addressing safety issues and long-term assessments of surgical meshes are crucial concerns Tufan Tarcan Professor of Urology Marmara University School of Medicine Istanbul (TR)

Pelvic organ prolapse (POP) and stress urinary incontinence (SUI) constitute a major age-related health problem in women. One in every eight women above age 45 has symptomatic POP1, and lifetime risk of undergoing a single operation for POP or SUI by the age of 80 is between one in every five to 10 women with repeat operations up to one in three of the cases2,3. Considering the increasing life expectancy and the changing lifestyle of women, it is not difficult to estimate an increase in the demand for pelvic floor surgery in the future. Surgical meshes were first used in 1950s in abdominal hernia repairs. After almost 40 years, they were used for the treatment of SUI (for both men and women) and POP with the intention to increase long-term success and durability of primary native tissue repairs. Suprapubic and then transobturator mid-urethral synthetic slings (MUSS) have quickly become the first choice of treatment for SUI associated with urethral hypermobility. They soon proved their long-term efficacy and safety compared to other surgical options and reached a total of 3.6 million sales between 2005 to 2013. Mesh-augmented abdominal or vaginal POP repair has also rapidly gained world-wide acceptance, especially after the introduction of pre-shaped meshes with new surgical insertion tools and tissue fixation anchors. According to the US Food and Drug Administration (FDA) in 2010, there were at least 100,000 POP repairs that used surgical mesh. About 75,000 of these were transvaginal procedures. Surgical meshes were, however, not free of complications that were mostly related to infection, tissue extrusion, mesh exposure and shrinkage leading to chronic pain, sexual dysfunction and decrease in quality of life. There were unfortunately a few randomized studies to objectively weigh the benefits of mesh augmented repairs against their complications. Increasing number of reports related to the complications of synthetic meshes forced the national authorities all over the world to re-assess the risk/benefit ratio of these medical devices. Reaction of National Associations to mesh–related complications The US FDA has been one of the most active players of mesh controversy. The FDA Manufacturer and User Facility Device Experience (MAUDE) database received over 1,000 reports of complications associated with the use of surgical mesh primarily for vaginal POP repairs between the years of 2005 and 2008. These complications included mesh erosion, infections, pain, urinary problems, and recurrence or worsening of prolapse or incontinence where serious complications requiring further surgery were described as “rare”.

compared to native tissue repair. In May 2014, FDA issued two proposed orders to re-classify the surgical meshes used for transvaginal POP repair from class II (moderate-risk device) to class III (high-risk device) and to require manufacturers to submit a pre-market approval (PMA) application. In January 2016, FDA finalized these two orders and all transvaginal surgical meshes became class III medical devices and manufacturers whose devices were already on the market became obligated to present their PMA within 30 months6. On the other hand, manufacturers of new devices must now submit a PMA before their devices can be approved for marketing, as required by federal law. At least four manufacturers have withdrawn their meshes from the USA market, so far. The FDA warnings and publications have certainly affected the use of surgical mesh for POP repair in the USA which has declined by 40–60%, according to one report7. Although these warnings created public confusion with regards SUI treatment, the use of MUSS did not drop in the USA. For example, 99% of the members of the American Urogynecologic Society continued to use MUSS for the management of SUI despite a significant drop in vaginal mesh-augmented POP repair at the same time interval8. In fact, starting from 2007, national medical authorities in France, UK, Canada and Australia also started to closely monitor the use of surgical meshes in POP and SUI repair and tried to create national regulations. These efforts, however, did not result in an overall consensus and national conclusions appeared to be quite different from each other. For example, in 2014 the Scottish government requested a suspension in the use of mesh implants in both POP and SUI repairs by the NHS in Scotland, pending safety investigations. SCENIHR requirements In 2015, The European Commission has asked the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) to assess the health risks of meshes used in urogynaecological surgery9. In the final document of SCENIHR, it has been stated that medical devices shall only be placed on the market, if they meet the essential requirements declared in the Annex I of the Council Directive 93/42/EEC and amendment 2007/47/EC. According to SCENIHR9, in addition to specific design-related requirements such as on biocompatibility, stability and usability, a medical device must: • have an acceptable risk/benefit ratio; • be designed based on state-of-the-art knowledge by observing the principles of inherent safety; • achieve the intended performance; • must not compromise the clinical condition and safety of the patients during the entire product lifetime as defined by the manufacturer; • must not be adversely affected by transport and storage; • have risks from unintended side-effects limited to an acceptable level when weighed against the device’s benefits; • be accompanied by all information required to use the device safely; and • have been proven safe and effective by clinical evidence.

In 2008, the US FDA released its first public health notification and advised surgeon training and informed The SCENIHR further recommended9: consent for patients and recommended cautious use of • The implantation of any mesh for the treatment of synthetic meshes and carefully monitoring the POP via the vaginal route should be only postoperative complications4. Interestingly, these considered in complex cases in particular after warnings of the FDA targeted both POP and SUI repairs failed primary repair surgery, although MUSS complications were far less in number • Limiting the amount of mesh for all procedures and severity compared to the complications seen with where possible. However, there is a need for mesh-augmented POP surgery. further improvement in the composition and design of synthetic meshes, in particular for POP Within two years after its first public health notification surgery. there was a fivefold increase in adverse event reports • The introduction of a certification system for received by the FDA regarding surgical meshes used in surgeons based on existing international vaginal POP repair. In reaction, the FDA conducted an guidelines and established in cooperation with the internal review and released a second Safety Update in relevant European Surgical Associations. July 20115. Contrary to its initial notification, this second • Appropriate patient selection and counselling, report stated that serious adverse events were not rare which is of paramount importance for the optimal in transvaginal mesh surgery, and transvaginal mesh in outcome for all surgical procedures, particularly POP repair did not conclusively improve clinical for the indications discussed. This should be based outcomes over traditional non-mesh repair. It was on the results of further clinical evidence, which further concluded that abdominal and vaginal should be collected in a systematic fashion for all implantations of surgical meshes had different of these devices. complication profiles and the anatomic benefit of mesh-augmented anterior vaginal wall repair did not The SCENIHR’s other conclusions are listed below9: necessarily result in a better symptomatic outcome or • The use of autologous graft material is not feasible decreased repeat surgery for recurrence when for POP because of the large mesh area required Monday, 27 March 2017

and the resulting donor morbidity. • The use of absorbable mesh inserted either via a transabdominal or transvaginal route is associated with a high failure rate. • Transvaginal surgery using non-absorbable synthetic mesh for POP involves a much greater surface area of mesh and is associated with a higher risk of mesh-related morbidity than seen with transabdominal insertion of mesh. • Synthetic sling SUI surgery is an accepted procedure with proven efficacy and safety in the majority of patients with moderate to severe SUI, when used by an experienced and appropriately trained surgeon. Consensus of the European Urology Association (EAU) and the European Urogynaecological Association (EUGA) on the use of implanted materials for treating pelvic organ prolapse and stress urinary incontinence: Because of obvious controversies related to the use of meshes in POP and SUI repair the EAU and the EUGA organised a consensus group meeting in November 2016 to investigate the current evidence and establish a multidisciplinary consensus statement that includes clear guidelines. This document that reflects the EAU and EUGA standpoint on surgical meshes is finalized and awaits publication. The main recommendations and conclusions of this report are summarized below: Patient counselling: 1) When considering surgery for SUI and POP, it is essential to evaluate other available less invasive options such as lifestyle interventions, pelvic floor muscle training (PFMT), pessary treatment, and drug therapy. 2) Surgeons should be adequately experienced in the management of SUI and POP and should have all of the therapeutic options available (or be able to refer to colleagues if required). Patients should be appropriately assessed and counselled prior to decision to undergo surgery, including the experience and results of the proposed technique by the surgeon. The factors influencing the surgical outcomes are: 1. Indication for which the material is used; 2. Overall surface area of the material used (lower overall surface area for SUI than POP); 3. Material characteristics (polymer used, physical characteristics of the mesh, size of the pores, surface area, biocompatibility, long term stability, compliance.); 4. Route of implantation, (e.g., vaginal or trans abdominal); 5. Patient characteristics (e.g. somatic inflammatory disease, obesity, smoking); 6. Associated procedures (e.g., hysterectomy); and 7. Surgeon experience Type of mesh: 1. When considering risk factors for mesh materials it is important to consider the following important issues: a. Overall surface area of the material used (which is greater for POP than for SUI) b. Product design (e.g., physical characteristics of the mesh, size of the pore as a predisposing factor to infection – in particular with a pore size less than 75 microns) c. Material (biocompatibility, long term stability, flexibility, elasticity etc.) 2. Types 2 and 3 (microporous, less than 10 microns, mono and multifilament) and Type 4 (sub-micronic and monofilament) are not appropriate for use in this clinical context. 3. Current evidence would not support the use of non-autologous biological materials, whether human or animal in origin. Type of indication: 1. The risk of use of a mesh increases with its surface area and, thereby, it’s increasing density. In this context, a clear distinction should be drawn between the tape used for a MUS and the larger amount of mesh used to treat POP. 2. The efficacy and use of implanted tapes for SUI is evident and they can be recommended for use in clinical practice. 3. Vaginally implanted mesh for POP is associated with increased risks. Its use should also be restricted to expert individuals working in specialised departments. Whilst the risk associated with the trans-abdominal insertion of mesh for POP is considered more acceptable, its use should also be restricted to specialist practice.

Despite world-wide acceptance, surgical meshes are not free of complications (Photo: EUT Archives)

Recommendations for the future: 1. Design implants specifically for their application, rather than extrapolate from indications in abdominal wall repair; 2. Establish accurate and complete databases registering the numerator and denominator, patient profile and surgical experience; 3. Establish long-term assessment in adequate randomly controlled trials; 4. Research new materials which should be introduced into clinical practice according to a cautious and rigorous process; 5. Follow the evidence-based EAU and IUGA guidelines; 6. Support and register the specialist training of surgeons in urology and urogynaecology; 7. Encourage multidisciplinary team working; 8. Develop appropriate information for patients; 9. Collaborate with patient advocacy groups; 10. Encourage pre-marketing safety and efficacy data before using a product in routine clinical practice; 11. Establish reference centres for re-interventions (complicated cases); and 12. Use condition-specific patient-reported outcome measures whenever possible. References 1. Slieker-ten Hove, M.C.P. et al., 2009. Symptomatic pelvic organ prolapse and possible risk factors in a general population. American journal of obstetrics and gynecology, 200(2), p.184.e1-7. Available at: http://linkinghub.elsevier. com/retrieve/pii/S0002937808010818 [Accessed December 7, 2016]. 2. Olsen AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol. 1997; 89(4):501-6. 3. Wu JM, Matthews CA, Conover MM, Pate V, Jonsson Funk M. Lifetime risk of stress urinary incontinence or pelvic organ prolapse surgery. Obstet Gynecol 2014;123(6):1201-6. 4. Schultz DG. FDA Public Health Notification: Serious Complications Associated with Transvaginal Placement of Surgical Mesh in Repair of Pelvic Organ Prolapse and Stress Urinary Incontinence [Online] Issued: October 20, 2008. http://www.fda.gov/MedicalDevices/Safety/ AlertsandNotices/PublicHealthNotifications/ucm061976. htm (accessed January 2017) 5. US FDA 2011. Urogynecologic Surgical Mesh: Update on the Safety and Effectiveness of Transvaginal Placement for Pelvic Organ Prolapse; 13 July 2011. http://www.fda.gov/ downloads/MedicalDevices/Safety/AlertsandNotices/ UCM262760.pdf (accessed January 2017) 6. FDA News Release: FDA strengthens requirements for surgical mesh for the transvaginal repair of pelvic organ prolapse to address safety risks. January 4, 2016. http:// www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm479732.htm (accessed January 2017) 7. Daly J, Frazer M. Decline and Fall, lessons learned from the troubled history of transvaginal mesh kits. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists; O&G Magazine 2014; 16(1), Autumn 2014. (Download: Publications/O&G Magazine/O&G Magazine Issues/Vol 16 No 1 Autumn 2014). 8. Clemons JL, Weinstein M, Guess MK, Alperin M, Moalli P, et al. (2013) Impact of the 2011 FDA transvaginal mesh safety update on AUGS members’ use of synthetic mesh and biologic grafts in pelvic reconstructive surgery. Female Pelvic Med Reconstr Surg 19: 191-198. 9. SCENIHR, 2015. Final opinion on the safety of surgical meshes used in urogynecological surgery, Available at: http://ec.europa.eu/health/scientific_committees/ emerging/docs/scenihr_o_049.pdf. 10. Consensus of the European Urology Association (EAU) and the European Urogynaecological Association (EUGA) on the use of implanted materials for treating pelvic organ prolapse and stress urinary incontinence. November 2016. In publication.

Monday 27 March 09.30-9.45: Plenary Session 6, Functional Urology

EUT Congress News

Emergency ureteroscopy EU for ureteric stones is gaining acceptance as a standard initial treatment option Dr. Juan A. Galán EULIS Board Member Head of Urology University Hospital of Vinalopó Elche (ES)

Guercio et al prospectively randomized 271 consecutive patients with ureteral calculi and normal renal function to EU (139) or delayed (100) URS. EU showed equal efficacy and safety compared with the elective procedure, but the stenting rate was lower in the first group (19% v 80% respectively). A recent meta-analysis was reported by Picozzi et al (2012), with the aim of understanding the role of this surgical procedure in the emergency setting as first-line treatment, comparing the immediate procedure with a delayed one in terms of stone-free rate and complications. 681 patients from six studies that fulfilled the predefined inclusion criteria were included.

According to the current EAU Guidelines on Urolithiasis, ureteroscopy (URS) is the elective option in treating mid and distal ureteral stones regardless of size, and also for upper ureteral stones bigger than 1 cm. Stone-free rates were 81.9% for the proximal ureter, 87.3% for the mid-ureter, 94.9% for the distal ureter URS is normally planned after patients were and 89.5% overall. The stone diameter seemed to previously stented (or percutaneously drained) as an affect the stone-free rate. An increase of the stone emergency procedure due to persistent pain or fever, diameter of 1 mm beyond 8 mm corresponded to a and in those diagnosed with ureteral calculi but reduction of stone-free rate of 5% and 8.1% for the without symptoms of urinary sepsis. distal and proximal ureters, respectively. Immediate ureteroscopy for ureteral stone colic seemed to be a Once patients with a renal colic arrive in the safe treatment with a high success rate. emergency room (ER), their obvious request is to have their pain relieved, and approximately 15% want their Retrospective studies stone immediately removed. Up to 87% patients These results are supported by posterior (also would accept waiting up to four weeks with medical retrospective) studies by Youn et al (2012), Matani et expulsive therapy (MET), when this possibility is al (2013), and Zarger-Shoshtari et al (2015). The first explained, even though having pain from time to one reported no differences in SFR and complications time; however, around 13% would still demand when comparing 67 EU to 159 URS before and after 48 surgical solution. With further explanation on the hours from admission who underwent stone retrieval. possible active treatment for the ureteral stone (where Matani retrospectively compared 244 EU to 659 available as emergency intervention), 78% and 37% elective URS with similar results on SFR and of the patients would accept the possibility of shock complications, although a higher rate of ureteric wave lithotripsy (SWL) within 24 to 48 hours or URS injuries (early and late) was documented in the EU within 24 hours, the latter option being as high as group (7% vs. 5.6%). The group from Auckland 64% after explaining URS as the most effective included 394 patients treated with EU for ureteral treatment for removing or fragmenting their stone(s). stones concluding that it was a feasible approach for the routine management of acute ureteric colic with a Depending on several factors related to ER and low complication rate. A subgroup of younger, urology services organization, health system, healthier patients with smaller and distal stones availability of anesthesiologists for these purposes, might, in their opinion, benefit the most from the and economical, familial and patient professional procedure. issues, the emergency active treatment of the stone can be offered to the patients with the rationale of a As renal function impairment can occur, mostly when fast solution of their problem, provided no septic bilateral or unilateral in single kidney ureteral stones, symptoms or lab signs of sepsis exist. For that this approach should be taken into account to rapidly purpose, emergency ureteroscopy (EU) should prove normalize a obstructive problem. After a successful EU feasible and safe when compared to elective URS and procedure renal function seems to return to normality offer at least similar stone-free rates. in 83.6 - 96.3% of patients within seven days depending on the different studies. In the past decade a few studies have been reported on the use of EU in patients with renal colic due to Another special subgroup of patients are pregnant ureteral stones. Unfortunately, although very useful, women with obstructive ureteral stones. The rule in most of them are retrospective (Table 1). these patients has been urinary diversion with stents due to the potential risks for both mother and fetus. Osorio et al first reported their series in 144 patients URS in the treatment of ureteral calculi during who have had obstructive ureteral stones and had pregnancy has recently been rising, for persistent undergone emergency ureteroscopy with stone renal colic patients. According to Zhang et al (2016), retrieval. The overall stone-free rate was 92.4%, who reported 117 EU treatments during pregnancy, better for stones less than 1 cm and for those distally early application of ureteroscopy, preferably in the located, with low complication rate. first 24 hours, may reduce the risk of pre-term birth. Sarica et al compared a group of 76 patients treated with EU to a group treated with URS after one week treatment with analgesic, finding neither differences in SFR (90.7% v 87%) nor in complication rates. No patient in EU group was re-admitted after the procedure. They concluded that EU has the main advantage of offering both immediate stone fragmentation and the relief of acute onset colic pain that caused extreme discomfort.

Although the complication rates after a URS with or without laser or pneumatic lithotripsy is very low (approximately 4-5%) and normally low-grade complications according to Clavien’s classification, ureteral stents are normally inserted once the procedure is performed to try to avoid obstructive and septic complications, although routine stenting doesn’t seem to be required as long as the procedure is uncomplicated and performed without balloon

Table 1: Outcomes of Emergency Ureteroscopy (EU). Current series. SFR: Stone-free rate; ARF: Acute Renal Failure; * n renal units; # covers all previous series. Author (year) Osorio et al (2007) Jiang et al (2008) Yang et al (2010) Guercio et al (2011) Sarica et al (2011) Al-Ghazo el al (2011) Picozzi et al (2012)# Youn et al (2012) Matani et al (2013) Galán et al (2013) Savic et al (2014) Zerger et al (2015) Zhang et al (2016) Total 20

EUT Congress News

n EU 144 27 49 141 76 244 681 67 244 40 90* 394 117 1633

% SFR 92.4 88.9 91.8 89.2 90.7 90.6 89.5 89.5 90.6 90 70.5 72 84.9 81

% stent 100 100 100 19 72.5 100 72.5 85 100 94 100 88.7

Design & particularities Retrospective Retrospective, ARF Retrospective, ARF Prospective Retrospective Retrospective Meta-analysis Retrospective Retrospective Retrospective Retrospective, ARF Retrospective Retrospective. Pregnancy

dilation of the ureteral orifice. Patients with a stent have significantly greater irritative and painful symptoms than those without a stent in the early post-operative period. In a recent CROES study (2014) on the outcomes of the ureteroscopic stone treatment, up to 21% of patients with distal ureteral stones needed ureteral orifice dilation, and 54.7% JJ stenting. Despite Guercio’s results, stenting rate after EU could possibly be higher due to its special setting (Table 1). The size of the instruments during URS or EU is critical to avoid ureteral injuries or ureteral orifice manipulation. Although pediatric ureteroscopes (4.5-6 Ch) exist, they are not available in most of urology departments. To minimize the stent-related symptoms, our group started performing Micro-URS, which is basically a URS employing the 4.85 F sheath of the microperc set and a 230 micron laser fiber. This technique has proven to be effective, safe, and reproducible in treating distal ureteral stones in women in a recent multi-center prospective study, and enables leaving patients unstented in the majority of the cases. It’s also been used as an emergency procedure for both men and women with promising results. With recent advances in technology, the growing trend toward one-stage definitive treatment, patient acceptability after proper information, and rising concerns over financial aspects, EU treatment of ureteric stones is becoming a standard initial treatment option. All the available information related to EU is currently obtained from a few studies in the literature though, and multi-centric randomized, prospective studies are warranted to clearly define the exact role of this approach for ureteral stones. Bibliography 1. Guercio S, Ambu A, Mangione F, et al. Randomized prospective trial comparing immediate versus delayed ureteroscopy for patients with ureteral calculi and normal renal function who present to the emergency department. J Endourol. 2011 Jul;25(7):1137-41. doi: 10.1089/end.2010.0554. PubMed PMID: 21682597.

Emergency URS to treat ureteric stones is becoming a standard initial treatment option due to technical advances and patient acceptance (Photo: EUT Archives)

2. Picozzi SC, Ricci C, Gaeta M, et al. Urgent ureteroscopy as first-line treatment for ureteral stones: a meta-analysis of 681 patients. Urol Res. 2012 Oct;40(5):581-6. doi:10.1007/ s00240-012-0469-z. PubMed PMID: 22367457. 3. Zhang S, Liu G, Duo Y, et al. Application of Ureteroscope in Emergency Treatment with Persistent Renal Colic Patients during Pregnancy. PLoS One. 2016 Jan 11;11(1):e0146597. doi: 10.1371/journal.pone.0146597. PubMed PMID:26751955; PubMed Central PMCID: PMC4709194. 4. Denstedt JD, Wollin TA, Sofer M, et al. A prospective randomized controlled trial comparing nonstented versus stented ureteroscopic lithotripsy. J Urol. 2001 May;165(5):1419-22. PubMed PMID: 11342889. 5. Caballero-Romeu JP, Galán-Llopis JA, Pérez-Fentes D, et al. Assessment of the Effectiveness, Safety, and Reproducibility of Micro-Ureteroscopy in the Treatment of Distal Ureteral Stones in Women: A Multicenter Prospective Study. J Endourol. 2016 Nov;30(11):1185-1193. PubMed PMID: 27565720.

Tuesday 28 March 08.35-8.40: Plenary Session 7, Stones, Emergency URS

UROLOGY CLEARLY DEFINED

Cheers! Have an after-work beer with us at our booth B43 and discover our clearly defined urology solutions. First come, first served. Every evening as of 17.00! Hitachi Medical Systems Europe Holding AG www.hitachi-medical-systems.eu

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Istituto Clinico Humanitas, Milan, Italy

Saturday, March 25

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Addenbrookes Hospital, Cambridge, UK

Sunday, March 26

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Monday, 27 March 2017

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The Platinum Hour We would like to invite you to attend the Platinum Hour drinks reception to meet and greet the Editors, Authors and Reviewers of The Platinum Journal. Please join us daily to toast the success of European Urology, “Your” Platinum Journal. To be held at the European Urology booth #B02. Daily from 17.00

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Monday, 27 March 2017

EUT Congress News

Urological implications of male hypogonadism Urologists need more training in managing male hypogonadism

Androgens play an important role in male development and male health. A lack of testosterone in early life can result in urogenital abnormalities, such as cryptorchidism and hypospadias. Later in life testosterone can decrease as a result of ageing, but mainly due to obesity and chronic diseases. The incidence of symptomatic male hypogonadism in ageing men is 2% to 5%. The main symptoms of men with low testosterone are erectile dysfunction and low sexual drive. Recent randomized controlled trials on testosterone therapy showed that of all symptoms of androgen deficiency only sexual symptoms improved significantly in the treated groups. Therefore, the urologists are now in the lead of diagnosing and treating male hypogonadism. Diagnosis The diagnosis of male hypogonadism is based on signs and symptoms of androgen deficiency, together with low serum testosterone levels. Table 1 highlights clinical symptoms suggestive for androgen deficiency. Table 1: Clinical symptoms and signs suggestive for androgen deficiency Delayed puberty Small testes Male-factor infertility Decreased body hair Gynaecomastia Decrease in lean body mass and muscle strength Visceral obesity Decrease in bone mineral density (osteoporosis) with low trauma fractures Reduced sexual desire and sexual activity Erectile dysfunction Fewer and diminished nocturnal erections Hot flushes Changes in mood, fatigue and anger Sleep disturbances

Diminished cognitive function Source: EAU guidelines on male hypogonadism 2016.1

The EAU guidelines on male hypogonadism recommend that screening for testosterone deficiency is only indicated in adult men with consistent and preferably multiple signs and symptoms as listed in Table 1. Causes of low testosterone Male hypogonadism can be classified in primary (testicular) forms and secondary (hypothalamicpituitary) forms. In ageing men it is usually a combination of both testicular and pituitary dysfunction that causes a decrease in testosterone production. With age testosterone levels decline by 1% to 2 % annually, but the main cause of low testosterone is obesity and chronic diseases. Serum testosterone is a biomarker of general health and is expected to remain between normal levels in healthy non-obese men. Improving lifestyle can result in a normalization of testosterone and will also decrease the chance for developing type 2 Diabetes Mellitus and reduce future cardiovascular mortality. Other common causes of hyponadism are Klinefelter syndrome, testicular tumors, cryptorchidism, varicoceles and abuse of anabolic steroids. A prolactinoma can also result in low testosterone due to a decrease of LH-production. It is advised to measure prolactine and LH if testosterone is below normal values. 22

EUT Congress News

References

Testosterone and sexual dysfunction Hypogonadism is present in 23 to 36% of men that present with sexual dysfunction. Testosterone modulates the brain and increases sexual desire and activity. It also improves penile response through binding with the androgen receptor. Spontaneous erections will decrease with low testosterone due to a reduction of nitric oxide production in the cavernous bodies of the penis. Recently, three large randomized trials on the effects of testosterone therapy in hypogonadal men showed a clear improvement of sexual symptoms. Brock G. et al. showed a significant increase of sexual arousal, interest and drive in hypogonadal men taking testosterone gel3. In a recent large study Snyder P. et al,. randomized 790 hypogonadal men, aged 65 and older, for either testosterone gel or placebo. The study showed that raising testosterone in hypogonadal men had a moderate beneficial effect on sexual symptoms and on mood4. Hackett et. al. showed in a large randomized trial in hypogonadal diabetes patients with sexual dysfunction that testosterone undecanoate injections substantially improved sexual function: sexual desire already improved after six weeks of therapy, erectile dysfunction first after three months of therapy and only significant in men with testosterone levels <8nmol/l5. PDE5-inhibitor or testosterone? A randomized trial, comparing Sildenafil and testosterone versus Sildenafil monotherapy did not show a clear benefit in favor of the combination therapy6. Therefore, the first-line treatment of erectile dysfunction remains a PDE5-inhibitor, since these drugs are highly effective and work immediately. Also, PDE5-inhibitors increase testosterone production, probably by an increased blood flow in the genitalia and an increase in sexual activity7. However, in PDE5-inhibitor non-responders measuring testosterone is advisable and in case of low testosterone a trial of testosterone therapy can be started. It will take at least three months before testosterone therapy will become effective. Risks of testosterone therapy Below are some risks and changes associated with testosterone therapy:

Metabolic syndrome Insulin resistance and type 2 diabetes mellitus

cardiovascular incidents and type 2 diabetes; • Sexual symptoms are most predictive for male hypogonadism and are currently the main indication for testosterone therapy; and • Urologist should learn how to diagnose and treat male hypogonadism: training in this area is of importance.

The European Male Ageing Study (EMAS) found that in a group of 3,396 European men sexual symptoms were most predictive for low testosterone2. The number of men with low testosterone in this study was 17%, but only 2.1% of men were symptomatic for androgen deficiency. The authors found that three sexual symptoms had a syndromic association with low testosterone levels, namely erectile dysfunction, decreased frequency of sexual thoughts and morning erections.

• Testosterone therapy increases the production of red blood cells and may result in an elevated hematocrit. This should be monitored before and during testosterone treatment, since this may lead to thrombosis in case hematocrit rises above 0,54. • Severe LUTS is a relative contraindication for testosterone therapy, since the prostate will enlarge slightly under testosterone therapy. IPSS-scores should be measured in men who start using testosterone. • It is unlikely that the chance for developing prostate cancer is increased by normalization of testosterone levels: data from large observational trails show no increase in prostate cancer. Men who have been successfully treated for prostate cancer can also be considered for testosterone therapy in case of symptomatic male hypogonadism, like erectile dysfunction. Locally advanced and metastatic stages of prostate cancer are absolute contraindications for testosterone therapy. PSA should be monitored at regular intervals in men who are treated with testosterone. • Recent large observational studies indicate that there is no increased risk for major adverse cardiovascular events (MACE) in men using testosterone. Hypogonadal men have an increased risk for MACE and this may be reduced by normalization of testosterone levels in combination with improving lifestyle8. Patients with uncontrolled cardiovascular diseases should first see a cardiologist before starting testosterone therapy. The urologist`s role in treating male hypogonadism Traditionally, diagnosing and treating male hypogonadism belonged to the expertise of the

10 ml vial of depo-testosterone (Photo: Wikimedia Commons/US DEA)

endocrinologist. However, since recent publications the focus has shifted towards treating male sexual dysfunctions as the main symptom of male hypogonadism. It is time that the urological community gets involved. For this we need training in understanding male reproductive endocrinology and in managing male hypogonadism. Key points • The main causes of adult onset male hypogonadism are obesity and chronic diseases: testosterone is a biomarker for male general health; • Losing weight and improving lifestyle are the most important goals in managing male hypogonadism, since this will increase testosterone and reduce the chance of

1. Dohle G et.al. EAU guidelines on male hypogonadism. EAU guidelines on male hypogonadism. https://uroweb. org/wp-content/uploads/EAU-Guidelines-MaleHypogonadism-2016.pdf. 2. Wu FC et.al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010 Jul 8;363(2):123-35. 3. Brock G et.al. Effect of Testosterone Solution 2% on Testosterone Concentration, Sex Drive and Energy in Hypogonadal Men: Results of a Placebo Controlled Study. J Urol. 2016 Mar;195(3):699-705. 4. Snyder, P.J., et al. Effects of Testosterone Treatment in Older Men. N Engl J Med, 2016. 374: 611. 5. Hackett G et.al. Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study. BJU Int. 2016 Nov;118(5): 804-813 6. Spitzer M, et al. - Effect of Testosterone Replacement on Response to Sildenafil Citrate in Men With Erectile Dysfunction: A Parallel, Randomized Trial. Annals of Internal Medicine. 157 (10) (pp 681 691), 2012. Date of Publication: 20 Nov 2012., 2012. 7. Spitzer M, et al. - Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 1 (6) (pp 913 918), 2013. 8. Anderson JL et.al. Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Am J Cardiol. 2016 Mar 1;117(5):794-9.

Monday 27 March 11.00-11.15: Thematic Session 12, Andrology

Come and meet with Peyronie’s experts TAKE THE CHANCE – TALK TO EXPERIENCED COLLAGENASE USERS Booth # H02 March 25, Saturday 10.00-10.30 15.30-16.00

Mr Amr Raheem Mr David Ralph

March 26, Sunday 13.00-13.30

Mr David Ralph

March 27, Monday 10.00-10.30

Mr Amr Raheem

XIAPEX® Abbreviated Prescribing Information (Peyronie’s Disease): (See XIAPEX Summary of Product Characteristics for full Prescribing Information). Presentation: Powder and solvent for solution for injection. The vial of powder contains 0.9 mg collagenase clostridium histolyticum. Indications: The treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. Dosage: Xiapex must be administered by a physician appropriately trained in the correct administration of the product and experienced in the diagnosis and treatment of male urological diseases. The recommended dose of Xiapex is 0.58 mg per injection administered into a Peyronie’s plaque. The volume of reconstituted Xiapex to be administered into the plaque is 0.25 ml. If more than one plaque is present, only the plaque causing the curvature deformity should be injected. A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two Xiapex injections and one penile modelling procedure. The second Xiapex injection is administered 1 to 3 days after the first injection. A penile modelling procedure is performed 1 to 3 days after the second injection of each treatment cycle. The interval between treatment cycles is approximately six weeks. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Treatment of Peyronie’s plaques that involve the penile urethra, due to potential risk to this structure. Warnings and Precautions: Allergic reactions – Following Xiapex injection, severe allergic reaction could occur, and patients should be observed for 30 minutes before leaving the clinic in order to monitor for any signs or symptoms of a serious allergic reaction Patients should be instructed to consult a doctor immediately if they experience any of these signs or symptoms. Emergency medication for treatment of potential allergic reactions should be available. Corporal rupture was reported as a serious adverse event after Xiapex injection in 5 out of 1044 patients (0.5%) in the controlled and uncontrolled clinical trials. In other Xiapex-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or haematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile haematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%). Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile haematoma. Use in patients with coagulation disorders – Xiapex must be used in caution in patients with coagulation disorders or those taking anticoagulants. See SmPC for details. Immunogenicity – As with any non-human protein medicinal product, patients may develop antibodies to the therapeutic protein. Special penile conditions/diseases not studied in clinical trials – Xiapex treatment in patients having a calcified plaque that could have interfered with the injection technique, chordee in the presence or absence of hypospadias, thrombosis of the dorsal penile artery and/or vein, infiltration by a benign or malignant mass resulting in penile curvature, infiltration by an infectious agent, such as in lymphogranuloma venereum, ventral curvature from any cause and isolated hourglass deformity of the penis has not been studied and treatment in these patients should be avoided. Long-term safety – Long-term safety of Xiapex is not fully characterised. The impact of treatment with Xiapex on subsequent surgery, if needed, is not known. Drug Interactions: Use of Xiapex in patients who have received tetracycline antibiotics e.g. doxycycline, within 14 days prior to receiving an injection of Xiapex is not recommended. Pregnancy & Lactation: Peyronie’s disease occurs exclusively in adult male patients and hence no relevant information for use in females. Driving and operating machinery: Minor influences on the ability to drive and use machines include dizziness, paresthesia, hypoesthesia, and headache. Patients must be instructed to avoid potentially hazardous tasks. Side Effects: Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. Very common (≥1/10): Penile haematoma, swelling, pain, ecchymosis. Common (≥1/100 to <1/10): Blood blister, Skin discolouration, Penile blister, Pruritus genital, Painful erection, Erectile dysfunction, Dyspareunia, Penile erythema. Injection site vesicles, pruritus, Localised oedema, Nodule Suprapubic pain, Procedural pain. For further information refer to summary of product characteristics. Legal Category: POM. Marketing Authorisation Holder: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden. Package Quantities, Marketing Authorisation Numbers and UK Basic NHS Price: XIAPEX 0.9mg powder and solvent for solution for injection, EU/1/11/671/001, £650. Further information is available on request from: medical.info@sobi.com, Tel: +46 8 697 20 00. Date of Preparation: February 2017. Adverse events should be reported to your local regulatory authority and to Sobi at DrugSafety@sobi.com SE-112 76 Stockholm Phone: +46 8 697 20 00 www.sobi.com

PP-2089

Prof. Gert Dohle Department of Urology Erasmus MC Rotterdam (NL)

Monday, 27 March 2017

How can microbiome affect the urinary tract? Urine microbiome: A new paradigm in urogenital infections and diseases Prof. Truls E. Bjerklund Johansen Oslo University Hospital Oslo (NO)

Dr. Vitaly Smelov IARC WHO Prevention and Implementation Group Lyon (FR)

Co-authors: Kurt Naber (DE) and Florian Wagenlehner (DE) A paradigm shift Until recently the generally accepted paradigm implied that urine of healthy people is sterile. In case of urinary tract infection (UTI) a significant bacteriuria is estimated by the number of colonies of known uropathogens (Figure 1).

of micro-organisms (overactive neurogenic bladder, female urethral syndrome, bladder pain syndrome/ interstitial cystitis and chronic pelvic pain syndrome/ chronic inflammatory prostatitis), and others again by the evidence of a host immune response (white cells in EPS of chronic prostatitis IIIa, Mast cell response in interstitial cystitis). As extended cultures and sequencing studies demonstrated the presence of micro-organisms in healthy people and in diseases where the diagnosis is based on “sterile urine”, we had to acknowledge that the concept of sterile urine was a myth5. However, sequencing technologies do not tell if genomes in the urine stem from living or dead micro-organisms and clinicians must keep in mind that antibiotics are only effective against living organisms. From a clinical perspective the term “sterile urine” might therefore be replaced by “being without significant numbers of culturable uropathogens”. Interestingly, the EAU Section of Infections in Urology (ESIU) classification of UTI from 2010 is the only classification that considers treatability by antibiotics as a criterion for severity assessment9. This classification is therefore in a good position to be developed further depending on new findings about the role of the microbiome in various urological diseases10.

The host reaction The symptom language of the lower urinary tract is very much the same in diseases thought to have different etiology and most symptoms can be explained as a host reaction. As metagenomic sequencing reveals that the presence of microIn the meantime numerous studies have shown that organisms in the genitourinary tract is very diverse many different microorganisms might be detected in the urine of practically all healthy people, if cultured on and varies with sex, age and sexual activity, the interplay between the genes of the micro-organisms specially enriched media1,2. Further, the development and the host is becoming more interesting. of metagenomic sequencing technologies (MGS) and the introduction of bioinformatics enabled us to From the field of infections we know that the host analyze complete genomes of microorganisms and reaction is precipitated by micro-organisms invading brought us into the omics era (Figure 2)3. The word urothelial cells or the blood stream. In patients with microbiome was introduced to describe the symptomatic UTI, there is a strong correlation “characteristic microbial community occupying a between urinary IL-8 levels and urinary neutrophil reasonably well defined habitat which has distinct numbers11. Children prone to develop pyelonephritis physico-chemical properties. The term not only refers to the micro-organisms involved but also encompasses have lower expression levels of chemokine receptors (CXCR1) than healthy controls and multiple mutations their theatres of activity”4. in the CXCR1 gene have been identified12. Man`s urine meets the criteria for being a habitat Mice that are lacking toll like receptor 4 (TLR4) do not with its own microbiome. We have learned that the develop inflammation and symptoms of UTI if they are urogenital tract in healthy people might harbor challenged with uropathogenic E. coli. Likewise, it has genomes from more than a hundred different been shown that children with dysfunctional TLR4 micro-organisms. This information challenges our reference points and the principles for classification of due to gene polymorphism are susceptible to develop asymptomatic bacteriuria (ABU) with a low diseases of the urogenital tract5. inflammatory response rather than symptomatic infection13. Disease classification Symptomatic UTIs are defined as a host reaction by Details of the immunological host response provide way of symptoms, findings of white cells or other immune reaction mediators as well as evidence for the evidence for a genetic predisposition towards presence of a causative pathogen. By early consensus, development of UTI and ABU. As this information is being unveiled our scientific focus is moving from the significant number of pathogens was set at 105 identification of single uropathogens in the diagnosis colony forming units per milliliter6. This number is infections to the role of genes from bacteria and modified by the clinical situation, the sampling viruses in the pathogenesis of urological diseases in technique and the identity of the suspected pathogen, for example a CFU of 102 is considered significant when general. urine is sampled by suprapubic puncture7,8. In general, Carcinogenesis the critical number of CFUs has been lowered with time and for tuberculosis, we use to say that detection We have known since long that there is a relationship between infections and cancer like in Helicobacter of a single bacillus is enough to diagnose the disease. pylori and gastric cancer; Epstein-Barr virus and Importantly, the lower the colony counts, the higher Non-Hodgkin´s and Burkitt`s lymphomas; and Human the likelihood of contamination. herpes virus 8 and Kaposi sarcoma. Within the genitourinary tract there is a relation between Some urological diseases have been defined by the Schistosoma hematobium and bladder cancer and presence of micro-organisms (urethritis, prostatitis, cystitis, pyelonephritis, sepsis), others by the absence between Human Papilloma Virus and several urogenital cancers. A relevant clinical experience is that immune deficiency increases the risk of developing both infections and cancer in the genitourinary tract.

Figure 1: Outcome of culture. Colonyforming units of E.coli in a Petri dish diagnosed by inspection

Monday, 27 March 2017

Figure 2: Outcome of 16S rDNA sequencing. Bacterial genera detected in healthy female urine. Reprinted from (3) A: Comparison of healthy female urine bacterial genera abundance determined by sequencing 2 different hypervariable 16S rDNA regions, V1V2 and V6. Relative abundance of 18 major bacterial genera found in the sequence pool of eight different urine samples are shown for the two 16S rDNA regions. Groups denoted “other” represent minor groups classified. Y-axis represents relative abundance. B: Heat map showing the relative abundance of bacterial genera across urine samples of eight healthy females. Genera denoted as phylum-genus, samples denoted as samplenumber_V1V2 or V6. Taxa marked with asterisk (*) could not be assigned to any genera, and are shown at the lowest common taxon: family and order. Color intensity of the heat map is directly proportional to log 10 scale of the abundance normalized sequence data as done by MEGAN.

mechanism which is met with increasing interest in prostate cancer is the effect of chronic inflammation which may cause DNA damage through oxidative stress and reactive oxygen species15. As for infections, polymorphisms of cytokine genes have been suggested as risk factors for prostate cancer development, and significant associations have been observed between prostate cancer and promoter variants in VEGF, IL8 and IL1016. TLRs with its 10 subtypes have a key role in angiogenesis, neoplasia and inflammatory response. TLRs interplay with DAMP (damage-associated molecular pattern) and PAMP (pathogen-associated molecular pattern) from both tumor and non-tumor micro-environments and TLRs appear to be a commonality in the pathogenesis of infection and cancer17. Numerous studies are exploring the possibilities of TLR activation to enhance the immune response and TLR inhibition to induce tolerance and decrease cancer-promoting gene activation in different malignant tumors18. Furthermore, microorganisms and prostate cancer cells have evolved similar strategies to evade destruction by responding to environmental pressure and both are undergoing selective evolution through genetic change. The role of genomes of micro-organisms in urinary tract carcinogenesis has become a research era of explosive growth which is triggered by metagenomic sequencing.

Antibiotic treatment Genomes from lots of bacteria and viruses may now be detected in urine and expressed prostatic secretion in healthy individuals. These genomes most likely stem from bacteria or viruses within the urothelial cells. From studies with enhanced culture techniques, we know that many microorganisms are alive and hence may be killed by antibiotics. It is largely unknown how the different microorganisms interact, but some commensals do prevent uropathogens from dominating the battlefield. A protective effect of commensals is supported by the negative effects of There are many similarities between sexually antibiotic treatment of asymptomatic bacteriuria in transmitted infections and cancer in terms of invasion, women19. This is also the principle behind probiotic spread through lymphatic vessels to regional lymph treatment with lactobacilli and bladder instillation nodes and through blood vessels to distant organs. treatment with apathogenic types of E. coli to prevent Years of latency and resistance to effective drug recurrences of UTI with uropathogenic E. coli20. treatment are seen in both infections and cancer. All bacteria that are exposed to antibiotics may Carcinogenesis may be caused by DNA from develop resistance, not just the causative pathogens microorganisms exploiting the host cellular in UTI. There is also a risk that members of the machinery for transcription and replication thereby normal human microbiome become extinct for certain interfering with genetic and epigenetic control periods of time. Recognition of the big diversity of mechanisms for differentiation and proliferation. micro-organisms makes it clearer to us that using These mechanisms are well described for HPV where broad spectrum antibiotics for prophylaxis and there is latency of 10-30 years between infection and treatment is to shoot sparrows with cannons. This is the manifestation of a malignant tumor and where an the rationale for recent studies on treatment of UTI effective vaccine is now available14. Another with anti-inflammatory drugs only, for phytotherapy

and for the development of antibodies against specific types of uropathogens. Moreover, the frequent use of antibiotics has strikingly been associated with an elevated risk of some malignancies21. Future research The concept of a urine microbiome has introduced a new paradigm in our understanding of urogenital infections and urological diseases in general. Our focus is shifting from pathogens to genes and the microbiome in general and numerous questions arise. When do all the different microorganisms enter the urinary tract, when are they alive, what is their interaction with each other and what is their role in the development of infections, stones, cancer, and other urological diseases? What is the effect of antibiotic prophylaxis and antibiotic treatment on the microbiome? A vast new research field is waiting to be explored. Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list. References 1. Hilt E, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, Brubaker L, Gai X, Wolfe AJ, Schreckenberger P: Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 2014; 52: 871–876. 2. Kogan MI, Naboka YL, Ibishev KS, Gudima IA, Naber KG. Human urine is not sterile – shift of paradigm. Urologia Internationalis 2015;94(4):445-52 3. Siddiqui H, Nederbragt AJ, Lagesen K, Jeansson SL, Jakobsen KS. Assessing diversity of the female urine microbiota by high throughput sequencing of 16S rDNA amplicons. BMC Microbiol. 2011 (Nov 2);11:244. doi: 10.1186/1471-2180-11-244. 4. Lederberg, J; McCray, AT (2001). “’Ome Sweet ‘Omics-a genealogical treasury of words”. Scientist.2001;15:8 5. Smelov V, Naber K, Bjerklund Johansen TE. Letter to the Editor: Diagnostic Criteria in Urological Diseases do not Always Match with Findings by Extended Culture techniques and Metagenomic Sequencing of 16S rDNA. The Open Microbiology Journal 2016;10:23-26 6. Kass EH. Chemotherapeutic and antibiotic drugs in the management of infections of the urinary tract. Am J Med 1955;18:764-7817 7. EAU Guidelines on Urological Infections M. Grabe (Chair), R. Bartoletti, T.E. Bjerklund Johansen, T. Cai (Guidelines Associate), M. Çek, B. Köves (Guidelines Associate), K.G. Naber, R.S. Pickard, P. Tenke, F. Wagenlehner, B. Wullt (http://uroweb.org/guideline/urological-infections/). European Association of Urology, 2015

Monday 27 March 10.30-10.45: Thematic Session 16, Killer bacteria and viruses in urology

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Implementation of high quality prostate MRI High-quality reading of prostate MRI is crucial for effective use Dr. Maarten de Rooij Department of Radiology & Nuclear Medicine Radboudumc Nijmegen (NL)

Co-Author: Prof. Jelle O. Barentsz (NL) Multiparametric MRI (mp-MRI) is now a wellestablished tool to improve the current diagnostic pathway of prostate cancer (PCa). Several recently published systematic reviews and meta-analyses show that the use of mp-MRI and mp-MRI targeted biopsy in men with a suspicion on prostate cancer (PCa) yields higher detection of significant PCa than the current standard of care using systematic transrectal ultrasound-guided biopsy (TRUS-GB)1. Perhaps even more important, the use of mp-MRI can cause a reduction of the detection of indolent disease - which does not require invasive treatment -, and can prevent unnecessary biopsies2,3. Therefore, when used as triage test, mp-MRI could be an important contributor in causing a shift in the current paradigm of over-diagnosis and over-treatment of PCa. However, other studies show less promising results, with highly variable negative predictive values (NVPs) ranging from 63 to 98% for the detection of clinically significant PCa4. One of the possible explanations for these variable results is that the reading in some of the studies was performed by non-trained radiologists or radiologists with little experience in reporting prostate MRI. In the hands of highly experienced readers, a ‘no’ is often a real ‘no’; with NPVs for clinically significant PCa ranging from 89 to 98%3,5-7. Given the disease frequency and the growing importance of prostate imaging, radiologists, but also urologists involved in prostate MRI, must be able to speak the same ‘language’, in order to secure high quality exams. In an effort to harmonize practices, professional guidelines as the European Society of Urogenital Radiology (ESUR), and the American College of Radiology (ACR) have recently adopted such a ‘language’; the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2)8,9, which is an updated version of the earlier recommendations published by the ESUR in 201210. PI-RADS In analogy to the Breast Imaging Reporting and Data System (BI-RADS), PI-RADS version 2 provides a standardized international ‘lexicon’ and interdisciplinary knowledge base for PCa imaging, which is suited for radiologists, urologists, and other clinicians ((radiation) oncologists, pathologists, etc.). It gives recommendations on (minimal) technical acquisition parameters, and provides standardized terminology for reporting. Also, it defines assessment categories to classify levels of suspicion on clinically significant PCa, which can be used to assist risk stratification and patient selection for biopsy. The PI-RADS assessment uses a five-point scale based on the likelihood that the mp-MRI findings correlate with the presence of clinically significant PCa, ranging from very low (score of 1) to very high (score of 5). The (appropriate) use of a standardized lexicon to communicate prostate MRI findings with the referring physicians and other specialists seems to improve the quality of the detection of PCa11.12. However, one of the drawbacks of the first version of the PI-RADS was that some studies found slightly lower reproducibility and accuracy values as compared to pre-existing subjective scoring systems (e.g. 3- or 5-point Likert scales)13-15. This could suggest that PI-RADS version 1 criteria did not completely reflect the expert readers’ judgement. The accuracy and agreement of PIRADS version 2, however, shows better accuracy and agreement between readers16-18. Greer et al. found sensitivity of 91% and specific agreement values for index lesions of 93% in a prospective detection and scoring scenario, using whole mount pathology as reference standard18. Also, the AUC seemed to improve when using PI-RADSv2 compared to the first PI-RADS version. In the study of Kasel-Seibert et al., the AUC values improved from 0.70-0.79 to 0.8319. Experience and training Rosenkrantz et al., stated that inappropriate use of PI-RADSv2 by new users, who did not have had 24

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sufficient training or experience, may be damaging clinical care20. The goal of proper prostate MRI training is to prevent this, and to fulfil the successive stages of learning; by teaching ‘unaware incompetent’ readers to first become ‘aware incompetent’, in order to train them further and become ‘aware competent’. To become ‘aware competent’, a proper initial course and extensive case exposure are essential. Experienced readers show improved image interpretation compared to less experienced readers21,22, but the minimum number of cases to complete the learning curve is not elucidated yet. Also, experienced readers tend to interpret prostate MRI less frequent as equivocal (PI-RADS 3)18. Based on own experience and progress from other disciplines, Puech et al proposed three levels of competence in reading prostate MRI23: (1) Level I: the reader is able to select the appropriate modality, able to review images, and to use the results. At this level, the technique is not performed. (2) Level II: the reader followed an initial training course, with practical experience on interpreting prostate MRI, but with a cover of double-reading. (3) Level III: the reader is able to independently Multiparametric MRI (mp-MRI) of a 59 years old man with a PSA level of 5 ng/ml, with a history of 1 previous negative TRUS report prostate MRI, under all circumstances, guided biopsy session. The mp-MRI, using anatomic axial and sagittal T2-weighted imaging (T2WI), diffusion weighted imaging without double-reading. Several studies agree that reading 50 prostate MRI cases can be considered as sufficiently trained, and accomplish competence level II. Other studies consider two years of genito-urinary imaging as experienced. Of course, several other factors also highly influence the learning curve; the dedication and quality of the individual radiologist, the quality of the initial course, the availability of histopathological and urological feedback during multidisciplinary meetings, and the learning process during consensusor double-readings. In our own expert centre, we provide two weeks of intensive training with double-reads and feed-back of more than 100 cases to reach competence level II/III and work autonomously. Even then, double-reading remains a commonly used way to improve reading robustness and prevent the false negative cases of clinically significant PCa. Certification and quality criteria The diagnostic challenges in breast cancer screening have many parallels with the diagnostic pathway that is currently evolving for PCa. Even though the PI-RADS is comparable with the BI-RADS, the breast imaging community is much further in the use of dedicated courses and (personal) certification, the development of quality criteria, and quality control. To improve the current diagnostic pathway of PCa, many lessons can be learned from the system in breast imaging. Several measures that could be used to secure high quality (reporting of) prostate MRI, could be to: • Make initial courses (CME certified), and (yearly) refresher (hand-on) courses mandatory for clinical readers. • Perform a minimum amount of cases per week (e.g. > 10 prostate MRIs/week). • Define an upper limit for the amount of equivocal (PI-RADS 3) diagnoses (e.g. < 20% of PI-RADS 3 cases in biopsy naïve men). • Define a lower limit for the amount of PI-RADS 4 and 5 cases that should yield significant PCa (e.g. > 65%). • Take part in multidisciplinary meetings and compare PI-RADS with histopathology. • Be transparent with your centre’s clinical outcome data. Prostate expertise network A pre-requisite for further development and evolution of high quality (reading of) prostate MRI is concentration of specific knowledge on this topic. By means of a worldwide network of prostate MRI expert centres - which are sharing their knowledge - the technique can be constantly updated and improved. Internet connectivity of centres with expertise will allow “double-reading” of difficult cases, with a subsequent better outcome/diagnosis. Of course, this could not only be beneficial for men with (a suspicion on) PCa, but also for fast implementation of newly validated technique, and development of a large scientific database. Conclusions Structured training and certification is important for radiologists that are willing to learn prostate MRI. Equally important however, is training of urologists,

(DWI) and dynamic contrast enhanced-MRI (DCE-MRI), shows a lesion in the anterior transition zone (TZ). On T2WI, the lesion is non-circumscribed, homogeneous, moderately hypo-intense, and does not respect the borders of the surrounding structures (score of 5/5). On DWI, the lesion is hypo-intense on ADC, with an ADC value of 557 (score of 5/5). On DCE-MRI the lesion shows wash-out of contrast (which is tumor suspicious). Since the lesion is located in the TZ, T2WI is the dominant sequence, leading to an overall PI-RADS score of 5; highly suspicious for clinically significant PCa. MR-guided in-bore biopsy determined Gleason 3+4=7 in all 3 biopsies.

and other involved physicians, to be able to communicate in the same ‘language’, since they have to rely on prostate MRI during daily clinical practice. For radiologists, this should include initial training courses, but also refresher (hands-on) courses and double-reading, (personal) certification, and quality control. Expert panels of the ESUR and ACR should be

on the lead to develop criteria to secure high quality (reading of) prostate MRI, and allow further implementation by the urological community. Editorial Note: Due to space constraints the reference list has been omitted. Interested readers can email at EUT@uroweb.org for a complete listing.

Prostate enucleation using low energy pulsed Thulium laser with preservation of ejaculation Dr J.B Roche Groupe Urologie Saint-Augustin – Bordeaux (Fr) In this session, consultant urological surgeon Jean-Baptiste Roche enucleates a 130g prostate using the 200W Hemera® Laser from Rocamed. Harnessing the latest in laser technology, this low-energy pulsed device provides excellent results in terms of post-operative urinary function, minimizing the risk of incontinence, pelvic discomfort, and storage-related symptoms. When combined with an anatomically precise application, this type of dissection affords the maximum level of protection to the patient’s ejaculatory function, and greatly reduces the risk of recurrence. The presentation gives a clear, accessible, step-by-step insight into laser-based prostate enucleation, showing all phases of the procedure, from dissecting the apex of the prostate through to nal morcellation.

Pre-recorded video Session

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

Visit Us Booth I26 Monday, 27 March 2017

Cutting-edge Science at Europeâ&#x20AC;&#x2122;s largest Urology Congress

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33rd Annual EAU Congress

Focus gives you... Insight With invited, thematic reviews and high-quality research articles

Research through a new lens

Monday, 27 March 2017

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PCa17 EAU Update on Prostate Cancer

15-16 September 2017 Vienna, Austria

New EAU onco-urology series

www.pca17.org

ELUTS17 European Lower Urinary Tract Symptoms meeting

12-14 October 2017 Berlin, Germany

www.eluts17.org

THE NEW DORNIER DELTA®III THE POWER TO TRANSFORM

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Monday, 27 March 2017

Learn and advance through ESU More learning opportunities with ESU’s expanded services patients. At least 16 areas in urology are covered in 52 courses from March 25 to 27 (Saturday to Monday). These courses range from Female Urology, Infections, Stones, Trauma, Male LUTS, onco-urology to paediatric urology, to name a few.

Dr. Joan Palou Chairman European School of Urology Fundació Puigvert Dept. of Urology Barcelona (ES)

Greek biographer and author, Plutarch, once said “For the correct analogy, the mind is not a vessel that needs filling, but wood that needs igniting.”

(SiMS). SiMS delivers the latest techniques of evidence-based applications in clinical practice. Top-notch surgical procedures and various approaches are presented step-by-step by renowned urologists. View the best surgical videos of leading experts in various fields of urology in Hall S15. For more information about SiMS, please visit www. surgeryinmotion-school.org.

Hands-on Training Courses The ESU continuously explores and pursues new urological approaches. In partnership with the EAU Sections, the ESU has established the state-of-the-art Hands-on-Training (HoT) Courses. These cutting-edge courses offer practice and development of individual skills through the use of advanced technology.

The HOT Courses at EAU17 includes training courses in Robotic Surgery, Laparoscopy, Diagnostics and Since its inception, the European School of Urology Follow-up, Functional Urology, and Endoscopy which (ESU) has stimulated learning, development of skills are facilitated by esteemed experts. Through the new and sharing of knowledge among urologists. course “Non-Technical Skills in Urology”, the ESU Currently, over 16,000 medical professionals from aims to raise awareness of the many benefits of around the world benefit from the ESU’s activities and non-technical skills in operating-room practice. The projects. Access to quality education is a top priority course is the first of its kind. It was launched on 25 of the ESU. Its success is anchored on the continued March (Saturday) but participants can still attend the support of the ESU faculty, a community of 150 course today at 10:00 to 12:00 or at 14:00 to 16:00. opinion leaders and experts in various urological specialties. On social media The ESU recognises the potential of social media in This year, at the 32nd Annual EAU Congress (EAU17), the field of urology and that is why it offers social the ESU delivers an array of its successful activities media courses and services during EAU17. such as courses, hands-on trainings, workshops, and new educational activities such as a surgical video “Personalised hands-on workshop for beginners” platform and social media courses. A total of four workshops are scheduled from 25 to 27 March from 11:00 to 13:00 for novices in social media. ESU Courses A Young Urologist Office (YUO) representative is the The ESU’s course programme at EAU17 covers the full designated guide and mentor. Each workshop is scope of urology; from the newest updates, practical tailored to personal interests, but topics could include insights, core theoretical knowledge to best practices. added value of social media to urology, terminologies The ESU has come a long way since its inaugural used, social media etiquette, to mention a few. eight ESU courses offered during the 13th EAU Congress in 1998 in Barcelona, to the current 52 “Advanced social media course: Take it to the next level” courses at EAU17. This advanced course was organised for healthcare professionals who are already active in social media This year, the ESU ensures that EAU17 participants but would like to expand their know-how. The course receive vital information regarding optimal care of covered topics such as source for scientific research,

Other ESU educational activities Masterclasses ESU’s masterclasses provide the high-level training to update and equip urologists with specialised skills. Thanks to the comprehensive programme of the masterclasses, deeper knowledge is gained in specific sub-specialised fields such as Female and Functional Reconstructive Urology, Lasers, Operative Benign Prostatic Obstruction, Urolithiasis, and Focal Therapy.

The ESU’s course programme covers the full scope of urology

EUREP The annual European Urology Residents Education Programme (EUREP) is one of the ESU’s flagship teaching programmes. For over two successful decades, EUREP has been providing significant updates and overview of the latest urological practice presented by a distinguished European faculty.

interaction with patients, measurement and analytics – impact factor, etc. Various social media experts with a urological background have shared their knowledge and experiences.

E-courses and webinars The ESU also offers online tools via its informative e-courses and webinars. These provide the users the flexibility to work on their professional development at their own pace.

Social Media Helpdesk For basic inquiries, The EAU Community Manager answers basic questions, assists in creating social media accounts, and helps post on various platforms at the Social Media Helpdesk from 11.00 to 13.00 on 25 to 27 March. No registration necessary. This service is for free.

All accredited e-courses comply with the EU-ACME and UEMS/EACCME guidelines for e-learning. The information provided is in line with the EAU Clinical Guidelines. The ESU’s new online educational tool, UROwebinars, offers urologists the latest developments and provides opportunities to interact and pose questions.

Surgery in Motion School EAU17 participants can experience the new educational video platform, Surgery in Motion School

To learn more about the European School of Urology, visit www.uroweb.org/education or contact the ESU at esu@uroweb.org.

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mpMRI as the new guide Arguing the need for targeted biopsies Dr. Peter Pinto Head, Prostate Cancer Section Director, Fellowship Program National Cancer Institute National Institutes of Health Maryland (USA) Prostate cancer is the only solid organ cancer that is traditionally diagnosed with a non-targeted biopsy technique. Currently, transrectal ultrasound prostate biopsy (TRUS-Bx) is the standard of care, even though ultrasound is not adequate for visualizing prostate cancer. TRUS-Bx, which involves a systematic sampling of the prostate by region, may only sample around 0.04% of the entire gland, and is well known to under-sample apical and anterior regions of the prostate1,2. The poor cancer detection rates of TRUS-Bx have led to a search for alternative approaches to prostate biopsy. Consequently, research in the field of prostate MRI and development of MRI-TRUS software fusion biopsy devices has ushered in a new era of accurate targeted prostate biopsies. As MRI-targeted biopsy (MRI-TB) becomes more widely available, we must ask ourselves if there is still a need for systematic biopsy. MpMRI Multiparametric MRI (mpMRI) consists of several modalities, including T2 weighted imaging, diffusion weighted imaging (DWI), dynamic contrast enhanced MRI (DCE), and sometimes MR spectroscopy. Combined, these modalities produce a sensitivity and specificity of 90% and 88% in the detection of prostate cancer foci > 0.5cc3. When prostatectomy specimens were analyzed in patient-specific molds based on mpMRI images, the positive predictive value was as high as 98%4. The excellent diagnostic capacity of mpMRI is what gives MRI-TB the potential to be a stand-alone technique. MRI-targeted biopsy MRI-TB involves using MRI images to guide biopsy of specific lesions in the prostate and can be accomplished in three ways: direct “in-bore” MRI biopsy, software fusion of MRI and ultrasound images (MRI-TRUS fusion biopsy), and cognitive fusion. In-bore MRI biopsy involves performing the prostate biopsy in the MRI gantry itself. This procedure is time consuming, involves more “opportunity cost” (time in the MRI scanner), and requires general anesthesia. MRI-TRUS fusion biopsy is now the most widely used MRI-TB technique. It is an office-based technique which involves registration of a previously obtained MRI image to the real-time ultrasound obtained during the procedure. Tumors that are found to be suspicious on mpMRI can be directly overlaid in-vivo. Cognitive fusion is a less commonly used form of image-guided biopsy in which the operator uses prior knowledge of prostate tumor locations on MRI to direct the needle in an ultrasound-guided biopsy. The clinical trial completed at the National Institutes of Health (NIH) demonstrated that MRI-TRUS fusion biopsy detected 30% more high-risk and 17% fewer low-risk cancers5, a result which has been corroborated by others and multiple systematic reviews6-8. In addition to this overall improved performance, fusion biopsy has also been found to have superior performance in enlarged prostates, where standard biopsy has a higher risk of under-sampling the gland, and in locations that are traditionally difficult to sample, such as anterior and apical regions2,7,9-11. An example of this is seen in Figure 1, which shows an anterior prostate lesion with Gleason 4+5 disease missed on multiple systematic biopsies and detected on MRI-TRUS fusion biopsy. This is one case demonstrating the accuracy of targeted biopsy- overall, MRI-TB alone has been found to be superior to standard biopsy in detecting and differentiating more clinically significant and fewer clinically insignificant cancers. It is this superior differentiating ability that gives MRI-TB another advantage over TRUS-Bx. As stated above, targeted biopsy is less likely to detect clinically insignificant, low-risk cancers. Both the PIVOT trial and the ProtecT trial, large, multicenter randomized studies, determined that treatment of these low-risk cancers did not significantly reduce mortality rates, while subjecting patients to the adverse events Monday, 27 March 2017

inherent to treatment12,13. The results of these studies speaks to the advantage of a targeted biopsy approach which would avoid the over diagnosis of clinically insignificant prostate cancer. It has been established that MRI-TB provides increased diagnostic accuracy, but is it accurate enough to stand on its own? What is the risk of foregoing standard TRUS-Bx? Research at the NIH determined that the addition of TRUS-Bx to MRI-TRUS fusion only resulted in a 2% increase in risk category from benign or low/intermediate risk to high-risk5. A recent study confirmed that only 4% of clinically significant cancers would be under-detected by MRI-TRUS fusion alone14. These results indicate that the use of MRI-TB alone can increase clinically significant cancer detection while maintaining a relatively low false negative rate. Prior Negative Biopsy MRI-TB has been of particular use in patients with one or more prior negative biopsies, as demonstrated by Vourganti et al, who found that TRUS-Bx missed half of all high-grade cancers detected by MRI-TRUS fusion biopsy9. A recent multi-institutional analysis determined that with each additional biopsy, the cancer detection rate on TRUS-Bx decreased while the cancer detection rate on MRI-TRUS fusion remained constant16. In light of the data supporting targeted biopsies in the prior negative cohort, a recent consensus statement was released by the American Urological Association and the Society of Abdominal Radiology recommending prostate MRI and MRI-TB for patients with prior negative TRUS-Bx17. Post-prostatectomy pathology Studies comparing the performance of MRI-TB to final pathology provide insight into how this method holds up to the “gold standard” for histologic diagnosis. One study calculated the sensitivity of fusion biopsy versus standard biopsy for predicting whole-gland pathology to be 77% vs 53%, and found MRI-TRUS fusion to have significantly greater predictive ability on ROC curve analysis than either TRUS-Bx or combined standard and fusion biopsy5. Another study demonstrated the concordance between in-bore biopsy and whole gland prostate specimens to be approximately 81% as compared to 55% on TRUSGB18. The high concordance of MRI-TB with final pathology provides further evidence for the use of targeted biopsy alone. Complications Many studies have documented a rise in complication rates after prostate biopsy, largely due to infections, as well as an increase in fluoroquinolone-resistant strains19. A review by Loeb et al determined that the number of cores obtained correlated with infection rates and post-biopsy pain20. An additional study analyzing the SEER database found a 1.7-fold increase in the rate of both hospitalizations and serious infectious complications for each additional prostate biopsy performed21. The correlation between both number of biopsy cores and additional biopsies and post-biopsy complications serve as a reminder that continued use of TRUS-Bx as well as MRI-TB do not come without risk. Using MRI-TB biopsy, a more accurate diagnosis can be made using fewer cores, theoretically decreasing complications from prostate biopsy. Conclusions MRI-TB, in particular MRI-TRUS fusion biopsy, has been shown in numerous studies to accurately detect the majority of clinically significant prostate cancers, many of which are missed on TRUS-Bx. In contrast, TRUS-Bx has a low diagnostic yield and adds to a great deal of the over-diagnosis of clinically insignificant cancers. The treatment of these low-risk cancers is a burden, not a benefit, and adds to both healthcare costs and complication rates. In addition, the inconclusive nature of a negative TRUS-Bx, particularly in patients with prior negative TRUS-Bx, leads to a great deal of unnecessary anxiety and concern for both patients and providers. Thus, in facilities with the appropriate equipment and training, and with adequate experience with prostate imaging and MRI-guided techniques, targeted biopsies alone should be considered for the evaluation and diagnosis of prostate cancer. Editorial Note: Due to space constraints the reference list has been shortened. Interested readers can email at communications@uroweb.org to request for the full list.

Figure 1: A 68-year-old male with elevated PSA and a history of multiple negative TRUS-Bx and one negative saturation biopsy. This T2W MRI image shows an anterior prostate lesion (asterisk), which was found to contain Gleason 4+5=9 cancer on MRI-TRUS fusion biopsy.

References

6. Valerio M, Donaldson I, Emberton M, et al. Detection of Clinically Significant Prostate Cancer Using Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy: A Systematic Review. European urology. Jul 2015;68(1):8-19. 7. Gayet M, van der Aa A, Beerlage HP, Schrier BP, Mulders PF, Wijkstra H. The value of magnetic resonance imaging and ultrasonography (MRI/US)-fusion biopsy platforms in prostate cancer detection: a systematic review. BJU international. Mar 2016;117(3):392-400. 8. Wegelin O, van Melick HH, Hooft L, et al. Comparing Three Different Techniques for Magnetic Resonance Imaging-targeted Prostate Biopsies: A Systematic Review of In-bore versus Magnetic Resonance Imagingtransrectal Ultrasound fusion versus Cognitive Registration. Is There a Preferred Technique? European urology. Aug 25 2016. 9. Vourganti S, Rastinehad A, Yerram NK, et al. Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. The Journal of urology. Dec 2012;188(6):2152-2157. 10. Borkowetz A, Platzek I, Toma M, et al. Comparison of systematic transrectal biopsy to transperineal magnetic resonance imaging/ultrasound-fusion biopsy for the diagnosis of prostate cancer. BJU international. Dec 2015;116(6):873-879. 11. Volkin D, Turkbey B, Hoang AN, et al. Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ ultrasonography fusion-guided biopsy increase the detection of anteriorly located prostate cancers. BJU international. Dec 2014;114(6b):E43-49. 12. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. The New England journal of medicine. Jul 19 2012;367(3):203-213. 13. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. The New England journal of medicine. Oct 13 2016;375(15):1415-1424.

1. Salami SS, Ben-Levi E, Yaskiv O, et al. In patients with a previous negative prostate biopsy and a suspicious lesion on magnetic resonance imaging, is a 12-core biopsy still necessary in addition to a targeted biopsy? BJU international. Apr 2015;115(4):562-570. 2. de Gorski A, Roupret M, Peyronnet B, et al. Accuracy of Magnetic Resonance Imaging/Ultrasound Fusion Targeted Biopsies to Diagnose Clinically Significant Prostate Cancer in Enlarged Compared to Smaller Prostates. The Journal of urology. Sep 2015;194(3):669-673. 3. Villers A, Puech P, Mouton D, Leroy X, Ballereau C, Lemaitre L. Dynamic contrast enhanced, pelvic phased array magnetic resonance imaging of localized prostate cancer for predicting tumor volume: correlation with radical prostatectomy findings. The Journal of urology. Dec 2006;176(6 Pt 1):2432-2437. 4. Turkbey B, Mani H, Shah V, et al. Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds. The Journal of urology. Nov 2011;186(5):1818-1824. Monday 27 March 5. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. 09.00-09.15: Plenary Session 5, Management of Comparison of MR/ultrasound fusion-guided biopsy with prostate cancer ultrasound-guided biopsy for the diagnosis of prostate cancer. Jama. Jan 27 2015;313(4):390-397. vprobeQuarterAdEUTFinal_Layout 1 2/14/17 10:14 PM Page 1

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Urothelium A dynamic structure with excellent communication skills

In fact, the urothelium is a very dynamic structure that forms a distensible barrier, regulates the transport of water, ions and solutes across the bladder mucosa and plays a pivotal role in sensing the bladder’s content. Urothelium: A dynamic barrier The urothelium can maintain a highly impermeable barrier for water, solutes and pathogens, despite large variations in mucosal surface area during bladder filling and voiding. Tight junctions at the apical membranes of adjacent umbrella cells create a high-resistance barrier for paracellular transport. The apical membrane of umbrella cells contains highly specialized plaques of lipids and transmembrane proteins (uroplakins) and is covered by a glucosamineglucan layer to create a high trans-epithelial resistance. The bladder is able to maintain this extra-ordinary barrier during bladder filling due to unfolding of the apical mucosal surface, flattening of the umbrella cells and expansion of their apical membrane by exocytosis of discoidal vesicles1,2.

“...the urothelium is an intelligent structure that acts as an impermeable and dynamic barrier against the toxic solutes of urine and forms a uro-epithelial sensory web that functions as the bladder’s senses.” Despite the presence of this specialized barrier, the high concentration gradients between the urine and the urothelium will drive passive leakage of ion and solutes into the (sub)urothelium. As such, the composition of urine can slightly be changed during urine storage. Therefore, it is not surprising that pathways for transport of Na+, K+, Cl-, urea and water have been described in the uroepithelium. Studies in humans and rodents have demonstrated that urothelial cells express aquaporines (AQP3, -4, -7, -9), urea transporters (UT-B), and a myriad of ion channels (including Na+, K+, Cl- and nonselective cation channels). These channels and transporters are involved in regulation of cell volume and osmolality when solutes or ions enter the uro-epithelium1,3. The uro-epithelial sensory web Underneath the impermeable apical barrier of the umbrella cells, urothelial cells interact with myofibroblasts, blood vessels and mucosal nerves to form a sensory signaling network, called the uro-epithelial sensory web1. This mucosal network is the principal sensory structure of the bladder enabling us to experience different “urinary” sensations: the urinary bladder cannot just determine its filling state, but can also discriminate changes in temperature, osmolality and the presence of irritant substances and infectious pathogens. Urothelial cells express a wide variety of ion channels and receptors, including TRP3, ASIC and ENaC channels, purinergic (P2X1-7 and P2Y2 and P2Y4), muscarinic, nicotinic, α and β adrenergic, cannabinoid (CB1 and CB2) and protease-activated 30

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Activation of these urothelial receptors can initiate a variety of responses: it can change the flux of water and solutes across the urothelium, stimulate (or inhibit) the trafficking of membrane vesicles and induce the release of signaling molecules to neighboring or underlying cells. The urothelium is able to release adenosine, ATP, NO, Ach and prostaglandins that can stimulate adjacent urothelial cells (autocrine) and underlying nerve fibers, interstitial cells and smooth muscle cells (paracrine)4. One of the most studied urothelial messengers is ATP. During bladder filling, urothelial cells gradually release ATP in response to mucosal stretch. This ATP will activate P2X2/3 receptors on neighboring urothelial cells, hereby promoting urothelial membrane trafficking to increase the mucosal surface area2. Secondly, ATP will activate P2X2/3 receptors in sensory nerve fibers, modulating the sensory input to the central nervous system5. Finally, by affecting smooth muscle tone (via P2X1 receptors) and interstitial cells (via P2Y receptors), ATP will also affect afferent signaling indirectly1. Alternatively, urothelial receptors allow these cells to respond to signaling molecules released by underlying nerve fibers and interstitial cells, including neuropeptides, Ach and ATP. Physiological and clinical relevance The physiological role of the bladder is to store urine and efficiently evacuate it at a socially convenient moment. The urothelium and its associated sensory web are indispensable for the urinary bladder to function normally. They allow the bladder to safely store highly concentrated ions and waste products excreted in the urine for a prolonged period.

Figure: The uro-epithelial sensory web. Illustration showing the interaction of urothelial cells, smooth muscle cells, interstitial cells and afferent nerve fibers. P2, type 2 purinergic receptors; NK neurokinin receptors, NGF-R, nerve growth factor receptor, M, muscarinic receptors; ASIC, acid sensing ion channel; TRP, transient receptor potential channel; PAR protease activated receptor; PG prostaglandin; Ach, acetylcholine

The sensory web will help the bladder to determine its filling state and will provoke rapid urine expulsion when irritants or bacterial agents are detected. Similarly, when the urothelial barrier is breached, the uro-epithelial sensory web will initiate a signaling cascade that stimulates bladder emptying to minimize re-absorption of urine. Moreover, it will stimulate the quick restoration of the urinary barrier. Consequently, malfunctioning of the urothelium can trigger or maintain bladder dysfunction. Several drugs specifically targeting urothelial receptors have been successfully used in preclinical models to treat a variety of lower urinary tract disorders3,6. It is anticipated that some of these drugs will proceed to clinical testing in the near future.

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Official Scientific Journal Deutsche Gesellschaft für Urologie

In conclusion, the urothelium is an intelligent structure that acts as an impermeable and dynamic barrier against the toxic solutes of urine and forms a uro-epithelial sensory web that functions as the bladder’s senses. As such, the urothelium is an interesting focus for new treatment strategies in lower urinary tract disorders.

Editorial Board

References

Editorial Committee

1. Birder, L. and K.E. Andersson, Urothelial signaling. Physiol Rev, 2013. 93(2): p. 653-80. 2. Wang, E.C., et al., ATP and purinergic receptordependent membrane traffic in bladder umbrella cells. J Clin Invest, 2005. 115(9): p. 2412-22. 3. Deruyver, Y., et al., Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality? BJU Int, 2015. 115(5): p. 686-97. 4. Merrill, L., et al., Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol, 2016. 13(4): p. 193-204. 5. Cockayne, D.A., et al., Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature, 2000. 407(6807): p. 1011-5. 6. Everaerts, W., et al., Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A, 2010. 107(44): p. 19084-9.

Monday 27 March 08.00-8.15: Plenary Session 6, Functional urology

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Editors M.P. Wirth, Dresden O.W. Hakenberg, Rostock D. Castro-Diaz, Santa Cruz de Tenerife B. Wullich, Erlangen A. Briganti, Milan S. Egawa, Tokyo S. Madersbacher, Vienna M.S. Michel, Mannheim V. Mirone, Naples R. Mundy, London J. Nordling, Herlev M. Porena, Perugia J.J. Rassweiler, Heilbronn H. Rübben, Essen A. Stenzl, Tübingen J. Stolzenburg, Leipzig Y. Sun, Shanghai Language: English ISSN 0042–1138 (print) e-ISSN 1423–0399 (online)

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The uro-epithelium is a highly specialized, stratified epithelium that covers the inner surface of the urinary tract from the renal pelvis to the distal urethra. The urothelium in the bladder has long been considered a mere passive barrier, but evidence is accumulating that it is much more than that.

(PAR) receptors, enabling these cells to detect mechanical stimuli (mucosal stretch) and chemical substances present in the urine or released by neighboring cells1,4.

Sensitivity

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Monday, 27 March 2017

Unlocking the potential of social media Leveraging social media is about taking our nursing expertise to social media Teresa Chinn MBE RN & Social Media Specialist WeNurses Bristol (GB)

In 2013 Fergusson wrote a paper titled “Is it time for the nursing profession to leverage social media?” In the paper he challenged thinking around social media and its use in healthcare. Given that this was some four years ago, it was a brave challenge indeed. Social media first hit our internet screens way back in 1997. The first recognizable social media site, Six Degrees, was created in 1997. It enabled users to upload a profile and make friends with other users. In 1999, the first blogging sites became popular, creating a social media sensation that’s still popular today (Hendricks 2013). However, social media is historically regarded as a social pastime, and the professional use of social media (despite Fergusson’s challenge in 2013) remains an underused and underestimated nursing resource. The benefits of social media for nurses are well documented; • Kenyon (2015) explains how social media can help us to understand the patient experience and tap into stories we would never normally hear; • Sinclair et al (2015) extol the virtues of the support gained through social media and the range of expertise available through social media; • Yaldren (2014) writes about the benefits of tapping into conferences from afar, communities of practice and increasing your circle of influence; and • Moorley and Chinn (2014) share how social media can be used for continuous professional development by nurses.

Using social media celebrate nursing practice Celebrating the good stuff is something that isn’t done enough in nursing. Even in the smallest everyday actions there can be something to share, celebrate and be proud of. Social media affords nurses the opportunity to celebrate nursing, to increase the general public’s understanding of nursing and to increase morale in the nursing workforce. Celebrating Enabling the people we care for to connect with each nursing can be as diverse as sharing a Tweet about Nurses need to start to be constructive about the use other and support each other is an area of social an implemented change that worked well to joining of social media to make it work for them, to make it media that needs to be developed and explored more. and sharing the global celebration that is work for their organisations, and to make it work for In addition, the connections that nurses make via International Nurses Day. If nurses can start to the people they care for …nurses need to start doing social media can mean that nurses have expertise address these four key areas then perhaps they can social media well. There are four broad areas in beyond their own locality and at their fingertips, really start to leverage social media. It’s time to call which nurses need to focus on to realise the potential leading to better outcomes for patients. Nurses can nurses to action, to use the technology that is out and harness the power of social media in healthcare: also learn from others experiences via social media, there and to communicate professionally in the way in enabling them to go straight to a solution that is which the public are communicating. Using social media to inform nursing practice known to work and not having to ‘re-invent the Social media has an enormous capacity to inform wheel,’ meaning that nurses will be more likely to get Leveraging social media isn’t about learning nursing practice; connections made are often global it right the first time for their patients. Social media something new or doing something difficult, it’s leading access to a whole world of expertise via the also offers huge opportunities to facilitate and foster about taking our nursing expertise and our humble smartphone. This then leads to learning via co-production; by existing in the same spaces it professional lives to social media. Nurses need to social media, through blogs, tweet, chats, videos, makes it easier for nurses and patients to understand have the courage to explore and think differently, and podcasts, Twitter updates, Facebook updates, one another and communicate. Finally, social media social media is a wonderful enabler; it is a global infographics, tapping into conferences remotely or can enable nurses to ask questions to the expert village of expertise at the touch of a button. If nurses even an increased access to opportunities beyond our crowd, giving a wider and more balanced view of can rise to the challenge of unlocking the potential of workplace. All of this can be used for professional things in, often, a short space of time. social media then both the profession and the development and to improve our practice. patients will reap the benefits. Using social media to share the nursing practice Furthermore, the resource of people that exists in Each and every day there is so much to learn from in At EAUN17 a special session will be dedicated to this social media is unprecedented and something that nursing; experiences of what has worked well and topic that aims to give people an understanding of nurses can hugely benefit from; and as more people what hasn’t worked quite so well shape our practice how social media is and can be used in nursing and use social media the greater the potential it has for and the actions of our teams and organisations. By healthcare. For more details, see box at the bottom informing nursing practice. The role that social media sharing these experiences more widely, nurses not and the congress website www.EAUN17.org has to play in health research is also worth only set themselves up as being open, generous and considering; researchers and academics are just supportive but also the organisations they work for Editorial Note: Due to space constraints the reference beginning to realise that social media gives access to and are associated with will become forward-thinking list has been omitted. Interested readers can email at a plethora of people and data. Advances are being organisations. Social media is a low-cost worldwide EUT@uroweb.org for a complete listing. made in this area, with the ultimate aim of informing platform; with many social media sites being free it’s practice. often only the time to engage that needs to be Monday 27 March considered. With the ease of use, accessibility and 09.45-10.15: 18th International EAUN Meeting; Using social media as part of nursing practice reach of social media added into the mix, social State-of-the-art 7: Unlocking the potential of social media in nursing, Room 1 With so many people engaging in social media it is media becomes a very attractive platform to share only natural that the people we care for are also using nursing practice. In recent years social media use by nurses has become more commonplace and more accepted as a professional tool. With social media being used globally by 2,307 billion people (and rising) (Chaffey 2016), the assumption can be made that nurses are using social media, albeit for social reasons. So the quest now is to encourage and support nurses to unlock the potential of social media with regards nursing.

these spaces to connect, learn and support each other. Nurses need to start to think in terms of how they can support and utilise this in their own practice, where once we would perhaps support a group of patients in a community centre we now need to think differently and use tools like WhatsApp, Twitter and Facebook.

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Monday, 27 March 2017